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How much design is there in asymmetric catalysis and
what makes a ligand to a privileged ligand
A Togni Department of Chemistry and Applied Biosciences
1
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
2
Privileged Ligands and Catalysts
TP Yoon EN Jacobsen Science 2003 299 1691
[] certain classes of synthetic catalysts are enantioselective over a wide range of different reactions Such catalysts may be called ldquoprivileged structuresrdquo in much the same manner that the term has been applied in pharmaceutical research to compound classes that are active against a number of different biological targets Privileged chiral catalysts offer much more than one might have imagined creating effective asymmetric environments for mechanistically unrelated reactions
Jacobsens definition
3
Examples of privileged ligands and catalysts given in the original Jaconsens paper
Hydrogenationhydroamination
hydrophosphinationhydrosilylation
allylic substitution conjugate additionco-polymerization
4
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
5
Non Catalytic Asymmetric Electrophilic Fluorination of Enolates Using N-F Reagents mdash The State of the Art up to 2001
SO2
NF
RR
1 (R=H) 2 (R=Cl)
NS
O O
Me
F
O
Ph1) LDA THF
2) 3
OPh
F
79 yield 88 ee
3
SO2
N
O2S
F
4
NO
Me Ph
O
RO
NO
Me Ph
O
RO1) Base
F
80-90 yield 86-99 de
N
N
OHH
ClO
OMe
2)
NN
Cl
F
+
+2 BF4
ndash
5
Bn
OSiMe3
Bn
O
F4 5
MeCN -20degC
86-99 yield up to 91 ee
Pioneering workbull E Differding RW Lang Tetrahedron Lett 1988 29 6087
Recent reviewsbull H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article)bull K Muntildeiz Angew Chem Int Ed 2001 40 1653 (Highlight)bull SC Taylor et al Tetrahedron 1999 55 12431bull GG Furin in Houben-WeylVol E10 pp 432-499 1999
Recent examplesbull Y Takeuchi et al J Org Chem 1999 64 5708bull FA Davis PVN KasuTetrahedron Lett 1998 39 6135bull N Shibata et al J Am Chem Soc 2001 123 7001bull D Cahard et al Org Lett 2000 2 3699Tetrahedron Lett 2001 42 1867Angew Chem Int Ed 2001 40 4214
6
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
2
Privileged Ligands and Catalysts
TP Yoon EN Jacobsen Science 2003 299 1691
[] certain classes of synthetic catalysts are enantioselective over a wide range of different reactions Such catalysts may be called ldquoprivileged structuresrdquo in much the same manner that the term has been applied in pharmaceutical research to compound classes that are active against a number of different biological targets Privileged chiral catalysts offer much more than one might have imagined creating effective asymmetric environments for mechanistically unrelated reactions
Jacobsens definition
3
Examples of privileged ligands and catalysts given in the original Jaconsens paper
Hydrogenationhydroamination
hydrophosphinationhydrosilylation
allylic substitution conjugate additionco-polymerization
4
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
5
Non Catalytic Asymmetric Electrophilic Fluorination of Enolates Using N-F Reagents mdash The State of the Art up to 2001
SO2
NF
RR
1 (R=H) 2 (R=Cl)
NS
O O
Me
F
O
Ph1) LDA THF
2) 3
OPh
F
79 yield 88 ee
3
SO2
N
O2S
F
4
NO
Me Ph
O
RO
NO
Me Ph
O
RO1) Base
F
80-90 yield 86-99 de
N
N
OHH
ClO
OMe
2)
NN
Cl
F
+
+2 BF4
ndash
5
Bn
OSiMe3
Bn
O
F4 5
MeCN -20degC
86-99 yield up to 91 ee
Pioneering workbull E Differding RW Lang Tetrahedron Lett 1988 29 6087
Recent reviewsbull H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article)bull K Muntildeiz Angew Chem Int Ed 2001 40 1653 (Highlight)bull SC Taylor et al Tetrahedron 1999 55 12431bull GG Furin in Houben-WeylVol E10 pp 432-499 1999
Recent examplesbull Y Takeuchi et al J Org Chem 1999 64 5708bull FA Davis PVN KasuTetrahedron Lett 1998 39 6135bull N Shibata et al J Am Chem Soc 2001 123 7001bull D Cahard et al Org Lett 2000 2 3699Tetrahedron Lett 2001 42 1867Angew Chem Int Ed 2001 40 4214
6
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Privileged Ligands and Catalysts
TP Yoon EN Jacobsen Science 2003 299 1691
[] certain classes of synthetic catalysts are enantioselective over a wide range of different reactions Such catalysts may be called ldquoprivileged structuresrdquo in much the same manner that the term has been applied in pharmaceutical research to compound classes that are active against a number of different biological targets Privileged chiral catalysts offer much more than one might have imagined creating effective asymmetric environments for mechanistically unrelated reactions
Jacobsens definition
3
Examples of privileged ligands and catalysts given in the original Jaconsens paper
Hydrogenationhydroamination
hydrophosphinationhydrosilylation
allylic substitution conjugate additionco-polymerization
4
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
5
Non Catalytic Asymmetric Electrophilic Fluorination of Enolates Using N-F Reagents mdash The State of the Art up to 2001
SO2
NF
RR
1 (R=H) 2 (R=Cl)
NS
O O
Me
F
O
Ph1) LDA THF
2) 3
OPh
F
79 yield 88 ee
3
SO2
N
O2S
F
4
NO
Me Ph
O
RO
NO
Me Ph
O
RO1) Base
F
80-90 yield 86-99 de
N
N
OHH
ClO
OMe
2)
NN
Cl
F
+
+2 BF4
ndash
5
Bn
