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TRANSCRIPT
Chiral Phosphoric Acid Catalysis: Ac2va2on Modes and Relevant Examples
Eric Newcomb
March 12th, 2012
Ar
Ar
OP
O O
OH
OH
OH
OH
OH
O
R
O
OAl
H
OR'
(≥2 equiv)
THF
Li
R
OHH
good yieldsvarying ee's
Superstoichiometric BINAL reagent (1979)
First Made as Racemate by von Richter (1873)
(R)-BINOL (S)-BINOL
BINOL In Organic Synthesis
von Richter, V. Chem. Ber. 1873, 6, 1252.Love, B. E. Curr. Org. Synth. 2006, 3, 169.Noyori, R.; Tanimoto, T. Y. J. Am. Chem. Soc. 1979, 101, 3129-3131.
2
BINOL Based Reagents In Organic Synthesis
Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363.Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725-2732.Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13760.
Asymmetric Epoxidation of Enones (2001)
Numerous Examples of BINOL Reagents (and Derivatives) in Asymmetric Synthesis
BINOL Backbone Generally Provides Good Chiral Induction
R1 R2
O
R1, R2 = aryl, alkyl
(R)-BINOL (5 mol%)La(O-iPr)3 (5 mol%)
Ph3As(O) or Ph3P(O) (5-15 mol%)
tBuOOH (1.2 equiv), 4Å MSTHF, rt R1 R2
OO
72 - 99% yield92 - 99% ee
Asymmetric Addition of Phenylacetylene to Aldehydes (2005)
O
HRPh
R = aryl, alkyl
InBr (10 mol%)(R)-BINOL (10 mol%)
Cy2NMe (50 mol%)CH2Cl2, 40 °C
RPh
OH
84 - 95% yield95 - 98% ee
Asymmetric Mukiayama Aldol (1995)
O
R H
OTMS
t-BuS
1) (S)-BINOL / Ti(O-iPr)4 (1:1) (20 mol%) 4Å MS, Et2O, -20 °C
2) H+ t-BuS R
O OH
R = aryl, alkyl 70-90% yield89-98% ee
3
Ac2va2on of Polarized Func2onal Groups
4
H-BondCatalysis
Lewis AcidCatalysis
Brønsted AcidCatalysis
Can chiral Brønsted acids fill in gaps between H-bonding catalysis and LA catalysis?
Are other modes of activation possible with chiral brønsted acids?
OHOH
Ar Ar
ArAr
O
O
Me
Me
TADDOL
Thiourea Catalyst
HNNH
O
t-Bu
NH
S
N
HO
t-Bu OCOt-Bu
OP
O O
OH
R
R
Chiral Phosphoric Acid
Bis-oxazolines
OTi
O
R
R
X
X
Ti-BINOL
N N
OOMe Me
R R[M]O O
[M]
RR
O HO
HO
R R
[Ti]
O
RR
O
O
XX
S
NN
Z
R R
H H
Ph
NR2
HR1
H
PO
OO
O*
N
HR1
PO
OO
O* O
H
H
MeNH
MeMe
TsPZ
YO
O
*
Me
Dual Activation
Covalent Activation
H-Bond/Ion-Pair Activation
O
Et
HMe
RTIPSO
PZ
OO
O
*
RO
PO
OO
O
*
HOH
O H
Bifunctional Activation
H-Bond/Ion-Pair Activation
PO
OO
O
*
HO
HO
OEt
Double H-BondActivation
Different Modes of Ac2va2on
5
Not Covered in Talk (But Worth Men2oning)
Liao, S.; List, B. Angew. Chem. Int. Ed. 2009, 49, 628-631.Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336-11337.
6
Asymmetric Counterion-Directed Catalysis (ACDC)
OPO
tBu tBu
O O
N N
OO tBu
tBu
tBu
tBu
Mn
cat
CO2iPrcat (5 mol%)PhIO (1.2 equiv)
benzene, rt, 2h
CO2iPr
O96% ee
Me
R1 CHOPh
Ph NH
R2
R1 = arylR2 = H, Me, Ph
R1 CHO
Me
R2
40 - 89% yield70 - 97% ee
(1.5 mol%)Pd(PPh3)4 (3 mol%)
5Å MS, MTBE, 40 °C, 8 - 24 h
then 2N HCl, Et2O, rt, 30 min
OP
O O
OH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Epoxidation
!-Allylation of Aldehydes
Dual Catalysis
Reactions which use the chiral acid with a metal, Lewis base, etc.
