catalytic asymmetric intramolecular pauson-khand...
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Catalytic Asymmetric Intramolecular Pauson Khand and Pauson Khand TypePauson-Khand and Pauson-Khand-Type
Reactions
Steven BallmerCHEM 535 S iCHEM 535 Seminar
October 9, 2008University of Illinois at Urbana-Champaign
Copyright © 2008 by Steven Ballmer
Synthetic Challenges
Co-Mediated [2+2+1] Cycloaddition1
Co Co
R1 R2
OC
OC
OCCO
CO
COO
HH
R2R1
+60-70 °C, 4 h
tolueneR2R1
Co2(CO)8
H H Ph EtH
hexacarbonyldicobaltalkyne complex
cyclopentenone
OHH
MeH
OHH
PhH
OHH
PhPh
OHH
EtEt
OHH
HH
43% 33% 45% 28% 23%
Co Co
OC CO
COR2
R1
R1
Side Products
CO
COOC
Co Co
OC
C COOC
CoOC CO
cyclopentadienylcobalt
(retro Diels Alder)norbornadiene
complexesO
HH
R2R1
O
OHH O
HR2
HHR2
diketones
Pauson and coworkers J. Chem. Soc., Perkin Trans. 1 1973, 977.
Pauson and coworkers J. Chem. Soc., Perkin Trans. 1 1973, 975.
CO
COOC(retro Diels-Alder) complexesHH H R1
Proposed Mechanism
Co Co
OC
C
COCO
CO
OCOC
OCCo Co
R1
OC
OC COCo Co
R1
OCCO
COdissociationX
R1 XR
XR
alkynecomplexation
CO
COOC OCOC
COCO OC CO
CO
R1
R
X X
COenyne
2CO
Co Co
R1
OCOC
CO
CO
CO
RCo Co
R1
OCOC
CO
CO
CO
RCo Co
R1
OC
OCCO
CO
COR
alkenecoordination isomerization
alkeneinsertion
X
OC OC CO
R1 Co(CO)3CO reductive
li i tireductive
lialkyl
XXX
Co Co
R
OCCO
CO
CO
R
OO
R R1
OC
OC
O
R R1
Co( )3
COCO
Co2(CO)6
eliminationcouplingmigration
+ CO
bicyclicc clopentenone
Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851.
Magnus and coworkers Tetrahedron 1985, 41, 5861.
cyclopentenone
Mechanistic Calculations
DFT (VWN/PW91xc) methodology
ethylenecoordination
acetylenecomplex
Pericàs and coworkers Pure Appl. Chem. 2002, 74, 167.
Pauson-Khand Reaction Promoters
Support for Proposed Mechanism
Co CoOC
OCCO
CO
CO
SMe OC
bishomopropargylic sulfide complexMixed Ar/N2 Matrix
bishomopropargylic sulfide complex
NMO H2O,DCM, rt, 5 d
Co CoOC
S
CO
CO
CO
Me
10-6 mbar12 K
OC CO
isolable pentacarbonyl complex
O
SMe
Gordon and coworkers J. Organomet. Chem. 1998, 554, 147.Krafft and coworkers J. Am. Chem. Soc. 1993, 115, 7199.
bishomoallylic sulfide
MS Support for Proposed MechanismH Ph
ESI collision-activated reaction (CAR) MS/MS- CO dissociation occurs first
Co CoOC
Ph2PCO
CO
PPh2
OC
H Ph
m/z = 716.0Idppm
Co Co
H Ph
OC CO
CO
Co CoOC
Ph2PCO
CO
PPh2 Ea = 34 kcal/molPh2P PPh2
m/z = 781.1
H Ph
[Idppm - H - CO]-
DFT calculations(B3LYP/LANL2DZ*)
Co CoOC
Ph2PCO
CO
PPh2
[Idppm - H - 2CO]-Ea = 12 kcal/mol
Gimbert and coworkers Org. Lett. 2003, 5, 4073.
X-Ray Crystal Support for Mechanism
OHOH
Co
Co
OCCO
OCOC
OCCo Co
OC CO
CO COOC
CO
hexacarbonyl alkyne complex η2-alkene pentacarbonyl alkyne complex
COCC
COH
Ph
HO Ph
Co2(CO)8
THF, rt, 15h
CoOC CO
OC
COPh O Ph
Evans and coworkers Angew. Chem. Int. Ed. 2007, 46, 2907.