OSiMe3
Bn
O
F4 5
MeCN -20degC
86-99 yield up to 91 ee
Pioneering workbull E Differding RW Lang Tetrahedron Lett 1988 29 6087
Recent reviewsbull H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article)bull K Muntildeiz Angew Chem Int Ed 2001 40 1653 (Highlight)bull SC Taylor et al Tetrahedron 1999 55 12431bull GG Furin in Houben-WeylVol E10 pp 432-499 1999
Recent examplesbull Y Takeuchi et al J Org Chem 1999 64 5708bull FA Davis PVN KasuTetrahedron Lett 1998 39 6135bull N Shibata et al J Am Chem Soc 2001 123 7001bull D Cahard et al Org Lett 2000 2 3699Tetrahedron Lett 2001 42 1867Angew Chem Int Ed 2001 40 4214
6
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Examples of privileged ligands and catalysts given in the original Jaconsens paper
Hydrogenationhydroamination
hydrophosphinationhydrosilylation
allylic substitution conjugate additionco-polymerization
4
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
5
Non Catalytic Asymmetric Electrophilic Fluorination of Enolates Using N-F Reagents mdash The State of the Art up to 2001
SO2
NF
RR
1 (R=H) 2 (R=Cl)
NS
O O
Me
F
O
Ph1) LDA THF
2) 3
OPh
F
79 yield 88 ee
3
SO2
N
O2S
F
4
NO
Me Ph
O
RO
NO
Me Ph
O
RO1) Base
F
80-90 yield 86-99 de
N
N
OHH
ClO
OMe
2)
NN
Cl
F
+
+2 BF4
ndash
5
Bn
OSiMe3
Bn
O
F4 5
MeCN -20degC
86-99 yield up to 91 ee
Pioneering workbull E Differding RW Lang Tetrahedron Lett 1988 29 6087
Recent reviewsbull H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article)bull K Muntildeiz Angew Chem Int Ed 2001 40 1653 (Highlight)bull SC Taylor et al Tetrahedron 1999 55 12431bull GG Furin in Houben-WeylVol E10 pp 432-499 1999
Recent examplesbull Y Takeuchi et al J Org Chem 1999 64 5708bull FA Davis PVN KasuTetrahedron Lett 1998 39 6135bull N Shibata et al J Am Chem Soc 2001 123 7001bull D Cahard et al Org Lett 2000 2 3699Tetrahedron Lett 2001 42 1867Angew Chem Int Ed 2001 40 4214
6
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
5
Non Catalytic Asymmetric Electrophilic Fluorination of Enolates Using N-F Reagents mdash The State of the Art up to 2001
SO2
NF
RR
1 (R=H) 2 (R=Cl)
NS
O O
Me
F
O
Ph1) LDA THF
2) 3
OPh
F
79 yield 88 ee
3
SO2
N
O2S
F
4
NO
Me Ph
O
RO
NO
Me Ph
O
RO1) Base
F
80-90 yield 86-99 de
N
N
OHH
ClO
OMe
2)
NN
Cl
F
+
+2 BF4
ndash
5
Bn
OSiMe3
Bn
O
F4 5
MeCN -20degC
86-99 yield up to 91 ee
Pioneering workbull E Differding RW Lang Tetrahedron Lett 1988 29 6087
Recent reviewsbull H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article)bull K Muntildeiz Angew Chem Int Ed 2001 40 1653 (Highlight)bull SC Taylor et al Tetrahedron 1999 55 12431bull GG Furin in Houben-WeylVol E10 pp 432-499 1999
Recent examplesbull Y Takeuchi et al J Org Chem 1999 64 5708bull FA Davis PVN KasuTetrahedron Lett 1998 39 6135bull N Shibata et al J Am Chem Soc 2001 123 7001bull D Cahard et al Org Lett 2000 2 3699Tetrahedron Lett 2001 42 1867Angew Chem Int Ed 2001 40 4214
6
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Non Catalytic Asymmetric Electrophilic Fluorination of Enolates Using N-F Reagents mdash The State of the Art up to 2001
SO2
NF
RR
1 (R=H) 2 (R=Cl)
NS
O O
Me
F
O
Ph1) LDA THF
2) 3
OPh
F
79 yield 88 ee
3
SO2
N
O2S
F
4
NO
Me Ph
O
RO
NO
Me Ph
O
RO1) Base
F
80-90 yield 86-99 de
N
N
OHH
ClO
OMe
2)
NN
Cl
F
+
+2 BF4
ndash
5
Bn
OSiMe3
Bn
O
F4 5
MeCN -20degC
86-99 yield up to 91 ee
Pioneering workbull E Differding RW Lang Tetrahedron Lett 1988 29 6087
Recent reviewsbull H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article)bull K Muntildeiz Angew Chem Int Ed 2001 40 1653 (Highlight)bull SC Taylor et al Tetrahedron 1999 55 12431bull GG Furin in Houben-WeylVol E10 pp 432-499 1999
Recent examplesbull Y Takeuchi et al J Org Chem 1999 64 5708bull FA Davis PVN KasuTetrahedron Lett 1998 39 6135bull N Shibata et al J Am Chem Soc 2001 123 7001bull D Cahard et al Org Lett 2000 2 3699Tetrahedron Lett 2001 42 1867Angew Chem Int Ed 2001 40 4214
6
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
C2 Symmetric Ligands in Transition-Metal-Catalyzed Enantioselective Electrophilic Fluorinations
up to 99 yieldup to 88 ee
O
COOtBu
OCOOtBu
F
(PhSO2)2NF EtOH rt5 mol Pd catalyst
up to 90 yieldup to 94 ee
P
PR2
Pd
HO
OH
PdP
PR2
R2 R2
(BF4)2
R = 35-Me2Ph
O
COOtBu
OCOOtBu
F
(PhSO2)2NF Et2O HFIP rt1 mol Cu catalyst
up to 96 yieldup to 85 ee
N
O
N
O
PhPh CuTfO OTf
P
PPh2
NiCl
Cl
Ph2
N S
OO
Ph N S
OO
Ph
F
5-10 mol Ni catalyst15 equiv (PhSO2)2NF
Et3SiOTf toluene ndash20degC
26-lutidine
T Suzuki Y Hamashima M Sodeoka Angew Chem Int Ed 2007 46 5435J-A Ma D Cahard Tetrahedron Asymmetry 2004 15 1007 Y Hamashima K Yagi H Takano L Tamas M Sodeoka J Am Chem Soc 2002 124 14530For a recent reviews see a) H Ibrahim A Togni Chem Comm 2004 1147 (Feature Article) b) PM Pihko Angew Chem Int Ed 2006 45 544 c) M Oestreich Angew Chem Int Ed 2005 44 2324 d) GKS Prakash P Beier Angew Chem Int Ed 2006 45 2172 e) VA Brunet D OHagan Angew Chem Int Ed 2008 47 1179 Organocatalytic approaches by Barbas Enders Joslashrgensen MacMillan etc
7
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Structure of Crystalline Stable Ti(TADDOLato) Complexes Used as Catalyst Precursors in the First Catalytic Asymmetric Fluorination