The Ini2al Publica2ons: Mannich-‐Type
Ph H
N
HO
Ph
HN
HO
CO2MeMe
Me
OTMS
OMe
(1.0 equiv) (3 equiv) Me
(10 mol%)
toluene, -78 °C, 4 h
OP
O O
OH
NO2
NO2
Me96% yield87% ee
Akiyama (2004)
Ph H
N
HO
Ph
HN
HO
CO2MeMe
Me
OTMS
OMe
(1.0 equiv) (3 equiv) Me
(10 mol%)
toluene, -78 °C, 4 h
OP
O O
OH
NO2
NO2
Me96% yield87% ee
Akiyama (2004)
Terada (2004)
OP
O O
OH
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
HN
Ph
Boc
Ac
Ac
(2 mol%)
99% yield95% ee
7
The Ini2al Publica2ons: Mannich-‐Type
Ph H
N
HO
Ph
HN
HO
CO2MeMe
Me
OTMS
OMe
(1.0 equiv) (3 equiv) Me
(10 mol%)
toluene, -78 °C, 4 h
OP
O O
OH
NO2
NO2
Me96% yield87% ee
Akiyama (2004)
N
HR1
PO
OO
O* O
H
H
Dual Activation
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.8
Discovery and Op2miza2on
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.
OP
O O
OH
OP
O O
OH
H
H
Ph H
N
HO
Ph
HN
HO
Me Me
CO2MeMe
Me
OTMS
OMe
(3 equiv)
OP
O O
OH
MeMe
Me
Me
Me
Me
Cat (30 mol%)
toluene, -78 °C
Cat t (h) Yield (%) ee (%) Cat t (h) Yield (%) ee (%)
22 57 0
20 100 27
27 100 60
OP
O O
OH
OP
O O
OH
H
H
Ph H
N
HO
Ph
HN
HO
Me Me
CO2MeMe
Me
OTMS
OMe
(3 equiv)
OP
O O
OH
MeMe
Me
Me
Me
Me
OP
O O
OH
OMe
OMe
OP
O O
OH
NO2
NO2
Cat (30 mol%)
toluene, -78 °C
Cat t (h) Yield (%) ee (%) Cat t (h) Yield (%) ee (%)
22 57 0
20 100 27
27 100 60
46 99 52
4 96 87
OP
O O
OH
OP
O O
OH
H
H
Ph H
N
HO
Ph
HN
HO
Me Me
CO2MeMe
Me
OTMS
OMe
(3 equiv)
OP
O O
OH
MeMe
Me
Me
Me
Me
OP
O O
OH
OMe
OMe
OP
O O
OH
NO2
NO2
Cat (30 mol%)
toluene, -78 °C
Cat t (h) Yield (%) ee (%) Cat t (h) Yield (%) ee (%)
22 57 0
20 100 27
27 100 60
46 99 52
4 96 87
Highest reactivity and enantioselectivity
9
Ini2al Substrate Screen
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.
Ar
HNCO2Me
Me MeAr H
NMe
Me
OTMS
OMe
OP
O O
OH
NO2
NO2
(10 mol%)
toluene, -78 °C
HNCO2Me
Me Me
98% yield89% ee(13 h)
HO
HNCO2Me
Me Me
100% yield89% ee(24 h)
HO
HNCO2Me
Me Me
100% yield85% ee(24 h)
HO
HNCO2Me
Me Me
100% yield80% ee(24 h)
HO
Me F Cl
HO HO
A small number of 4-substituted aryl aldimines were screened and displayed excellent yields and good ee's
10
Diastereoselec2ve Reac2on Scope
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.
R1 H
N
HO
R1
HN
HO
CO2R3
H
R2
OTMS
OR3
(1.0 equiv) (1.5 equiv) R2
HN
HO
CO2Et
Me
HN
HO
CO2Et
Me
HN
HO
CO2Et
Me
HN
HO
CO2Et
Me
HN
HO
CO2Et
MeMeO F Cl Me
HN
HO
CO2Et
MeS
HN
HO
CO2Et
Me
HN
HO
CO2EtHN
HO
CO2Et
MeO
HN
HO
CO2Me
OSiPh3
100% yield87:13 syn/anti
96% ee100% yield
92:8 syn/anti88% ee
100% yield91:9 syn/anti
84% ee
100% yield86:14 syn/anti
83% ee100% yield
94:6 syn/anti81% ee
81% yield94:6 syn/anti
88% ee91% yield
95:5 syn/anti90% ee 100% yield
93:7 syn/anti91% ee
92% yield93:7 syn/anti
87% ee
79% yield100:1 syn/anti
91% ee
(10 mol%)
toluene, -78 °C, 24 h
OP
O O
OH
NO2
NO2
11
Changes to Aldimine are Not Tolerated
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756-6764.
