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Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Long LiteratureBenoit Cardinal-David
October 2009
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Cat*
Y R
Z
Y Y
Z
Key Reference:
Chapter 10Recent Advances in Catalytic
Asymmetric DesymmetrizationReactions
Some Definitions
Desymmetrization: The removal of an element of symmetry from a symmetric object
Asymmetric Desymmetrization or Enantioselective Desymmetrization
Redundancy?
Some Definitions
Desymmetrization: The removal of an element of symmetry from a symmetric object
Asymmetric Desymmetrization or Enantioselective Desymmetrization
Redundancy?
Y Y
Non Asymmetric Desymmetrization
R
Y R
Y Y
R
Y R
ZZ
Asymmetric Desymmetrization
Some Definitions
Cat*Y
X
Z Z
Y
enantiotopic groups
Enantioselective Desymmetrization
R
Y
X
Z Z
R
Enantiotopic group
selection
meso
Not Covered Here …
• Enzymatic Desymmetrization
• Stoechiometric Desymmetrizations
Ex.: Enantioselective Ketone Desymmetrization
Me
Me
O
Ph NLi
Ph
Me Me
TMSCl
THF, -78 oC
Me
Me
OTMS
1. O3, -78 oC
2. NaBH4
98% ee
81% yieldover 2 steps
HO2C OH
Me Me
Berkowitz, W. F.; Wu, Y. J. Org. Chem. 1997, 62, 1536.
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Benzoylation of Meso Diols:Trost’s Dinuclear Asymmetric Zinc Catalyst
Trost, B. M.; Mino, T. J. Am. Chem. Soc. 2003, 125, 2410.
Trost, B. M. et al, Chem. Eur. J. 2008, 14, 7648.
OH
Me
NN
OHAr
ArHO
ArAr
Ar =
A
OH
R
OH 5 mol% A
10 mol% Et2Zn
Toluene, -15 oCO
O
Ph
OBz
R
OH
Best enzymatic desymmetrization result for R = Me: 70% yield, 60% ee
OBz OH
OBz OH
OMe
OBz OH
Cl
OBz OH
94% yield
91% ee
99% yield
93% ee
89% yield
90% ee
97% yield
93% ee
OBz OH
S
OBz
Me
OH
78% yield
70% ee
88% yield
90% ee
Desymmetrization of 2-Substituted 1,2,3-Propanetriols
Jung, B.; Kang, S. H. Proc. Natl. Acad. Sci. USA 2007, 104, 1471.
A
N
Br
N
N
O
t-Bu
Ph
HO
OH
RCu
ON
Ph
t-Bu
N
H
N
Br
OHCl O
Ph
OH OH
RHO
10 mol% A
10 mol% CuCl2BzCl (1.1 equiv.)
Et3N (1.2 equiv.)
THF, rt
OBz OH
HO R
OBz OH OBz OH OBz OH
OBz OH
99% yield
92% ee
99% yield
93% ee
99% yield
94% ee
99% yield
95% ee
OBz OH OBz OH
99% yield
92% ee
99% yield
95% ee
HO HO HO
HO HO HO
Ph CH2OBn Bn
n-Bu i-Pr Me
NHC Catalyzed Desymmetrization cis-1,2-Cyclohexane Diol
Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371.
OH
OH
N
O
NN
Mes
BF4
Ph
O
H
30 mol% K2CO3
15 mol% 18-crown-6
MnO2 (15 equiv.)
Proton sponge (1 equiv.)
CH2Cl2, -30 oC
58% yield
80% ee
OH
O
O Ph
30 mol%
Miller’s Remote Desymmetrization of a Bis-PhenolCatalyzed by a Small Peptide
Miller, S. J. et al, J. Am. Chem. Soc. 2008, 130, 16358.
Miller, S. J. et al, J. Am. Chem. Soc. 2006, 128, 16454.
HO
MeMe
Me
OH
2.5 mol% Peptide
Me
O
O
O
Me
80% yield
95% ee
CHCl3, -30 oC
HO
MeMe
Me
OAc
BOCHN
HN
NH
HN
NH
HN
O
O MeMe
N
N
Me
O
NHTrt
O
O-t-Bu
O
O
O
OMe
Bn
Peptide
Miller’s Remote Desymmetrization of a Bis-PhenolCatalyzed by a Small Peptide
Miller, S. J. et al, J. Am. Chem. Soc. 2008, 130, 16358.