Preparation and structure L Hintermann D Broggini A Togni Helv Chim Acta 2002 85 1597For a review on TADDOLs see D Seebach et al Angew Chem Int Ed 2001 40 93
Ar=PhenylL2 =DME
Ar=1-NaphthylL=NCMe
These isolated reagents are more reliable than when generated in situ
OO
Ar
ArOAr
ArO
Ti
Cl
ClL L TADDOLs are derivatives of
tartaric acid
In C2 symmetric complexes the aryl groups will pairwise adopt an edge-on and a face-on orientation
1-Naphthyl substituents are crucial for selectivity in the fluorination of β-keto esters (empirical finding)
8
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
TiCl2(TADDOLato)-Catalyzed Fluorination of Various 13-Dicarbonyl Compounds With Selectfluorreg
General conditions 5 mol catalyst (isolated complex) room temperature MeCN solvent 15min-2d 80-90 isolated yield
L Hintermann A Togni Angew Chem Int Ed 2000 39 4359
OO 1-Naph
1-NaphO
1-Naph
1-NaphO
Ti
Cl
ClMeCN NCMe
O
O O
90 ee
FO
O O
88 ee
FS
O O
91 ee
F
O
O O
82 ee
F
N
O O
F
84 ee
O
O O
F
86 ee
O
O O
F
dr = 965 35
O
ON
O O
F
59 ee
Problem The enol form of a 13-dicarbonyl compound undergoes uncatalyzed fluorination with N-F reagents
N N CH2ClF
2 BF4ndash
++
9
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
A Simple Mechanistic HypothesisThe catalyst is a cationic Ti monochloro complex
An SN2 processat the F atom
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
F
R OR
O O
MeF
N N FCl
S
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash MeCN
++
+
+
Cl
Ti
O
OOO
OR
MeR
MeCN
OO
Np
Np
Np
Structure type has precedent in the literature
H-M Gau et al Inorg Chim Acta 2001 314 105
A postulated mechanism reflects a typical implicit situation and sequence Find a ligand andor catalyst first optimize the reaction (and publish) understand the reaction and the efficacy of the catalyst (if you have time)
10
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
A Model Enolato Complex and Its Fluorination
77 ee (71 ee in the catalytic reaction)
Re-side attack forSS-TADDOL
A C2-symmetric complexin solution (by 2D NMR)Major product (ca 75) in a mixture of three clearly detectable diastereoisomers
SS
Cl
Ti
Cl
O O
MeCN NCMe
OO
Np
Np
Np
Np Et OBn
O O
Me
Et OBn
O O
MeF
N N F
Cl
R
O
Ti
O
O O
OBnO
Me Et
O
OONp
Np
Np
Np
OBn
Et
Me++
Nandash
C6H6 rt 80-90
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
11
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Possible Diastereoisomeric Forms of [Ti(TADDOLato)(carbonylenolato)]2 Complexes
OTiO
OOO
O
R
O
O ONp
NpNp
O
R
R
R
OTiO
OOO
R
O
O
O ONp
NpNp
R
OR
R
OTiO
OOO
R
O
O
O ONp
NpNp
O
R
RR
TiOO
O ONp
NpNp
O
OO
R
R
OO
O
R
R
TiOO
O ONp
NpNp
O
OR
OOO
R
O
TiOO
O ONp
NpNp
O
OR
OOO
O
R
R
RR R
A Face-on ReFace-on Re (C2)
D Edge-on ReEdge-on Re (C2)
B Face-on SiFace-on Si (C2)
E Edge-on SiEdge-on Si (C2)
C Face-on ReFace-on Si (C1)
G Edge-on ReEdge-on Si (C1)
M Perseghini M Massaccesi Y Liu A Togni Tetrahedron 2006 62 7180
12
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Four Most Stable Octahedral Ti Enolate Adducts Containing Cl in Axial Position ndash QMMM Models
00 (63) kcalmolS-product
(Face-on Re)
11 (56) kcalmolS-product
(Edge-on Re)
13 (75) kcalmolR-product
(Face-on Si)
28 ( 61) kcalmolR-product
(Edge-on Si)
13
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Origin of Enantioselectivity as From the QMMM Computational Model
Cl
Ti
O
OOO
O
Me
MeCN
OO
Np
Np
Np
The face-on naphthyl group in RR-TADDOL shields the Re enantioface of the chelating enolate
Interplanar distance of ca 36 Aring
The attack of the electrophile is only possible from the Si-side
14
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Origin of Enantioselectivity as From the Crystal Structure of a Bis(enolato) Complex
O
Ti
O
OOO
OBnO
OO
Np
NpNp
BnO
A C₂ symmetric bis(carbonylenolato) complex displays the same local structural features in the solid state as the computed model
The average distance of the enolato ligand from the naphthyl plane is 36 Aring and the interplanar angle is 5deg
RR-TADDOL leads to preferential Si-side attack
15
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Mechanistic DescriptionStructural and kinetics studies confirm postulated mechanism
kHkD = 098 plusmn 005 for
Me O
O O
Me HDF
RR Cl
Ti
Cl
OO
THFTHF
OO
Np
Np
Np
Np
R OR
O O
Me
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
F
R OR
O O
MeF
S
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
Np
ndash H+
ndash Clndash ndash THF
+
+
Cl
Ti
O
OOO
OR
MeR
THF
OO
Np
Np
Np
HD
HD
N FPhSO2
PhSO2
rate = k [catalyst][NFSI]
[THF]+ k [substrate][NFSI]
Mihai Viciu to be published
16
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Free Energy Profile and Spin Density From Constrained Molecular Dynamics Simulations of the F-Transfer Step
S Piana I Devillers A Togni U Roumlthlisberger Angew Chem Int Ed 2002 41 979
CPMD simulation with the system immersed in a 46 times 49 times 44 Aring box of 557 acetonitrile molecules
Total simulation time 48 ps for T = 300 K
ΔG kcalsdotmol-1 ρpol
17
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Actual Fluorination Step Involves a (Concerted)Dissociative Electron-Transfer Process