η2-alkene pentacarbonyl alkyne complex (viewed down Co-Co bond)
Pauson-Khand Regioselectivity
Catalytic and Intramolecular Pauson-KhandFirst Intramolecular
First Catalytic
Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436.
Jeong and coworkers J. Am. Chem. Soc. 1994, 116, 3159.
Asymmetric Catalytic CycleCO
RO Cl M
P
OC MPP
CO
Cl
reductive*
*
chiralcatalyst
metallacyclohexenone+ CO
- CO
R
MX
PP
Cl
R
Cl MPelimination
-
*
* *
carbonX O
R R
XCOinsertion
complexationCO * enyne
bicycliccyclopentenone
monoxide
X MPP
Cl
RX M P
PCl
RX
oxidativeaddition
*
**
*
catalyst/enynecomplex
metallacyclpentene
+ CO
- COX M P
COCl
P*complex
CO pressure-dependenceti t d ith i d CO-reaction rate decreases with increased CO pressure
-enantioselectivity decreases with increased CO pressure
Reagent-Directed StereocontrolR
P filledfilled
open
open
Ph Ph
Co
COCOCO
CO
Open/ClosedQuadrantsP
P
Ph Ph
Ph
CoCo
XH
((S)-BINAP)Co2CO6
P filled open
PhPh
Co
COCO
CO
PhP P
PhCo Co
PhPhCO ligandsnot shown
CO ligands not shown
X O
R
X O
R
Ph Ph COCO
HHR isomer S isomer
Co CoP PPh
Ph
P
P
PhPh
Co
Co
CO
COCO
CO
filledfilledopen
open
Open/ClosedQuadrants
((R) BINAP)Co CO P
Ph PhR
CO ligandst h
Ph
CO ligands not shownfilledopen((R)-BINAP)Co2CO6 P
P
Ph Ph
CoCo
not shown
HX
Substrate-Directed StereocontrolH
CoR1R2
H H
(CO)3 R2
R1
O
R
H
R1R2
H H
RCo2(CO)8
R1
HH H
HH
Co
H
R
R(CO)2
O
R
H
R1
R2H
RR2
RH
chairconformer
favoredolefin rotamer
R isomerR
R1
R2
olefin rotamer
R2
R1
O
R
H
R1R2
H
H
disfavoredolefin rotamer
Co1
H
(CO)3
Co2(CO)8
R1H H
H
O
RR1
R2
H
R RR
H
Co
H
R1R2
R(CO)2
HCo2(CO)8H
R2 Rchairconformer
H
H
H
HS isomer
Development of Cobalt Catalysts
RX
20 mol %((S)-BINAP)Co2CO6 X O
R
DME, reflux,1 atm CO H1 atm CO
14 h 24 h 24 h 15 h60% i ld
14 h
O
H
HMeO2CMeO2C
O
H
MeMeO2CMeO2C
O
Me
MeMeO2CMeO2C TsN O
H
H
TsN O
H
Me
14 h53% yield90% ee
31% yield63% ee
90% yield0% ee
60% yield93% ee
13% yield62% ee
P
Ph PhR
HPh Ph
R
R
H Me Me
R P
P
PhPh
CoCo
CO ligandsnot shown
X
HP
P
PhPh
CoCo
XX O
H
favored
H
disfavoredX O
R
H
Hiroi and coworkers Tetrahedron Lett. 2000, 41, 891.Hiroi and coworkers Tetrahedron: Asymmetry 2000, 11, 797.
Development of Rhodium Catalysts
Jeong and coworkers J. Am. Chem. Soc. 2000, 122, 6771.
Development of Iridium Catalysts
Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852.
Development of Titanium Catalysts
Buchwald and coworkers J. Am. Chem. Soc. 1996, 118, 9450.Buchwald and coworkers J. Am. Chem. Soc. 1996, 118, 11688.