Miller, S. J. et al, J. Am. Chem. Soc. 2006, 128, 16454.
BOCHN
HN
NH
HN
NH
HN
O
O MeMe
N
N
Me
O
NHTrt
O
O-t-Bu
O
O
O
OMe
Bn
Peptide
R % Yield % ee
Ph
Me
Et
i-Pr
40
42
60
62
50
52
63
73
Drawback: Peptide is Substrate specific ...
HO
R
OH
2.5 mol% Peptide
Me
O
O
O
Me CHCl3, -30 oC
HO
R
OAc
Enantioselective Silyl Protection of AlcoholsCatalyzed by an Amino-Acid Based Small Molecule
Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.;Snapper, M. L. Nature 2006, 443, 67.
N
N
HO OH
HO OH
Me
NH
O
HN Me
t-Bu
t-Bu20-30 mol%
TBSCl, Hunig's
TBSO OH
TBSO OH
Entry Product % Yield % ee
OTBS
OH
OTBS
OH
OH
OTBS
OTBS
OH
1
2
3
4
55 87
82 96
96 88
82 92
Entry Product % Yield % ee
OTBS
OH
OTBS
OH
Me
Me
OTBS
OH
5
6
7
93 93
96 95
84 90
Enantioselective Silyl Protection of AlcoholsCatalyzed by an Amino-Acid Based Small Molecule
Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443, 67.
N
N
HO OH
HO OH
Me
NH
O
HN Me
t-Bu
t-Bu20-30 mol%
TBSCl, Hunig's
TBSO OH
TBSO OH
Proposed Transition State Model
OO
O
NN
H
Me
Me
H
Me
Me
t-Bu
H
N
N
Me
H
H
H
Si
Me
MeCl
t-Bu
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Desymmetrization of Cyclic Anhydrideswith Modified Cinchona Alkaloids
Entry Product % Yield % ee
1
2
3
90 95
95 97
85 96
O
H
H
O
O
CO2Me
CO2H
H
H
O
Anhydride
O
O
H
H
CO2Me
CO2H
H
H
O
O
O
O
OCO2H
CO2Me
O
O
O
Me
MeCO2Me
CO2HMe
Me
OMe
O
O
CO2H
CO2Me
Me
4
5
88 98
56 91
N
O
N
OMe
DNQ (dihydroquinyl)
N
O
N
OMe
HH
DHQD (dihydroquinidyl)
OO
DHQDDHQD
(DHQD)2AQN
OO
DHQDHQ
(DHQ)2AQN
or
5-30 mol% (DHQD)2AQN or (DHQ)2AQN
MeOH
-30 oC, Et2O
Conditions:
Deng, L. et al, J. Am. Chem. Soc. 2000, 122, 9542.
Cinchona Alkaloids-Derived Bifunctional Catalystsfor Desymmetrization of Meso Anhydrides
N
NH
S
O
O
CF3
F3C
N
MeO
H
H
A
Chin, J. et al, Angew. Chem. Int. Ed. 2008, 47,7872.
Entry Product % Yield % ee
1
2
92 96
90 96
O
Anhydride
O
O
H
H
CO2H
CO2Me
H
H
O
O
O
Me
MeCO2H
CO2MeMe
Me
OMe
O
O
CO2Me
CO2H
Me
3 88 95
95 91
O
O
O
CO2Me
CO2H
4
5 mol% AMeOH
Et2O, rt
Conditions:
Improvement:
- Lower Catalyst Loading
- Reactions performed at rt
Transtion State Model
Chin, J. et al, Angew. Chem. Int. Ed. 2008, 47,7872.
N
MeO
N
O
O
OO
H
Me
S
O
O
CF3
CF3
H
For another example using cinchona alkaloid-derived thioureas, see:
Connon, S. J. et al, J. Org. Chem. 2008, 73, 2454.
Alkylative Desymmetrization of Cyclic Anhydrides
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248.