A singlet diradical(EPR silent)
For reviews on electron-transfer chemistry see 1) J-M Saveacuteant Adv Phys Org Chem 2000 35 117 2) R Rathore JK Kochi Adv Phys Org Chem 2000 35 193
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
NN
F
Cl
N NCl
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
Np
NpNp
ClTi
O
OOO
OR
MeR
MeCN
OO
Np
NpNp
Np
F
N N FCl
++
+
+
SET
Fluorine atom transfer(radical recombination)
+
18
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Frontier Orbital Considerations
LUMO of [F-TEDA]2+
σ(N-F) ndash9531 eV N-F 1390 Aring (exp 137(2) Aring)
SOMO of [F-TEDA]+
ndash10144 eV N-F 1974 Aring
RE Banks et al Acta Cryst C 1993 49 492 For previous frontier-orbital considerations on N-F reagents see K Sudlow AA Woolf J Fluorine Chem 1994 66 9
HOMO
of enolato complex
ndash endash
B3LYP6-31G level
19
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Simple Frontier Orbital Requirement for Electrophilic Atom-Transfer Reactions to (Potentially) Occur
SET
R
ORO
O
E ERn
Rm
LUMO (σEndashE)HOMO
-
R
ORO
O
ERn
+ RmEndash
O O
MeMe
O N
HMe
Me
ICl
MeS
Me
SMe
N
O
O
Cl
SCl
All orbitals at the B3LYP6-31G level
20
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Summary Various Hetero Functionalizations of 13-Dicarbonyl Compounds Using One and the Same Catalyst
absolute configuration known for at least one derivative
F L Hintermann A Togni Angew Chem Int Ed 2000 39 4359Cl L Hintermann A Togni Helv Chim Acta 2000 83 2425FCl R Frantz L Hintermann M Perseghini D Broggini A Togni Org Lett 2003 5 1709OH P Toullec C Bonaccorsi A Mezzetti A Togni Proc Natl Acad Sci 2004 101 5810SPh M Jereb A Togni Org Lett 2005 7 4041
R1 OR3
O O
R2
R1 OR3
O O
R2SPh
R1 OR3
O O
R2F
R1 OR3
O O
R2Cl
R1 OR3
O O
FCl
R1 OR3
O O
R2HO
NCS
Selectfluor
SelectfluorNCS(R2=H)
N SO2PhO2N
H
O
RR Cl
Ti
Cl
OO
NCMeMeCN
OO
Np
Np
Np
Np
Catalyst precursor(Np = 1-naphthyl)
up to 90 ee up to 93 ee
up to 88 ee
up to 65 ee up to 94 ee
PhSCl (F5C6SCl) toluene rt
Problem The enol form of a 13-dicarbonyl compound may undergo uncatalyzed reaction with the electrophile
21
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Introductionndash Privileged ligandsndash C1 vs C2 Symmetric ligands
TADDOLs in the Ti-Catalyzed Enantioselective Fluorination of 13-Dicarbonyl Compoundsndash Understanding the origin of enantioselectivity
Ferrocenyl Derivatives as Prototypes for C1 Symmetric Ligandsndash Modular synthesis and applicationsndash Conformational aspectsndash Steric bulk shape and sizendash Electronic effects by peripheral substituents
22
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Modularity of Classical Ferrocenyl LigandsPrototypes for C1 Symmetric Ligands
Me Ferrocene fragment(carrier of the chiral information)Fe
Ligand fragment 2(achiral nucleophilicsynthon)
L1 L2Ligand fragment 1(achiral electrophilic synthon)
The assembly of the three components occursin two consecutive stereoselective (-specific) synthetic steps
Step 12 Step 21
Synthetic scheme allows the preparation of ligands containing PP PN PO PS NN combinations of donor atoms
Ligand libraries become accessible (and are partly commercially available)
23
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Josiphos and Pigiphos Are Readily Available
A Togni C Breutel A Schnyder F Spindler H Landert A Tijani J Am Chem Soc 1994116 4062
See also EP 0 564 406 A1 (Priority 02041992 CH)
Pierluigi (Pigi) Barbaro A Togni Organometallics 1995 14 3570
Combination of a bulky trialiphatic phosphine with one or two triaryl phosphines
Josiphos Steric and electronic differentiation between the two P donors
Pigiphos is a rare example of a chiral triphosphineFlexible coordination geometry facial and equatorial (d6) distorted planar (d8) tetrahedral (d10)
Josiphos
Pigiphos
Fe
NMe2
MeFe PPh2
NMe2
Me
Fe PPh2
PCy2
Me
PFe PPh2
Fe
Ph2PUgis amine
24
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
A Togni et al Organometallics 1995 14 5415
Regioselectivity R1 is bulky andorelectron-withdrawing
Synthesis of Pyrazole-Containing Ferrocenyl Ligands
NMe2
MePAr2
R1 R3
OO
R2
H2NNH2
NNH
R3R2
R1
Fe Fe
NMe
NR3
R2
R1
PAr2
Several combinations of Ar R1 R2 and R3
AcOH 70-90 degC
80-90 yield
+
25
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Ph2PCy2P
Ph2P
PCy2
Ph2PCy2P
Ph2P
Cy2P
PPh2PCy2
Ph2P
PCy2
Si
O
O
HN
O
NH
Si
Si
O
OHN
O
HN
Si
NP N P
NP
NP Si
O
OHN
ONH
Si
Si
OO
HNO NH
Si
Si
O
ONH
O
HN
Si
Si
O
ONH
ONH Si
SiO
ONH
OHN
Si
Si
OO
NH O
HN
Si
PPh2Cy2P
Ph2PCy2P
PPh2
PCy2
PPh2PCy2
Ph2PPCy2
PPh2
Cy2P
PPh2PCy2
PPh2
PCy2
Ph2P
Cy2P
Fe
PPh2Cy2P
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Incorporation of Josiphos Into Dendrimers
C Koumlllner B Pugin A Togni J Am Chem Soc 1998120 10274
C Koumlllner A Togni Can J Chem 200179 1762
26
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
For recent reviews see a) H-U Blaser B Pugin F Spindler M Thommen Acc Chem Res 2007 40 1240-1250b) H-U Blaser W Brieden B Pugin F Spindler M Studer A Togni Topics in Catalysis 200219 3-16See also A Togni Angew Chem Int Ed Engl 1996 35 1475-1477
Examples of Past and Present Production-Scale Applications of Josiphos Ligands in Catalytic Asymmetric Hydrogenations
NH3C