Expansion of Substrate Scope
XR
•
X
RR1
R
MeO2C
MeO2C
R2R1
allenynes dienenesdienynes
X O
R
X
R
OX O
H
HR
R1X O
H
HR
R1
MeO2CMeO2C
R
O
HR2
R1
dienylcyclopentenones
-methylenecyclopentenones
R1R2
vinylcyclopentenones
vinylcyclopentanones
-methylenecyclopentanones
X
• R2
R3
X O
R3R2
H
H
X•
PhO2S
OX
SO2Ph
RRH H
-methylene vinylcyclopentanones
allenenes cyclopenteonesdiene-allenes
Bicyclic Dienones from Allenynes
XR
•
XR
•MM X
R
•XX
R
O O
RCOCO M M
bi li di ll
non-catalyticnon-asymmetric
bicyclic dienone -methylenecyclopentenone
allenyne
non asymmetric
X•
MeS
X O
MeS
Fe(CO)5, TMANO, THF
rt, h (100 W)
O O OHO Ph Ph
O
MeS 60%
O
SMe
OO
SMeSMe
O
SMe45%15% 30%19%
Fe(CO)3
cyclopentadienoneiron complex
Narasaka, K.; Shibata, T. Chem. Lett. 1994, 315.
iron complex
α-Methylene Cyclopentenones from Allenynesy
XR
•
XR
•MM X
R
•XX
R
O O
RCOCO M M
non-catalytic
bicyclic dienone -methylenecyclopentenone
allenyne
non-asymmetricMo(CO)6 (1.2 equiv), DMSO
PhMe, 100 °C, 3 hX O
TMS
XTMS
•
triquinane sesquiterpenesmethylenomycin antitumor agents
O
TMS
O
TMS
O
TMS
O
TMS
MeMe
HO Me68% 47% 30% 0%
no cycloaddition
TMS
•
Me
Brummond and coworkers Tetrahedron Lett. 1995, 36, 2407.
-no cycloaddition-starting material decompostion
Vinyl Cyclopentenones from DienynesRR
MeO2C
MeO2C
R2
[RhCl(CO)(PPh3)2], AgSbF6
DCE, CO
R1
MeO2CMeO2C
R
O
HR2
R1
MeO2C
Me
OMeO2C
TMS
OMeO2C
O
89% 85% 43%1 mol% Rh, Ag1 atm COrt, 14 h
2 mol% Rh, Ag2 atm COrt 12 h
1 mol% Rh, Ag1 atm COrt, 40 h
MeO2CO
HMeO2C
O
HMeO2C
O
Hi-Pr i-Pr i-Pr
rt, 12 h
5 l% Rh A 1 mol% Rh Ag
MeO2CMeO2C
Me
O
H
MeO2CMeO2C
O
H
96% 45% 42%MeO2CMeO2C
O
H Me
1 mol% Rh, Ag1 atm COrt, 24 h
5 mol% Rh, Ag1 atm COrt, 32 h
1 mol% Rh, Ag1 atm COrt, 30 h
MeO2CM O C
Me
O MeO2C
Me
OMeO2C
Me
O
86% 90% 96%2.5 mol% Rh, Ag2 atm CO40 °C, 12 h
2.5 mol% Rh, Ag1 atm CO40 °C, 12 h
2.5 mol% Rh, Ag2 atm CO40 °C, 10 h
Wender and coworkers Angew. Chem. Int. Ed. 2003, 42, 1853.
MeO2CH
MeO2CH
MeO2CHMe Me
Vinyl Cyclopentanones from Dienenes
Wender and coworkers J. Am. Chem. Soc. 2004, 126, 5948.
α-Methylene Cyclopentanones from Diene-Allenes
Wender and coworkers Angew. Chem. Int. Ed. 2006, 45, 2459.