FePh2P
PCy2
Me
(R,S)-JOSIPHOS
Entry Product % Yield % ee
1
2
74 89
89 94
O
H
H
O
O
CO2H
H
H
O
Anhydride
O
O
H
H
CO2H
H
H
O
O
O
Me
MeCO2H
Me
Me
3 72 92
O
O
Ph
Ph
O
Ph
O
O
O
R
R
5 mol% Pd(OAc)2
6 mol% JOSIPHOS
Ph2Zn (1.1 equiv.)
R
O
Ph
R
O
OH
THF, rt
Alkylative Desymmetrization of Cyclic Anhydrides
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248.
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174.
FePh2P
PCy2
Me
(R,S)-JOSIPHOS
80% yield91% ee4-fluoro-styrene
Prevents β-hydride eliminationof the presdumed acyl-ethyl Nickel intermediate
O
O
O
H
H
O
Et
H
HCO2H
10 mol% Ni(COD)2
12 mol% i-PrPHOX
Et2Zn (1.2 equiv.)
THF, rt
25 mol% 4-Fluoro-styrene
Entry Product % Yield % ee
1
2
74 89
89 94
O
H
H
O
O
CO2H
H
H
O
Anhydride
O
O
H
H
CO2H
H
H
O
O
O
Me
MeCO2H
Me
Me
3 72 92
O
O
Ph
Ph
O
Ph
O
O
O
R
R
5 mol% Pd(OAc)2
6 mol% JOSIPHOS
Ph2Zn (1.1 equiv.)
R
O
Ph
R
O
OH
THF, rt
Alkylative Desymmetrization of Cyclic Anhydrides
FePh2P
PCy2
Me
(R,S)-JOSIPHOS
80% yield91% ee4-fluoro-styrene
Prevents β-hydride eliminationof the presdumed acyl-ethyl Nickel intermediate
Drawbacks - Only with succinic anhydrides
- Only with commercially available R2Zn (R = Alkyl, Aryl)- In situ prepared nucleophiles failed
O
O
O
H
H
O
Et
H
HCO2H
10 mol% Ni(COD)2
12 mol% i-PrPHOX
Et2Zn (1.2 equiv.)
THF, rt
25 mol% 4-Fluoro-styrene
Entry Product % Yield % ee
1
2
74 89
89 94
O
H
H
O
O
CO2H
H
H
O
Anhydride
O
O
H
H
CO2H
H
H
O
O
O
Me
MeCO2H
Me
Me
3 72 92
O
O
Ph
Ph
O
Ph
O
O
O
R
R
5 mol% Pd(OAc)2
6 mol% JOSIPHOS
Ph2Zn (1.1 equiv.)
R
O
Ph
R
O
OH
THF, rt
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248.
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174.
Hypotheses
• The presence of halides / triflates from the in situ formation of mixed organozinc nucleophiles
inhibit the reaction with Pd(II).
• Rh(I) / Rh(III) couple tolerates nucleophiles (and aqueous conditions) at high temperaturtes,
as demonstrated by Hayashi:
Hayashi, T. et al, Chem. Rev. 2003, 103, 2829.
Nuc Brt-Bu-Li
Nuc Li
LiBr
Zn(OTf)2Nuc ZnOTf
LiOTf
Rhodium Catalyzed Desymmetrization of Meso Anhydrideswith Mixed Organozinc Reagents
Johnson, J. B.; Bercot, E. A.;Williams, C. M.; Rovis, T. Angew.
Chem. Int. Ed. 2007, 46, 4514.
O
O
O
Me
Me
Nuc-Li / Zn(OTf)2(1:1)
4 mol% [Rh(cod)Cl]28 mol% Ligand
DMF, 50 oCNuc
O
CO2H
Me
Me
O
P
O
N
PhPh
PhPh
O
O
Me
Me
Ligand
O
CO2H
Me
Me O
CO2H
Me
Me
F
O
CO2H
Me
Me
O
Me
O
CO2H
Me
Me
N
Me
O
CO2H
Me
Me
O
O
MeO
75% yield
85% ee
78% yield
87% ee
82% yield
85% ee
84% yield
86% ee
88% yield
88% ee
Rhodium Catalyzed Desymmetrization of Meso Anhydrideswith Mixed Organozinc Reagents
Johnson, J. B.; Bercot, E. A.;Williams, C. M.; Rovis, T. Angew.