CH3
OCH3
CH3OCl
H
P
MeFe
PPh2
S-Metolachlor(Syngenta)
2
Ir
S
NHHN
O
H H
P(t-Bu)2
MeFe
PPh2
COOH
(+)-Biotin(LONZA)
Rh
Sitagliptin(Merck)
Rh
F
FF
NN
NN
ONH2
CF3
PtBu2
MeFe P(4-F3CPh)2
27
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Rh(Josiphos)-Catalyzed Hydrogenation of Tetrahydropyrazine Derivatives Intermediates in the Synthesis of Indinavir
Pilot scale at LONZA
H NN
ONHO
O
H NN
ONHO
O[Rh(COD)2]BF4Josiphos ligand
SC=2000
MeOH 90degC 50 bar H2
96 ee
P(t-Bu)2
MeFe PPh2
N NN
OH
O
NH
ONH OH
Indinavir (Crixivan Merck Sharp amp Dohmeantiviral HIV-1-protease inhibitor)
JF McGarrity W Brieden R Fuchs H-P Mettler B Schmidt O Werbitzky in Large Scale Asymmetric Catalysis HU Blaser E Schmidt (Eds) Wiley-VCH Weinheim 2003 p 283
28
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
CS Shultz SD Dreher N Ikemoto JM Williams EJJ Grabowski SW Krska Y Sun
PG Dormer L DiMichele Org Lett 2005 7 3405 (Merck amp Co)
Ru-Catalyzed Hydrogenation of N-Sulfonylated-α-dehydroamino Acids Synthesis of an Anthrax Lethal Factor Inhibitor
P(t-Bu)2
MeFe PPh2
O
HOOCHN
S
F
O O
O
HOOCHN
S
F
O O
RuCl2(P-P)LnNEt3
H2 EtOH
O
HN
S
F
O O
O
HOHNP-P =
97 ee
29
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Asymmetric Hydrogenation of Unprotected Enamines(Collaboration Merck - Solvias)
1) Y Hsiao et al J Am Chem Soc 2004 126 9918See also 2) N Ikemoto et al J Am Chem Soc 2004 126 3048 3) KB Hansen et al J Am Chem Soc 2009 131 8798
Up to 97 ee
F
FF
NN
NN
ONH2
CF3
MK-0431 (Merck)Sitagliptin (Januvia)
Diabetes 2 ndash DPP IV Inhibitor
P(t-Bu)2
MeFe
P(t-Bu)2Me
Fe P CF32
PPh2
R OMe
NH2 O
R OMe
NH2 ORh Josiphos ligand
R NHPh
NH2 O
R NHPh
NH2 O
H2
Rh Josiphos ligand
H2
30
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
More Josiphos Applications
Rh-Catalyzed hydrogenation of iminesenamines (Zhong (Merck) 2009)
Ru- and Os-Catalyzed hydrogenation and transfer hydrogenation of aryl methyl ketones (Baratta 2007-2008)
Cu-Catalyzed β-boration of β-unsaturated carbonyl compounds (Yun 2006)
Pd-Catalyzed hydrophosphonation of alkenes (Han 2006)
Cu-Catalyzed Michael addition of Grignard reagents to αβ-unsaturated esters and thioesters (Feringa 2005)
Rh-Catalyzed hydroboration of vinyl arenes (Crudden 2004)
Cu-Catalyzed PMHS reduction of nitroalkenes and acyclic enones (Carreira Lipshutz 2003)
Rh-Catalyzed Michael addition of organotrifluoroborates to enones (Genet 2002)
Rh-Catalyzed ring opening of oxabicyclic substrates (Lautens 2000)
31
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Steric vs Electronic Effects1) Structural characteristics and the soft concept of conformational rigidity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
32
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Conformation of Pyrazole-Containing Ferrocenyl Ligands
X-ray crystallographic and 2-D NMR studies in solution show comparable conformations in both the free ligands and their complexesIs conformational rigidity a requirement
33
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
$
amp$
$
$
($
$$ amp$ )$ $ $ $ $ $
$
amp()+-
0)+(1amp2345$4+amp627+898()8424)2amp2342amp+((+amp9(
ampamp2824+
5lt=-amp)gt+gt2)42
The Josiphos Conformational Space as Defined by Two Crucial Torsion AnglesExperimental Values from X-Ray Crystal Structures
M = Cu(I) Ru(II) Pd(0) Pd(II) Pt(II) Rh(I) Ir(I) Ir(III) W(0) Re(I) Re(V)
Sign of torsion angle valid for (R)-(S) absolute configuration
Complexes show a higher conformational degree of freedom of the P1 phosphino group
A proper simplistically understood conformational rigidity of the whole ligand scaffold is not present
34
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Orientation of P-M-P Plane Depending on Torsion Angles α1 and α2
α1=-65degα2=-24deg
α1=-25degα2=-13deg
α1=+9degα2=-21deg
α1=+30degα2=-32deg
α1=-66degα2=+84deg
α1=-88degα2=+74deg
35
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Pd
L1
L2R
R
Pd
L1
L2
R
R
Nu Nu
Pd-Catalyzed Asymmetric Allylic Amination
Stereoselectivity of Pd-catalyzed allylic alkylation and amination depends ultimately on1) ratio of configurational diastereoisomers of π-allyl complexes2) rate of nucleophilic attack on different diastereoisomers3) site of nucleophilic attack (trans to L1 or L2)
36
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
A Togni U Burckhardt V Gramlich PS Pregosin R Salzmann J Am Chem Soc 1996 118 1031
The Steric Effect of a Crucial Substituent in the Pd-Catalyzed Allylic Amination ndash Shape Rather Than Size
X-rayX-ray
PhPh FeP
NNPd Ph
Ph
71 exo-syn-anti isomer40 ee (S-enantiomer)
+
Ph
FeP
NNPd
Ph
Ph
Ph
100 exo-syn-syn isomergt 99 ee (R-enantiomer)
+
PhPh FeP
NN
Pd Ph
Ph
+
100 exo-syn-anti isomerno reaction
R = Ph 1-Np 2-Np 4-Py Cy 3-NO2-Pht-Bu Adamantyl
Ph Ph
OCOR
NH2
Ph Ph
NHCH2Ph3 mol Pd(dba)2 Ligand
40 degC THF
rac R = Me OEt 85-95 yieldup to gt99 ee
N
Me
N
Fe
PPh2R
37
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Nucleophilic Attack trans to Phosphorusis Highly Preferred
P Bloumlchl A Togni Organometallics 1996 15 4125
Ph
FeP
NNPd
Ph
a) R-product
b) S-productgt 200 (gt 99 ee)
Single exo-syn-syn isomer (2D-NMR studies)
NuNu
a)
b)
+
RS
ΔΔGne gt 3 kcalmol-1