Ph
HNCO2Me
Me MePh H
NMe
Me
OTMS
OMe
HNCO2Me
Me Me
28% yield20% ee(33 h)
HNCO2Me
Me Me
56% yield3% ee(46 h)
HNCO2Me
Me Me
76% yield39% ee(43 h)
OP
O O
OH
NO2
NO2
OH MeO
X X
(10 mol%)toluene, -78 °C
HNCO2Me
Me Me
98% yield89% ee(13 h)
HO
Ph
HNCO2Me
Me MePh H
NMe
Me
OTMS
OMe
HNCO2Me
Me Me
28% yield20% ee(33 h)
HNCO2Me
Me Me
56% yield3% ee(46 h)
HNCO2Me
Me Me
76% yield39% ee(43 h)
OP
O O
OH
NO2
NO2
OH MeO
X X
(10 mol%)toluene, -78 °C
HNCO2Me
Me Me
98% yield89% ee(13 h)
HO
2-hydroxyl substituent is essential for high reactivity and enantioselectivity
12
Two Poten2al Pathways
POH
OO
O*
OP
O O
OH
BIPOL instead of BINOLwas used in calculations
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756-6764.
BHandHLYP/6-31G* level of theory
13
N
HO
Ph H
POH
OO
O*
N
O
Ph H
PO
OO
O
*
HH
N
O
Ph H
PO
OO
O*
HH
N
O
Ph H
PO
OO
O* H
H N
O
Ph H
PO
OO
O
*
HH
Ph
O
OMe
NH
OH
OTMS
OMeNu
CP2i CP1i
CP2n CP1n
Cat EI
monocoordinationpath
dicoordinationpath
0
-6
-10
-14
0.0
-10.5
-13.3
-11.4 -11.2
-14.2
-5.4
-8.8
Cat+Nu+EI
CP2n
CP1n
TS1t CP2i
CP1i
TS2i
TS1i
to products
Rel
ativ
e en
ergy
(kca
l/mol
)
Reaction coordinate
monocoordinationpath
dicoordinationpath
Other Examples of Dual Ac2va2on
Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K. Synlett 2005, 141-143.Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070-13071.
14
N
HR1
PO
OO
O* O
H
H
Dual Activation
N
Ar
HO
Me
OMe
OTMSAcOH (1.2 equiv)toluene, -78 °C
N
Ar O
OH
Me(5 mol%)
OP
O O
OH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
72 - 100% yield76 - 91% ee
Asymmetric Aza Diels-Alder
Asymmetric Inverse Electron-Domand Aza Diels-Alder
N
Ar
HO
toluene
R = 9-anthryl
(10 mol%)
OP
O O
OH
RORHN
HO
Ar ORR = alkyl59 - 95% yield88 - 97% ee
R
Direct Mannich Reac2on
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.
Terada (2004)
OP
O O
OH
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
HN
Ph
Boc
Ac
Ac
(2 mol%)
99% yield95% ee
NR2
HR1
H
PO
OO
O*
H-Bond/Ion-Pair Activation
15
Catalyst Evalua2on
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
HN
Ph
Boc
Ac
Ac
OP
O O
OH
H
H
OP
O O
OH
OP
O O
OH OP
O O
OH
Cat (2 mol%)
Cat Yield (%) ee (%) Cat Yield (%) ee (%)
92 -12 95 56
88 90 99 95
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
HN
Ph
Boc
Ac
Ac
OP
O O
OH
H
H
OP
O O
OH
OP
O O
OH OP
O O
OH
Cat (2 mol%)
Cat Yield (%) ee (%) Cat Yield (%) ee (%)
92 -12 95 56
88 90 99 95
High Enantioselectivity
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.
16
Substrate Scope
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.
HNBoc
Ac
AcMeO
HNBoc
Ac
AcMe
HNBoc
Ac
AcBr
HNBoc
Ac
AcF
HNBoc
Ac
Ac
Me HNBoc
Ac
Ac
93% yield90% ee
98% yield94% ee
96% yield98% ee
94% yield96% ee
94% yield93% ee
99% yield92% ee
OP
O O
OH
N
R H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
HN
R
Boc
Ac
Ac
(2 mol%)
Changes to R are tolerated 17
PO
O
O
O
R
R
H PO
O
O
O
R
R
H
PO
O
O
O
R
R
HPO
O
O
O
R
R
H
NH
Ph
Boc
NH
Ph
Boc
NPh
Boc
H
NPh
Boc
H
trans-1(0.0)
trans-2(0.8)
cis-2cannot locate
cis-1(6.9)
Relative energy of activated imine complexes (kcal/mol)
R = biphenyl
On the B3LYP/6-31G(d, p) level of theory
Leads to the observedstereoselectivity
Proposed Ac2va2on Mode
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
HN
Ph
Boc
Ac
Ac
Cat (2 mol%)
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.Gridnev, I. D.; Kouchi, M.; Sorimachi, K.; Terada, M. Tet. Lett. 2007, 48, 497-500.