Chem. Int. Ed. 2007, 46, 4514.
O
O
O
Me
Me
Nuc-Li / Zn(OTf)2(1:1)
4 mol% [Rh(cod)Cl]28 mol% Ligand
DMF, 50 oCNuc
O
CO2H
Me
Me
O
P
O
N
PhPh
PhPh
O
O
Me
Me
Ligand
Drawback - Only with succinic anhydrides
O
CO2H
Me
Me O
CO2H
Me
Me
F
O
CO2H
Me
Me
O
Me
O
CO2H
Me
Me
N
Me
O
CO2H
Me
Me
O
O
MeO
75% yield
85% ee
78% yield
87% ee
82% yield
85% ee
84% yield
86% ee
88% yield
88% ee
Desymmetrization of meso-3,5-Dimethyl Glutaric Anhydrides:Synthesis of syn-Deoxypolypropionate Molecules
Cook, M. J.; Rovis, T.
J. Am. Chem. Soc. 2007, 129, 9302.
5 mol% [Rh(nbd)Cl]210 mol% t-Bu-PHOX
1.7 equiv. RZnX
THF, 50 oC
CO2Me
Me
O OO
Me Me
O
R
Me
then diazomethane
Me
O
Me
85% yield
95% ee
O
OMe
Me
O
Me
80% yield
94% ee
O
OMe
Me
Me
O
Me
66% yield
89% ee
O
OMe
Me
AcO
O
Me
76% yield
94% ee
O
OMe
Me
Cl
Me
O
Me
85% yield
95% ee
O
OMe
Me
O
Me
85% yield
95% ee
O
OMe
Me
Ph
t-Bu-PHOX
PPh2
O
N
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Desymmetrization Ruthenium-Catalyzed Hydrogen Transfer
Noyori, R. et al, Angew. Chem. Int. Ed. 1997, 36, 208.
OH
OH
H
H
Acetone
0.2 mol% A
OH
O
H
H
70% yield
96% ee
N
Ru
N
Me
Me
Me
Ts
Ts
A
Only one example
Palladium-Catalyzed Oxidation with Molecular Oxygen
Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725.
OH
OH
5 mol% Pd(nbd)Cl220 mol% sparteine
Toluene, 80 oC, O2
3A Mol. sieves
O
OH
72% yield
95% ee
Only one example
Desymmetrization of meso-Secondary Allylicand Homoallylic Alcohols
Li, Z.; Zhang, W.; Yamamoto, Y. Angew. Chem. Int. Ed. 2008, 47, 7520.
R1 R1
OHR2
R3 R3
R21 mol% VO(OiPr)32 mol% A, B or C
TBHP (1.2 equiv.)
CH2Cl2, 0 oC or -10 oC
R1 R1
OHR2
R3 R3
R2
O
N
N
O
Ph
Ph
OH
O
OH
Ph
Ph
A B, R = Ph
C, R = p-Mes-C6H4
N
N
OCR3
OH
O
OH
CR3
OH
51% yield
92:8 dr
97% ee
OH 2 mol% VO(OiPr)34 mol% C
CHP (1.2 equiv.)
CH2Cl2, 0 oC or -10 oC
O
Ph Ph
OHO
52% yield
94:6 dr
95% ee
OHO
62% yield
99:1 dr
95% ee
Me Me
OHO
52% yield
98:2 dr
95% ee
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Asymmetric Desymmetrizationby Opening of meso-Epoxides and Aziridines
Cat*X
X = O, NR
R RR R
HX Nu
Nu
Two Major players:E. N. Jacobsen, M. Shibasaki
Important area of Research:• Substrates easy to prepare
• Rapid access to useful building blocks(1,2-amino alcohols, 1,2-diamines, β-amino acids)
Desymmetrization by Opening of Epoxides with TMSN3Catalyzed by (salen)Cr(III) Complexes
Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N.J. Am. Chem. Soc. 1995, 117, 5897.
Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
O
RR
TMSN3
1. 2 mol% A, Et2O
2. CSA, MeOHR R
N3 OH
80% yield
88% ee
N3 OHN3 OH
NCOCF3
N3 OH
Me Me
N3 OH
97% yield
93% ee
87% yield
95% ee
65% yield
82% ee
N3 OH
O
77% yield
94% ee
N N
OO
t-Bu
t-Bu t-Bu
Cr
Cl
t-Bu
A
Ring Opening of meso-Epoxides with TMSCNCatalyzed by (pybox)Lanthanide Complexes
Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001.
90% yield
91% ee
TMSO CNTMSO CN
NCOCF3
TMSO CN
Me Me
TMSO CN
83% yield
92% ee
72% yield
87% ee
80% yield
90% ee
NO
N N
O
RR
A, R = t-Bu
B, R = Ph
Reaction time: 4-7 days
O
RR
TMSCN
10 mol% YbCl3
12 mol% A or B
R R
TMSO CN
CHCl3
Ring Opening of meso-Epoxides with Phenolic OxygenNucleophiles Catalyzed by
Gallium Heterobimetallic Complexes
Shibasaki, M. et al, J. Am. Chem. Soc. 2000, 122, 2252.
O
RR
10 mol% A
R R
HO OAr
MeO OH
Toluene,
4A mol. sieves
O
O
O
Li
Ga
O
A
Drawbacks• Low reactivity: Reaction time = 4-7 days
• High catalyst loading
72% yield
91% ee
HO OArHO OAr
Me Me
HO OAr
88% yield
85% ee
72% yield
91% ee
Solution by Jacobsen: Oligomeric (salen)Co Complexes
Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687.
Key: Monomeric salen complexes operate by a second-order mechanism.
Hypothesis: Oligomeric catalysts would improve the reactivity by minimizing the entropy cost.
Co(salen)
Linker
Co(salen)
Linker
n
n = 1-5
Solution by Jacobsen: Oligomeric (salen)Co Complexes
Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687.
Key: Monomeric salen complexes operate by a second-order mechanism.
Hypothesis: Oligomeric catalysts would improve the reactivity by minimizing the entropy cost.
Co(salen)
Linker
Co(salen)
Linker
n
n = 1-5
O
1.5 mol% oligomer(with respect to Co)
CH3CN / CH2Cl2
4 oC, 11h
OH
OH
98% yield
94% ee
Ring Opening of meso-Aziridines with TMSN3
Other significant contributions in the field:First organocatalyzed example with chiral phosphoric acids: Antilla, J. C. et al, JACS 2007, 129,12084.
Ring opening with anilines: Schneider, C. Angew. Chem. Int. Ed. 2009, 48, 4849.
• First highly enantioselective example by Jacobsen with Cr(salen) complexes: Org. Lett. 1999, 1, 1611.
• Improved by Shibasaki: J. Am. Chem. Soc. 2006, 128, 6312.
N
RR
TMSN3
1-10 mol% Y(OiPr)3
2-20 mol% A
O
NO2O2N
RR
CH3CH2CNN3HN
O
O2N
NO2
A
O
O
HO
F
F
P
Ph
Ph
O
HO
97% yield
92% ee
ArOCHN N3 ArOCHN N3
NCbz
ArOCHN N3
Me Me
ArOCHN N3
99% yield
94% ee
87% yield
95% ee
94% yield
95% ee
94% yield
86% ee
N3ArOCHN
Ring Opening of meso-Aziridines with TMSN3
• First highly enantioselective example by Jacobsen with Cr(salen) complexes: Org. Lett. 1999, 1, 1611.
• Improved by Shibasaki: J. Am. Chem. Soc. 2006, 128, 6312.
N
RR
TMSN3
1-10 mol% Y(OiPr)3
2-20 mol% A
O
NO2O2N
RR
CH3CH2CNN3HN
O
O2N
NO2
A
O
O
HO
F
F
P
Ph
Ph
O
HO
Application to the synthesis of Tamiflu
EtO2C
NHAc
O
NH2.H3PO4
HN
N3
O
Ar
96% yield
91% eeTamiflu
Ring Opening of meso-Aziridines with TMSCN
Shibasaki, M. et al, J. Am. Chem. Soc. 2006, 128, 16438.