Allyl rotation(X-ray studies)
Increased electrophilicity
PN
PdP N
PdP N
+ +
ΔΔGDaggertc = 9 kcalmolΔΔGDagger
tc = 2 kcalmol
(Ab initio studies)
38
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
NH
NPd
PH3
NH3
trans to P trans to NNH
NPd
PH3
ΔΔGDagger = 8 kJmol42 kJmol
NH
NPd
PH3
NH3
50 kJmol
36 kJmol
NH3+
41 kJmol
NH3+
+
Calculated Energetics (DFT) of Nucleophilic Attackin a Non-Distorted Model Complex
P Bloumlchl A Togni Organometallics 1996 15 412539
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
PdP N
PdP N
PdP N
+
+ +
Nucleophilic attack is favored by P trans influenceΔΔGDagger
tc = 8 kJmol
ΔΔGDaggertc = 38 kJmol ΔΔGDagger
ct = 29 kJmol
Enhancedelectrophilicity
for C out of plane
Sterically induced rotation of π-allyl ligand dominates site-selectivityirrespective of cistrans relationship to donor atoms P and N
The Effect of a Sterically Induced Distortion on Frontier Orbitals (LUMO) ndash Computational Studies
40
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
PhPh Fe
P
NNPd
Ph
Ph
Ph
Ph
FeP
NNPd
Ph
Ph
exo-syn-anti (71)
+
exo-syn-syn (29)
+
S R
Isomer ratio reflects enantioselectivity
9-Anthryl Substituent Induces a Change in the Preferred Configuration at Allyl Ligand
41
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
PhFe
P
NN
Pd
Enforced anti-arrangement(X-ray and 2D-NMR)
+
Ph
but no reaction with PhCH2NH2
A Triptycyl-Substituted Pyrazole LigandFixation of Pd-Allyl Configuration
in a Rationally Designed Chiral Environment
42
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Ph
Ph
PdP N
Ph
Ph
P NPd
Nu
Nu
Pd(II)-(η3-Allyl) Pd(0)-(η2-Olefin)
The Triptycyl Substituted Pd-π-Allyl ComplexWhy Does it Not React With a Nucleophile
Plausible explanation The side-on movement of the allyl fragment that has to take place upon nucleophilic attack in order to form a Pd(0)-olefin complex is hampered by the presence of the triptycyl substituent
43
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Both Opposite Ligand Position and Allyl ConfigurationLead to the Same Sense of Induction
The combination of steric configurational and electronic regiochemical control
U Burckhardt D Drommi A Togni Inorg Chim Acta 1999 296 183
PMe
NN
Ph
Ph
PhPh
PdNN
MePd
FeFeP
Ph
Ph
Ph
Ph
Ph Ph
NHCH2Ph
(S)
Ph Ph
OCOOEtNu-Nu-
exo-syn-syn endo-syn-syn
950 ee resp 945 ee
rac
44
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Comparing Two Isomeric Ligands
Two different donor combinations P C(carbene) and P sp2-N
The two ligands and their complexes are isoelectronic and essentially isostructural
How do they compare in reactivity and selectivity
For other examples of bidentate ferrocenyl carbene ligands see H Seo H Park BZ Kim SU Son YK Chung Organometallics 2003 22 618
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
MePdR
R+
PdR
R+
X-ray
45
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Nucleophilic Attack by an Amine on Cationic Pd-π-Allyl Complexes
Conditions CHCl3 298 K reactions monitored by UVVIS andor NMRAmines benzylamine piperidine ndash Counterion CF3COOndash
Fe
N CN
PPh2
Me
Fe
N NC
PPh2
Me
PdR
R+
PdR
R+
Fe
N CN
PPh2
Me Pd
NHR2R
RFe
N CN
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
Fe
N NC
PPh2
Me Pd
NHR2R
RFe
N NC
PPh2
Me Pd
COOMe
MeOOC
NHR2
slow
k2
DMFU
fast
dr 8515exoendo 8218
46
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
The Kinetics of Nucleophilic Attack by an Amine
Clean second order kinetics for both types of ligands
The nucleophilic attack on the PC complexes is three orders of magnitude slower than on the PN complexes
ndash d[Pd-allyl complex]dt
= k2 sdot [Pd-allyl complex] sdot [Amine]
F Visentin A Togni Organometallics 2007 26 3746
Ligand Allyl subst Amine k2 (molmiddotdmndash3)
PC H Piperidine (226plusmn007)middot10ndash2
PC H Benzylamine (34plusmn01)middot10ndash4
PN H Piperidine 335plusmn009
PN H Benzylamine 0687plusmn0009
PN Ph Piperidine (141plusmn002)middot10ndash2
PC Ph Piperidine ca 5middot10ndash5
47
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Pd-Catalyzed Allylic Amination Using the PCarbene LigandldquoNucleophilic Confusionrdquo
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF32 yield after 120 h5 ee S-enantiomer for (R)-(S) ligand
Ph Ph
OCOOEt
Ph Ph
N
15 mol [Pd(η3-allyl)(PC)]CF3CO2
40 degC THF63 yield after 120 h6 ee S-enantiomer for (R)-(S) ligand
NH
Ph Ph
OCOOEt
NH2
Ph Ph
NHCH2Ph
15 mol [Pd(η3-allyl)(PN)]CF3CO2
40 degC THFquant yield after 40 h98 ee S-enantiomer for (R)-(S) ligand
48
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
N
Me
N
Fe
PPh2
Ph Ph
OCO2Et
Ph Ph
NHCH2Ph
[Pd(dba)2 ]+ Ligand
[Pd(dba)2 ]+ Ligand+ 10 Eq NH4PF6
[Pd(η3-Ph2Allyl)(L)]PF6
[Pd(η3-Ph2Allyl)(L)]PF6+ 2 Eq NBu4F
[Pd(dba)2 ]+ Ligand+ 2 Eq NBu4F
991 (220)
67 (11)
33 (2)
987 (153)
gt995 (gt400)
Catalyst Precursor ee (er)
40 degC THF PhCH2NH2
3 mol Pd-catalyst
PF6- Selectivity
Killer
F- Selectivity Enhancer
U Burckhardt et al Tetrahedron Asymmetry 1997 8 155
A Remarkable Anion Effect in the Pd-CatalyzedAllylic Amination
49
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Ph
Ph
P
NPd
+
endo-syn-syn
+
exo-syn-syn
Ph
PhP
NPd
Ph Ph
OCOOEt
Ph Ph
OCOOEtSimilar rates of oxidative addition