18
NR2
HR1
H
PO
OO
O*
H-Bond/Ion-Pair Activation
Authors claim that in the trans-2 and cis-1 H-bond complexesthe imine is completely shielded by the bulky R groups
If Boc is changed to a benzyl or methyl ester errosion of ee is observed(26% and 6% ee, respectively)
Calculations can provide useful data into reactivity, but ocassionally they do not reflect reality
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
Ar = 4-(!-Naph)-C6H4
HN
Ph
Boc
Ac
Ac
(2.5 mol%)
>99% yield92% ee (R)
OP
O O
O
Ar
Ar
Ca
2 Chiral calcium phosphate catalyst givessimilar results to Tereda's original data
N
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
Ar = 4-(!-Naph)-C6H4
HN
Ph
Boc
Ac
Ac
(2 mol%)
88% yield>27% ee (S)
OP
O O
OH
Ar
ArWashed with HCl to remove alkali or
alkaline-earth metals
Gives poor selectivity and the opposite enantiomer
OP
O O
OH
Ar
ArN
Ph H
Boc
acac (1.1 equiv), CH2Cl2, rt, 1 h
Ar = 4-(!-Naph)-C6H4
HN
Ph
Boc
Ac
Ac
(2 mol%)
99% yield95% ee (R)
Terada's original result
(catalyst purified on silica gel)
Is the Acid the Catalyst?
Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010, 49, 3823-3826.
19 Washing with HCl to remove salts does not typically have such a drastic effect on selectivity
Other Examples of Imine Ac2va2on
NR2
HR1
H
PO
OO
O*
H-Bond/Ion-Pair Activation
OMeO N
H Ar
BocO
PO O
OH
Ar
Ar (2 mol%)
DCE, -35 °C, 24 h
Ar = 3,5-dimesitylphenyl
OMeOAr
HNBoc
80 - 96% yield86 - 97% ee
Aza-Friedel-Crafts Alkylation of Furan
Most transformations proceeding through imine activation are bifunctional
(i.e. activate the nucleophile as well)
Daisuke Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126, 11804-11805.20
Moving Past Imine Substrates
NR2
HR1
H
PO
OO
O*
H-Bond/Ion-Pair Activation
O
Et
HMe
RTIPSO
PZ
OO
O
*
H-Bond/Ion-Pair Activation
Potential activation
of less polarizedsubstrates
21
A New Acid Catalyst
POH
OO
O* P
NH
OO
O*
Tf
Authors claim increase in acidty may cause better activation
Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627.
Et
OMe
MeTIPSO toluene, -78 °C, 3 h
(5 mol%)
OP
O O
NH
Tf
<10 % yieldee not determined
(1.5 equiv)
Et
OMe
MeTIPSO
Me
Me
Et
O
TIPSOtoluene, -78 °C, 3 h
(5 mol%)
OP
O O
NH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Tf
95% yield92% ee
>98/<2 endo/exo
(1.5 equiv)
22
Substrate Scope
Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627.
Et
OMe
RPO
Me
R
Et
O
POtoluene, -78 °C, 3 h
(5 mol%)
Me
Me
Et
O
TBSO
Me
Me
Et
O
TIPSO
Me
Et
O
TIPSO
Me
Bn
Et
O
TIPSOH H
Me
Et
O
TIPSO
Me
Et
O
TIPSO
Me
Et
O
TIPSO
Me
Et
O
TIPSO
OTBS OMOM OH OBz
43% yield92% ee
95% yield92% ee
43% yield88% ee
99% yield85% ee
99% yield92% ee
99% yield87% ee
35% yield82% ee
99% yield91% ee
OP
O O
NH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Tf
When methyl vinyl ketone was used, enantioselectivity decreased to ~50% ee 23
O
Et
HMe
RTIPSO
PN
OO
O
*Tf
O
Et
Me
RTIPSO
PN
OO
O
*Tf
H
H-Bonding ActivationIon-Pair Activation
Me
R
Et
O
TIPSO
no proposed model of stereoinduction mentioned
Could the silylated phosphoramide be the active catalyst?(lewis acid catalysis)
PN
OO
O*
Tf
TIPS
(5 mol%)
OP
O O
NH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Tf
OTIPS
Ph"silylated catalyst"
Et
O
(25 mol%)
CH2Cl2, rt, 30 min -78 °C
Me
MeTIPSO
No Reaction-78 °C, 3 h
(1.5 equiv)
silyl phosphoramide most likely is not the catalyst in the Diels-Alder reaction
Proposed Ac2va2on Mode
Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627.24
PHO
OHO
NH
TfPHO
OHO
OH
Second and third pKa values are about 4 and 5 pKa units lower
OP
O O
NH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
TfO
PO O
OH
i-Pri-Pr
i-Pr
i-Pr
i-Pr
i-Pr
pKa = 4.22 pKa = 3.34
! pKa is about 1 pKa unit
in DMSO (25 °C)
Is the Catalyst a “Stronger” Acid?
Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627.Burlingham, B. T.; Widlanski, T. S. J. Org. Chem. 2001, 66, 7561-7567.Christ, P.; Lindsay, A. G.; Vormittag, S. S.; Neudörfl, J-M.; Berkessel, A.; O'Donoghue, A. C. Chem. Eur. J. 2011, 17, 8524-8528.
Acidity may be playing a role but aryl substituent on BINOL seems to have greatest impact
Still, N-triflyl phosphoramides do tend to activate carbonyls more efficiently than the analogous phosphoric acids
25
An Example of Stronger Acid Ion-‐Pair Ac2va2on
O
Et
HMe
RTIPSO
PZ
OO
O
*
H-Bond/Ion-Pair Activation
26 Rueping, M.; Theissmann, T.; Kuenkel, E.; Koenigs, R. Angew. Chem. Int. Ed. 2008, 47, 6798-6801.
O
EtO2C CF3 R
(1 mol%)
o-xylene, 10 °C, 34 h
Ar = p-MeOC6H4R = arylEtO2C R
HO CF3
OP
O O
NTf
Ar
Ar
Carbonyl-Ene
46 - 96% yield92 - 97% ee
Ac2va2on of Aldehydes: Aza-‐Ene Type Reac2on
Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122-4125.
PO
OO
O
*
HO
HO
OEt
Double H-BondActivation
O
HEtO2C
HNCO2Me
Ph
OP
O O
OH
(5 mol%)
4Å MS, CH2Cl2, rt, 1 hEtO2C
NCO2Me
Ph
OH H3O+
EtO2C
O
Ph
OH
O
HEtO2C
HNCO2Me
Me
OP
O O
OH
(5 mol%)
4Å MS, CH2Cl2, rt, 1 hEtO2C
NCO2Me
Me
OH H3O+
EtO2C
O
Me
OH
93% yield95% ee
78% yield95% ee
Terada (2008)
27
Catalyst Evalua2on
Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122-4125.
OP
O O
OH
Ar
ArO
HEtO2C
HNCO2Me
Ph
H3O+
EtO2C
O
Ph
OH(5 mol%)
Ar Yield (%) ee (%)
4-CH3C6H4
4-CF3C6H4
4-t-BuC6H4
3,5-t-Bu2C6H3
2,4,6-(CH3)3C6H2
93 95
82 94
99 98
37 2
40 -8
CH2Cl2, 4 Å MS, rt, 1 h
High yield and enantioselectivityO
PO O
OH
t-Bu
t-Bu
28
OP
O O
OH
t-Bu
t-Bu(5 mol %)
CH2Cl2, 4 Å MS, rtThen, H3O+
O
HEtO2C
HNCO2Me
R2R1
EtO2C
O
R2
OH
R1
EtO2C
O
R2
OH
R1
EtO2C
O
Ph
OH
Me
(E)-enecarbamates were used (Z)-enecarbamates were used
EtO2C
O
Ph
OH
Me
EtO2C
O
Et
OH
MeEtO2C
O
Et
OH
Me
73% yield>99 : <1 anti:syn>99% ee (anti)53% ee (syn)
73% yield96 : 4 anti:syn99% ee (anti)56% ee (syn)
11% yield72 : 28 anti:syn26% ee (anti)88% ee (syn)
74% yield50 : 50 anti:syn28% ee (anti)69% ee (syn)
EtO2C
OOH
89% yield89 : 11 anti:syn99% ee (anti)98% ee (syn)
Extremely high enantioselectivites and anti selectivities were observed in the reactions of(E)-enecarbamates
Poor enantioselectivities and diastereoselectivities were observed in the reactions of(Z)-enecarbamates
Substrate Scope
Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122-4125.
OP
O O
OH
t-Bu
t-Bu(5 mol %)
CH2Cl2, 4 Å MS, rtThen, H3O+
O
HEtO2C
HNCO2Me
R2R1
EtO2C
O
R2
OH
R1
EtO2C
O
R2
OH
R1
29
OP
O O
OH
OP
O O
OH
MeMe
Me
Me
MeMe
O
HEtO2C
HNCO2Me
Ph
H3O+
EtO2C
O
Ph
OH
93% yield95% ee
O
HEtO2C
HNCO2Me
Ph
H3O+
EtO2C
O
Ph
OH
40% yield8% ee
Double H-bond activationagrees with enantioselectivity
Double H-bond activationcan help explain lack of reactivity
and enantioselectivity
The aryl substituents force a comformational change in catalyst blocking both faces towards attack
Proposed Ac2va2on Mode
PO
OO
O
*
HO
HO
OEt
Double H-bond activation
OP
O O
OH
O
HEtO2C
HNCO2Me
Ph
H3O+
EtO2C
O
Ph
OH
93% yield95% ee
Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122-4125.