99% yield
98% ee
ArOCHN CNArOCHN CN
NCbz
ArOCHN CN
Me Me
ArOCHN CN
99% yield
94% ee
99% yield
96% ee
98% yield
98% ee
O
ArOCHN CN
84% yield
96% ee
N
RR
TMSCN
2 mol% Gd(OiPr)3
3 mol% A
2,6-dimethylphenol (1 equiv.)
O
RR
THF, 40 oCCNHN
O
NO2 O2N
A
O
O
HO
F
F
P
Ph
HO
O
Ph
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Ring Opening of Bridged Systems: Rh-CatalyzedAsymmetric Alcoholysis of Oxabenzonorbornadiene
Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122, 5650.With phenols: Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2, 1677.
With thiols: Leong, P.; Lautens, M. J. Org.Chem. 2004, 69, 2194.
Fe
Pt-Bu2
Me
PPh2
PPF-Pt-Bu2
OH
OMe
OH
O
96% yield
97% ee
Me
Me
94% yield
93% ee
OH
O
OH
O
OH
O
MeO OH
OMe
Me
Me
Br
Br
OH
OMe
O
O
87% yield
97% ee
79% yield
97% ee
88% yield
96% ee
92% yield
99% ee
66% yield
98% ee
ROH
0.125 mol% [Rh(COD)Cl]2
0.25 mol% PPF-Pt-Bu2
THF, 80 oC
O
OH
RO
Expansion of Substrate Scope through Halide EffectEffect of Counterion over Reactivity
Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170.
Entry %yield
1
2
3
4
5
6
NR
NR
17
60
42
81
Additive
none
Bu4NF (5 equiv)
Bu4NCl (5 equiv)
Bu4NBr (5 equiv)
Bu4NI (5 equiv)
Bu4NI (5 equiv)
CSA (1 equiv)
time(h)
24
5
5
5
2
2
2.5 mol% [Rh(COD)Cl]2
5 mol% DPPF
Additive
THF, reflux
O
OH
NNH
Rationalization of the Halide Effect
Lautens, M.; Fagnou, K.; Yang, D. J. Am. Chem. Soc. 2003, 125, 14884.
• Dimer 63: Less prone to nucleophilic attack/more stable when X = I (vs X = Cl) as
demonstrated by Buchwald for Pd dimers.
• Regeneration of active catalyst 69 from 67 would be faster for X = I
Expansion of Substrate Scope through Halide EffectEffect of Counterion over Selectivity
Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170.
Fe
Pt-Bu2
Me
PPh2
PPF-Pt-Bu2
[Rh(COD)X]2 = [Rh(COD)Cl]2 + 2AgOTf, then 2R4NX
X %yield %ee
Cl
Br
I
F
OTf
92
90
97
91
93
74
78
92
96
96
PhNHMe
0.5 mol% [Rh(COD)X]2
1.5 mol% PPF-Pt-Bu2
THF, reflux
O
OH
N
Me
Ph
Expansion of Substrate Scope through Halide Effect
Fe
Pt-Bu2
Me
PPh2
PPF-Pt-Bu2
Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170.
Lautens, M.; Fagnou, K.; Yang, D. J. Am. Chem. Soc. 2003, 125, 14884.
OH
N
OH
95% yield
91% ee
93% yield
97% ee
OH
N
OH
90% yield
98% ee
93% yield
98% ee
N
O
O
MeO2C
MeO2C
OH
O
93% yield
92% ee
O
R
R = Me: 71% yield
91% ee
R = CH=CH2:
OH
Bn2N
86% yield
99% ee
Nu
0.5 mol% [Rh(COD)I]2
1.5 mol% PPF-Pt-Bu2
THF, reflux
O
OH
Nu
Ring Opening of Bridged Systems: Pd-Catalyzed AsymmetricAlkylative Ring Opening of Oxabicyclic Alkenes
Me2Zn
5 mol% (MeCN)2PdCl2
5 mol% DIPOF
ClCH2CH2Cl, reflux
O
OH
MeOPMB
OPMB
OPMB
OPMB
93% yield
90% ee
Me2Zn
5 mol% (MeCN)2PdCl2
5 mol% DIPOF
ClCH2CH2Cl, reflux
84% yield
95% ee
OH
MeMe
HO
Me
OH
MeMe
O
Lautens, M.; Hiebert, M.; Renaud, J.-L. Org. Lett. 2000, 2, 1971.See also: Carretero, J. C. et al. J. Am. Chem. Soc. 2005, 127, 17938.