(no kinetic resolution)
Slow with PF6-
(tight ion pairs )
Fast with F-
(Coordination)
R-Product S-Product
more stable
F- ensures Curtin-Hammett conditions
S R
A plausible explanation of the anion effect
50
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Steric vs Electronic Effects2) The ability of peripheral substituents to influence both activity and selectivity
Ligands as the carriersof the chiral information
Steric propertieseg bulk conformation
Electronic propertieseg donoracceptor ability
Stereoselectivity(Activity)
Intuitive repulsive ground-state effects(rational design)
Elusivetransition-stateeffects(empiricism )
Steric tuning is achieved by a judicious choice of substituents according to their size and shape ndash Influence on conformation and configuration (diastereomeric intermediates)
Electronic tuning is very often dependent on sterically less relevant peripheral ligand substituents ndash Alteration of donoracceptor properties of coordinating atom
51
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
E N Jacobsen et al
Electron-donating groups favor a late transition state and hence a better stereodifferentiation in the oxygen-transfer process as indirectly shown by a more pronounced secondary inverse isotope effect
Electronic Effects in the Asymmetric Mn-Catalyzed Epoxidation of 22-Dimethylchromene
NN
OMn
OCl
X X
HHX = OMe 96 ee
X = NO2 22 ee
52
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
A L Casalnuovo T V RajanBabu et al J Am Chem Soc 1994 116 9869
An electron-withdrawing group on phosphorus leads to a differential increaseof the rate of product reductive elimination starting from diastereoisomericNiCN(η3-benzyl) complexes
Electronic Effects in the Asymmetric Ni-Catalyzed Hydrocyanation of Vinylarenes
MeO MeO
CN
OOOPh
OPhOPAr2
OAr2P CF3F3C MeMe
HCN [Ni(COD)2] L
Ar =
91 eeL
16 ee
53
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
See also G Consiglio et al Helv Chim Acta 1995 78 883
Highly Stereoregular Pd-Catalyzed CO Propene Copolymerization Using Ferrocenyl Ligands
13C NMR Spectrum in d2-HFIPMAS 13C NMR Spectrum (RT)
Stereoregularity gt90 and up to gt96 as judged by NMR
OCO O
++
nn2 3
4
1
75 bar COPd-Catalyst50degC 3h
Δ
54
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
([α]D=-450)
Model PdCl2 complexes displayvery similar conformations of the PAr2 groups in the solid state
A Togni G Consiglio et al Angew Chem Int Ed 2000 39 2486
CatalystProductivity(g(gPd)-1h-1
Polymer)50 220 370 1800
Effect of Ligand Peripheral Substituents on Catalyst Productivity
PCy2Me
Fe P
CF3
CF32
PCy2Me
Fe P
OMe
OMe2
PCy2Me
Fe P
H
H2
PCy2Me
Fe P
CH3
CH32
55
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Mesityl substituent decisive for high enantioselectivity of main productMinor electronic and steric effects of R substituents on phenylsFormation of small amounts of achiral product
Markus Baumann
Asymmetric Heck Reaction
NMeN
Fe
Me
Me
Me
P
O+ PhOTf
3 mol [Pd(dba)2]6 mol Ligand
NEt(i-Pr)2 (2 eq)THF 70degC quant
O Ph O Ph O
Ph
+ +
2
Rn
Rn=(m-CF3)2
Rn=(m-SiMe3)2
Rn=(p-OMe)
Rn=(p-CF3)
1 (34ee)
8 (62ee)
1 (46ee)
1 (10ee)
94 (88ee)
90 (95ee)
97 (96ee)
96 (95ee)
5
2
2
3
56
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
A Schnyder et al Organometallics 1997 16 255
Ligand Electronic Tuning From 5 to 985 ee in the Rh-Catalyzed Hydroboration of Styrene with Catecholborane
NMeN
Fe
PMe Me
F3C
F3CNMeN
Fe
PMe Me
CF3
F3CF3C
F3C
NMeN
Fe
PF3C CF3
MeO
MeO
NMeN
Fe
PMe Me
MeO
MeO
NMeN
Fe
PF3C CF3
NMeN
Fe
PMe Me
NMeN
Fe
PMe Me
Me2N
Me2NNMeN
Fe
PF3C CF3
F3C
F3C
95 ee985 ee
5 ee72 ee
33 ee
98 ee90 ee
40 ee
the worst
and the best
57
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Steric and electronic tuning of pyrazole and phosphine ligand fragments
Pioda G Togni A Tetrahedron Asymmetry 1998 9 3903
Up to 85 ee in the hydrosilylation of 13-cyclohexadieneHigh catalytic activity TON up to 104 TOF up to 103 h-1
Pyrazole-Phosphine Ligands in the Pd-Catalyzed Hydrosilylation of Olefins
NMeN
Fe
Me
Me
Me
PPh2
1) HSiCl3 01 mol PdCl2(L)
2) Oxidative Workup
OH
NMeN
Fe PPh2
NMeN
Fe PPh2
Me
39ee 76ee 99ee
Catalytic activity
NMeN
Fe
MeO
OMe
OMe
PPh2
NMeN
Fe
Me
Me
Me
P
CF3
CF3
2
82ee 91ee
58
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Correlation of log[(S)(R)] with σp+ indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
X
Fe PPh2
N N
Mes
Me
X
1) cat PdCl2(L)
2) Oxidation
X=Cl 67 ee (S)X=NMe2 64 ee (R)
= L
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=078rsup2=0996
NMe₂
OMe
Me
ClH
Inversion ofenantioselectivity
Fe P X
N N
Mes
Me
1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
OH
-08
-06
-04
-02
0
02
04
06
08
-2 -15 -1 -05 0 05
+σp
log[S][R]
ρ=014rsup2=0986
NMe₂OMe
Me HCl
Linear Free-Energy Relationshipfor the Hydrosilylation of p-Substituted Styrenes
59
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Correlation of log[(S)(R)] with σp + indicates the development of a positive chargein the transition state of the enantioselectivity-determining step
Linear Free-Energy Relationship for the Hydrosilylation of Styrene Using p-Substituted Phenylphosphino Ligands
Fe P X
N N
Mes
Me
OH1) cat PdCl2(L)