30
Examples of Double H-‐Bond Ac2va2on
PO
OO
O
*
HO
HO
OEt
Double H-BondActivation
31
O
H CO2Et
R1
R2
R3
R4
(5 mol %)
toluene, 4 Å MS, rt, 24-48 h
Ar = Phenyl
O
CO2Et
R1
R4
R2
R3
56-95% yield79->99% anti97-99% ee
OP
O O
OH
Ar
Ar
Hetero Diels-Alder
X
O
n
R1O
H CO2R2
X = O, S, CH2
(5 mol %)
toluene, 0-50 °C, 72 h
Ar = 2,4,6-(Me)3C6H2
OP
O O
OH
Ar
Ar
X
O
n
R1 OH
CO2R2
42-86% yield50/50-95-5 syn/anti
48-84% ee
Aldol
Momiyama, N.; Tabuse, H.; Terada, J. J. Am. Chem. Soc. 2009, 131, 12882.Pousse, G.; Le Cavelier, F.; Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett. 2010, 12, 3582.
Chiral Phosphoric Acid Catalyzed Oxida2on
Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, 2840-2843.
Ph OO
OPh
(10 mol %)
H2O2(aq) (30%), CHCl3, -40 °C
R = Pyren-1-yl
OP
O O
OH
R
R
Ding (2008)
99% yield88% ee
RO
PO
OO
O
*
HOH
O H
Bifunctional Activation
32
OP
O O
Z
R
R
OP
O O
Z
R
R
Cat R Z t (h) yield (%) ee (%)
OH
OH
OH
Ph OO
OPh
Cat (10 mol %)
H2O2(aq) (30%), CHCl3, rt
C6H5 24 99 12
24 72 163-MeOC6H4
12 99 184-NO2C6H4
2,4,6-(i-Pr)3C6H2 OH 24 99 37
Phenanthr-9-yl OH 24 72 54
Phenanthr-9-yl NHTf 12 99 5
Pyren-1-yl OH 24 73 57
OH
OH
OH
95 7124Pyren-1-yl
Pyren-1-yl
Pyren-1-yl
OHPyren-1-yl
48
43
18
88
65
99
78 (0 °C)
88 (-40 °C)
88 (-40 °C)
N-triflyl phosphoramide is very activebut gives poor enantioselectivity
Cooling the reaction and washing with4N HCl increases yield
Better reactivity is observed with catalyst that is washed with HCl
More typical effect than the reversal of stereoselectivity discussed earlier
Catalyst Evalua2on
Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, 2840-2843.33
Substrate Scope
Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, 2840-2843.
R1O
OO
R1(10 mol %)
H2O2(aq) (30%), CHCl3, -40 °C
R = Pyren-1-yl
R2
R2
OO
H
OO
H
OO
H
OO
H
OO
H
O O
H
O O
H
Me MeO X
OO
HMe
MeO
O O
H
OMe
MeO
OO
Me
99% yield88% ee
99% yield93% ee
99% yield85% ee
99% yield83% ee (X = Br)82% ee (X = Cl)84% ee (X = F)
91% yield86% ee
(1 mol % cat), 80 h99% yield83% ee
99% yield58% ee
99% yield57% ee
99% yield55% ee
36 h
99% yield61% ee
24 h
OP
O O
OH
R
R
34
PO
OO
O
*RO
OH
POH
OO
O
*P
O
OO
O*
O H O
R
O
O
R
H2O2
H2O
P
OO
OO
*
RP
OH
OO
O
*
O
R
OO
R
H2O2OH
HO O
H
P
O
OO
O
*
R
O
H
OO H
H
H2O
Path A Path B
Experimental data and DFT calculations indicate the oxidation of the catalyst by hydrogen peroxide is unlikely
Based on DFT calculations, the hydrogen bonds lower the energy barrier in both the attack of the peroxide
and the collapse of the Criegee intermediate
Proposed Mechanism
Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, 2840-2843.Xu, S.; Wang, Z.; Li, Y.; Zhang, X.; Wang, H.; Ding, K. Chem. Eur. J. 2010, 16, 3021-3035.