Bicyclo[5.3.0]decenones from AllenenesPhO2S
SO PhSO Ph
X•
OX
SO2Ph
OX
SO2Phisomerization to, -unsaturated
ketone
[RhCl(CO)2]2, CO
PhMe, 120 °C
H
OO
H
SO2PhSO2Ph
MeO2CMeO2CPhO2S
PhO2S49%36%
73%25:75
5 mol% Rh10 atm CO
82%35:65
10 mol% Rh10 atm CO
47%60 40
10 mol% Rh10 atm CO
H H
SO2Ph SO2PhSO2Ph
49%15:85
cis:trans
36%60:40
cis:trans2.5 mol% Rh5 atm CO
5 mol% Rh10 atm CO
25:75cis:trans
35:65cis:trans
60:40cis:trans
TsN OO OO
H HH
SO2Ph SO2Ph2
33%93:7
cis:trans
73%80:20
cis:trans
30%100:0
cis:trans
10 mol% Rh10 atm CO10 mol% Rh
10 atm CO10 mol% Rh10 atm CO
SO2Ph
cis:trans10 atm CO
•PhO2S
MeO2CM O C
•PhO2S
MeO2CM O C
[2+2]adduct
5 mol% [RhCl(CO)2]2,5 atm CO
Mukai and coworkers Org. Lett. 2006, 8, 1217.
MeMeMeO2C
MeO2C
68%Me
MeO2C
Me
MeO2CMe
adductPhMe, 120 °C
olefin isomerizationRh
Applications in Synthesis
Synthesis of Isocarbacyclin
OO
MeMe
1 atm CO,5 mol% (CO)6Co2-(2-methyl-3-butyn-2-ol)
OO
H
MeMe
10 mol% Et3SiH 10 mol% CyNH21+
O O
OHHO
H
OHHO
TMS O
TMS
H10 mol% Et3SiH, 10 mol% CyNH2,DME, 65 °C, 15 min;
1, reflux, 6 h
(CO) C (2 th l 3 b t 2 l)
1
51%
33%OHHO
L-ascorbic acid
Livinghouse conditions(CO)6Co2-alkyne complexes
as Co2(CO)8 surrogates
(CO)6Co2-(2-methyl-3-butyn-2-ol)
HO MeMe
(OC)6Co2
H H Me
CO2H
4
3Me
HMe
(CO)3Me
(CO)3
OHOH
isocarbacyclinCo
Co
H
O
O HMe
TMS(CO)2
Co
Co
H
O
OMe
TMS(CO)2
H
Saito and coworkers J. Org. Chem. 2004, 69, 8133.
-Prostacyclin (PGI2) analogue-metabolically stable
Synthesis of Steroidal Skeletons
Chung and coworkers J. Org. Chem. 2006, 71, 8264.
Synthesis of (-)-Pentalenene
-unnatural enantiomer of triquinane
Fox and coworkers Org. Lett. 2007, 9, 5625.
natural product-bio precursors to pentalenolactone
antiobiotics
Synthesis of Tricyclic Sesquiterpenoids
MeTBSO
MOMO•
CO Me
O
MeTBSO
MOMO5 mol% [RhCO(dppp)2]Cl,
1 atm CO, PhMe,reflux, 1 h
74%
HOHO
Me
H
MOMO CO2Me CO2Me
H RhLO
H H
H
H
H
Me CO2Me
MOMOTBSO
RhLn
O
O
HO
OMeMeMe
equatorial chair
MOMO HMe MeH
AcO
Ac2O, TEA, DMAP,DCM, 0 °C to rt
HOO
equatorial, chair
H
MeO2COTBS
RhLn
H
MOMORhLnTBSO
CO2Me
AcOMe
H H
H
dimethylD-tartrate
HO
HO
OMeOMe
Oaxial, chair equatorial, boat
Mukai and coworkers Org. Lett. 2008, 10, 2385.
isolated from Jatropha neopauciflora
Conclusion and Future Directions
Conclusion and Future Directions
• The Pauson-Khand reaction is a highly versatile and efficient transformation for the synthesis of cyclopentenones.
• The Pauson-Khand reaction enables construction of complex molecules in a convergent and atom economic fashion from structurally simple precursors.
• The catalytic, asymmetric, intramolecular variant is highly enabling for the synthesis of stereodefined bicyclic cyclopentenones.
• Reagent-directed stereocontrol absent in context of complex g pmolecule synthesis.
• Further research must seek out more general conditions for the catalytic, asymmetric, intramolecular Pauson-Khand reaction.y , y ,
Acknowledgements
Prof. Scott E. DenmarkCHEM 535 class
Prof. Martin D. BurkeBurke Group