2) Oxidation
X=CF3 68 ee (S)X=NMe2 45 ee (S)
2
60
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
bull Clean first-order dependence on olefinbull Electron-rich olefins react faster
Overall Rate for the Hydrosilylation of p-Substituted Styrenes Correlates With Hammett Parameter σp
X
Fe PPh2
N N
Mes
Me
X
OH1) cat PdCl2(L)
2) Oxidation
= L
61
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Mechanism of the Pd-Catalyzed Hydrosilylation of Styrenes
PdN
P
Cl
Cl
PdN
P H
SiCl3
R
PdN
P
R
SiCl3
N
PdP
HCl3Si
N
Pd
P
Cl3Si
R
R
Olefin insertionbull Enantioselectivity determiningbull HD exchange shows reversibility
Reversible olefin coordinationOpening of chelate ring 1st order in both olefin and Pdfast HSiCl3
oxidative addition0th order in silane
C-Si reductive eliminationbull Rate determining
Unclear formation
σp
σp+
Experiments with perdeutero styrene and HSiCl3 show a nearly statistical hydrogen isotope distribution in the methyl group of the product
62
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Result Both a strong trans influence of SiCl3 and a large steric contribution account for bond elongations and distortion
TK Woo
HH P
PdSiCl3SiCl3
NNH H
HH
HH P
PdSiCl3SiCl3
NNH H
FeP
PdSiCl3SiCl3
NN
FeP
PdSiCl3SiCl3
NN
HH P
PdSiCl3SiCl3
NNH H
HH P
PdSiCl3SiCl3
NN
H3CH
HH
H
Model 1
Model 2
Models of Pd(SiCl3)2 Complex for QMMM Computational Studies
63
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Olefin insertion onlyslightly exothermic
Stabilization via π-coordinationof benzyl ligand (η3-mode)
High activation barrier forreductive elimination Rate determining
A Magistrato TK Woo A Togni U Roumlthlisberger Organometallics 2004 23 3218
Reaction Profile for the QM Model System
PPd
H
SiCl3NN
HH
PPd
HSiCl3
NN
HH
PPd
HSiCl3
NN
HH
PPd
SiCl3NN
HH PPd
SiCl3NN
HH
1900
22
-02
-83
141
52
PPd
SiCl3NN
HH
PPd
Cl3SiNN
HH
64
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Only one configurationalisomer considered
endoendo-syn
PPdH
SiCl3NN
Fe
PPd HSiCl3NN
FeFe P
Pd
SiCl3NN
PPd HSiCl3NN
Fe
Cl3Si
PPd
SiCl3N
Fe
N
PPd
Cl3SiNN
Fe
PPdH
SiCl3NN
Fe
PPd
NN
Fe
Cl3Si
R
-35
09
TS1
TS2
-205
+-103
+styrene
00
42+48
61
Dagger Dagger
Complete Reaction Profile for Styrene QMMM Model 1
65
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
si-side coordinatedExo +16 kcalmol
Precursor of S-product(observed for styrene)
re-side coordinatedEndo 00
Precursor of R-product(observed for 4-(dimethylamino)styrene)
FeP
PdH
SiCl3NN
PPd
HSiCl3
NN
Fe
Pd(II)-(η2-Styrene) Complexes QMMM Model 1
66
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Reaction Pathways for the Formation of Diastereoisomeric η3-Styryl Intermediates ndash QMMM Model
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPd
H
SiCl3NN
Fe
PPd
SiCl3NN
Fe
PPdSiCl3NN
Fe
PPd
SiCl3NN
Fe
48
00
1609
51
-103
-113
Pathway to S-product
Pathway to R-product
endo-syn
exo-synendo
exo
Fast equilibration Curtin-Hammett situation
kcalmol
67
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Pathway to S-product
Pathway to R-product
endo-syn
exo-syn
NMe2
PPd
HSiCl3NN
Fe
PPdH
SiCl3NN
Fe
NMe2
PPd
SiCl3NN
Fe
NMe2
PPdH
SiCl3NN
Fe
Me2N
PPd
SiCl3NN
Fe
PPdSiCl3
NN
Fe
NMe2
PPd
SiCl3NN
Fe
Me2N
48
00
08
03
16
-172
-155
exo
endo
Reaction Pathways for the Formation of Diastereoisomeric η3-(4-Dimethylamino)styryl Intermediates QMMM Model 1
68
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Hydrosilylation of Perdeuterostyrene With Proteosilane
DD
D
D5
HndashSiCl3 [PdL]
DD
D
D5
HO H DD
H
D5
HO H DH
H
D5
HO H DD
D
D5
HO D
oxid workup
+ + +
MeD2 MeD1 MeD0 MeD3MeD0
MeD1
MeD2
13C-1H-HZQCNMR
MeD2
MeD11 equivsilane
5 equivsilane
EI-MS
The deuterium label at the β-carbon of styrene is selectively scrambled by the silane under hydrosilylation conditions
69
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Endo RExo SStyrene 4-(Dimethylamino)styrene
e endo-synf endo-antig exo-synh exo-anti
A Magistrato A Togni U Roumlthlisberger Organometallics 2006 25 1151
Comparison of Reaction Profiles for Styrene and 4-(Dimethylamino)styrene
70
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
styrenestyrenestyrenestyrene 4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styrene4-dimethylamino)styreneIntermediate Relative
Energy(kcalmol)
(at rt)
ee Intermediate RelativeEnergy
(kcalmol)
(at rt)
ee
endo-syn -103 123
75 (S)[65 (S)]
endo-syn -172 859
81 (R)[64 (R)]
endo-anti -81 03 75 (S)[65 (S)]
endo-anti -156 58 81 (R)[64 (R)]exo-syn -113 204
75 (S)[65 (S)] exo-syn -155 48
81 (R)[64 (R)]
exo-anti -106 669
75 (S)[65 (S)]
exo-anti -153 35
81 (R)[64 (R)]
Prediction of absolute stereoselectivity based upon calculated relative energy of diastereoisomeric η3-benzyl intermediates
71
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
Conclusions
Many factors contribute in making a ligand to a privileged one modular synthesis being one of the most important initial success is another
A thorough knowledge of structural and mechanistic features is a requirement in order to understand why a privileged ligand is such
However ex-novo design of new privileged ligands is mostly illusory
72
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