35
Other Examples of Bifunc2onal Ac2va2on
RO
PO
OO
O
*
HOH
O H
Bifunctional Activation
36 T. Sakamoto, T. Itoh, J.; Mori, K.; Akiyama, T. Org. Biomol. Chem. 2010, 8, 5448-5454.Huang, D.; Wang, H; Xue, F.; Guan, H.; Lijun Li, L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350-6353.Chen, X-H.; Qiang Wei, Q.; Luo, S-W.; Xiao, H.; Gong, L-Z. J. Am. Chem. Soc. 2009, 131, 13819-13825.
NH
R1
R2
O (10 mol %)
DCE/Mesitylene (1:1), -40 °C, 3 Å MS
Ar = 2,4-(CF3)2-C6H3
OP
O O
OH
Ar
Ar
R3
1,4 Addition of Substituted Indoles
NH
R1
R2O
R3
37-98% yield58-92% ee
(10 mol %)
CH2Cl2, 0 °C
Ar = 2,4,6-(i-Pr)3C6H2
OP
O O
OH
Ar
ArXH
RX = O, NTs, NTrisyl
XH
R
Br
Bromocyclization
36-97% yieldUp to 91% ee
NAc
O
NH
R1
R2CO2Et
CO2Et
(10 mol %)
CH2Cl2, 3 Å MS, 25 °C
Ar = 2-Napthyl
OP
O O
OH
Ar
Ar
R3
O
R H NAc
O
R2
R3H2NCO2Et
CO2Et
Dipolar Cycloaddition
59-97% yield81-98% ee
N Br
O
O
Reac2ons with Unac2vated Alkenes
Ackerman, L.; Althammer, A. Synlett 2008, 995-998.Althammer, A. Ph.D. Thesis, Georg-August-Universitaet Goettingen, Oct. 2008.
RNuHO
PO O
OH
R
R cat NuR
HR
R
Chiral phosphoric acids have been shown to activate polarized FGs (imines, carbonyls, etc.)
Is it possible to utilize these acids in asymmetric reactions of less polarized FGs?
Potential for reactivity not found in either Lewis acid catalysis or H-bonding catalysis
37
NHBnN
PhPh
Bn
PhPh
Me1,4-dioxane, 130 °C, 20 h
72% yield17% ee
(10 mol %)
OP
O OOH
CF3
CF3
CF3
CF3
Ackerman (2008)
Sole example of this catalyst in asymmetric hydroamination of unactivated alkeneuntil 2011
Intramolecular Hydroamina2on
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.
MeNH
MeMe
TsPZ
YO
O
*
Me
Covalent Activation
NHTsMe
TsN
MeMe
99% yield96% eePhF, 4 Å MS, 23 °C, 48 h
R = 10-(2,4,6-(CH3)3-C6H2)-9-anthracenyl
R
R
OP
O S
SH
(10 mol %)
Toste (2011)
38
R
R
OP
O X
ZH
NHTs
MeMe
Me TsN
MeMe
Me
Me
cat (10 mol %)
solvent, temp, 48 h
Catalyst R substituents Solvent Temp (°C) Yield (%) ee (%)
1 X = Z = S, R = 1-napthyl
2 X = Z = O, R = 1-napthyl
3 X = S, Z = NTf, R = 1-napthyl
4 X = O, Z = NTf, R = 1-napthyl
CDCl3
CDCl3
CDCl3
CDCl3
30
30
30
30
91
0
89
0
41
NA
46
NA
OP
O S
SH OP
O S
NH
Tf
Structure used to guideoptimization
Any derivitization of this thio phosphoramide structure
led to low yields
Intramolecular Hydroamina2on: Ini2al Screen
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.39
30 98 62
15 91 78
15 92 94
R
R
OP
O S
SH
NHTs
MeMe
Me TsN
MeMe
Me
Me
cat (10 mol %)
solvent, temp, 48 h
Catalyst R substituents Solvent Temp (°C) Yield (%) ee (%)
Bulky dithiophosphoric acids 7 and 8 provided the best yields
and enantioselectivities in the hydroamination reaction
5 R = 9-anthracenyl
5 R = 9-anthracenyl
6 R = 10-phenylanthracenyl
7 R = 10-(3,5-bis-t-Bu-C6H3)-9-anthracenyl
8 R = 10-(2,4,6-(CH3)3-C6H2)-9-anthracenyl
CDCl3
PhF
PhF
PhF
PhF
15
23
96
98
96
96
OP
O S
SH OP
O SSH
tBu
tBu
tBu
tBu
Me
Me
Me
Me
MeMe
Intramolecular Hydroamina2on: Op2miza2on
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.40
NHTs
MeMe
TsN
MeMe
NHTsMe
n
TsN
MeMe
n
ONHTs
MeMeMe
Me
ONHTs
OTsN
OTsN Me
Me
MeMe
NHNs
Me
Me
MeMe
NsN
MeMe
MeMe
NHTs
MeMe Me
MeTsN
MeMe
MeEt
7 (10 mol%)
PhF, 4 Å MS30 °C, 48 h
70% yield94% ee
7 (10 mol%)
PhF, 4 Å MS30 °C, 48 h
90% yield, 4.7:1 (E/Z)95% ee (E), 90% ee (Z)
n = 199% yield96% ee
n = 291% yield97% ee
8 (10 mol%)
PhF, 4 Å MS23 °C, 48 h
8 (10 mol%)
PhF, 4 Å MS23 °C, 48 h
81% yield90% ee
8 (10 mol%)
PhF, 4 Å MS23 °C, 48 h
8 (20 mol%)
PhF, 4 Å MS60 °C, 48 h
70% yield90% ee
67% yield92% ee
Dienes Allenes
Substrate Scope R
R
OP
O S
SH
7 R = 10-(3,5-bis-t-Bu-C6H3)-9-anthracenyl8 R = 10-(2,4,6-(CH3)3-C6H2)-9-anthracenyl
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.41
Expansion to (Ac2vated) Carbon Nucleophiles
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.
NMe
EE
MeO
NMe
EE
MeO
75% yield91% ee
R
R
OP
O S
SH
(20 mol%)
PhF, 4 Å MS, 48 h, rt
R = 10-phenylanthracenyl
16 examples of the asymmetric hydroamination reaction
Good yields and ee's
42
Mechanis2c Studies
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.
NHTs
MeMe
Me
NHTs
MeMe
Me
SMe
PSO
O*
Proposed Mechanism
Covalent activation?
NHTs
MeMe
Me
SMe
PSO
O*
Observed in TOF-MS of aliquotsfrom reaction mixture
PPhPh
S
SHD S
PPh
Ph
S
1:1 CDCl3/D2O
23 °C, 48 h
>95% D incorportation
>95% cis product
PEtOEtO
S
SHPPhO
PhO
S
SH
Labile under D2O conditions
43
Probing the Hypothesized Mechanism
NHTs
MeMe
Me
NHTs
MeMe
Me
SMe
PSO
O*
SN2'TsN
MeMe
Me
Me
Proposed Mechanism
NHTs
MeMe
Me
SMe
PSO
O*
SN2'TsN
MeMe
Me
Me
SDP
SOONH
MeMe
R
SP
S OO
D
H
NHR
MeMe SH
PSO
ON D
HMe
Me
R
syn addition1,4 syn product
44 Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G. J. Mol. Struct. 1983, 103, 197-208.Borrmann, T.; Stohrer, W-D. Liebigs Ann. 1996, 1593-1597.
NH
MeMe
SO2
MeO
DNSO2
MeMe
MeO
Br
Br
OP
O S
SD(+/-)
1:1 CDCl3/D2O, 50 °C, 48 h
4:1 cis/trans
When using TfOD as a catalyst: 1:1 cis/trans
NH
MeMe
SO2
MeO
DNSO2
MeMe
MeO
Br
Br
OP
O S
SD(+/-)
1:1 CDCl3/D2O, 50 °C, 48 h
4:1 cis/trans
When using TfOD as a catalyst: 1:1 cis/trans
SN2' reactions are known to proceedvia a syn pathway
(producing the observed product)
No Other Proposals of Covalent Ac2va2on
MeNH
MeMe
TsPZ
YO
O
*
Me
Covalent Activation
45
Overview
NR2
HR1
H
PO
OO
O*
N
HR1
PO
OO
O* O
H
H
MeNH
MeMe
TsPZ
YO
O
*
Me
Dual Activation
Covalent Activation
H-Bond/Ion-Pair Activation
O
Et
HMe
RTIPSO
PZ
OO
O
*
RO
PO
OO
O
*
HOH
O H
Bifunctional Activation
H-Bond/Ion-Pair Activation
PO
OO
O
*
HO
HO
OEt
Double H-BondActivation
46
Expanding A Young Field
47
Stereochemical Induction
Arene - Arene Interactions
H-bonding/Ion-Pair Activation
Exploration of New Reactivity
Rueping, M.; Uria, U.; Lin, M-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732-3735.
Ar
Me OH
OH O
Me
Ar80 - 95% yield84 - 94% ee
R
R
OP
O O
NHTf
(5 - 10 mol%)
toluene, -78°C
Allylic Substitution via Chiral Ion-Pair
Ar
Me OH
OH O
Me
Ar80 - 95% yield84 - 94% ee
R
R
OP
O O
NHTf
(5 - 10 mol%)
toluene, -78°C
Allylic Substitution via Chiral Ion-Pair
Ar
Me
OH
PNTf
OO
O
*
Acknowledgments
48