Fe
DIPOF
Ph2P
N
O
Me
Me
Ring Opening of Bridged Systems:Application to the Total Synthesis of Ionomycin
Lautens, M. et al. Org. Lett. 2002, 4, 1879.
O O
Me
OHH
OH O
O
HO
Me
MeOH
OH
Me H Me
Me Me Me Me Me
Reductive Ring Opening:
Lautens, M.; Rovis, T.JACS 1997, 119, 11090.
DIBAL-H
5 mol% Ni(COD)2
10 mol% (S)-BINAP
Toluene, 65 oC
95% yield
95% ee
OH
MeMe
OTIPS
MeMe
OOH
1. Swern Ox.
2. DIBAL-H, Toluene, -78 oC
3. PMBCl, KHMDS, THF
HO
Me Me
OH
TIPSO OPMB
OH
MeMe
OPMB
82% yield
over 3 steps
O3
MeOH/CH2Cl2, -78 oC
then NaBH4
85% yield
Reversal of Stereocontrol for Cu-Phosphoramidite-CatalyzedRing Opening of Oxabicyclic Alkenes
Feringa, B. L. et al. Org. Lett. 2002, 4, 2703.
Cu
OZnOTf
Et
L*
OH
Et
58% yield
83/17 (anti/syn)
80% ee
F
F
OH
Et
65% yield
90/10 (anti/syn)
88% ee
MeO
MeO
OH
Et
90% yield
99/1 (anti/syn)
>99% ee
Me
Me
OH
Et
82% yield
90/10 (anti/syn)
97% ee
OMe
OMe
Et
85% yield
92/8 (anti/syn)
92% ee
Me
Me OH
O
OP N
Ph
Ph
Me
Me
Ligand
(S,R,R)
O
3 mol% Cu(OTf)2
1.0 equiv. Zn(OTf)2
7 mol% Ligand
Toluene, rtR2Zn
OH
R
R R
anti syn
OH
R
R
Ring Opening of Oxabicyclic Alkenes: Expansion ofNucleophile Scope with Organoboronic Acids
Lautens, M. et al. Org. Lett. 2002, 4, 1311.
OH
OMe
OMe
Me
88% yield
95% ee
OH
OMe
OMe
0% yield
Me
OH
OMe
OMe
Cl
95% yield
95% ee
OH
OMe
OMe
MeO
87% yield
96% ee
Fe
Ligand
Ph2P
Me
(t-Bu)2P2.5 mol% [Rh(COD)Cl]2
5 mol% Ligand
Cs2CO3 (5M) in H2O (0.5 equiv.)
THF, rtArB(OH)2
O
OMe
OMeAr
OH
OMe
OMe
2.5 mol% [Rh(COD)Cl]2
5 mol% Ligand
Cs2CO3 (5M) in H2O (0.5 equiv.)
THF, rt
O
PMB
PMB
OH
PMB
PMB
Me B(OH)2
Me 95% yield
92% ee
Enantioselective Ring Opening of Azabicyclic Alkenes
Menard, F.; Lautens, M. Angew. Chem. Int. Ed. 2008, 47, 2085.Opening w/ amine nucleophiles: (a) Lautens, M. et al. J. Am. Chem. Soc. 2006, 128, 6837.
(b) Yang, D. et al. Org. Lett. 2008, 10, 4723.
2.5 mol% [Rh(COD)OH]2
5 mol% (S,R)-tBu-josiphos
THF, rtN
NBoc
Boc
Ar-B(OH)2
N
Ar
NHBoc
Boc
Fe
(S,R)-tBu-josiphos
P
PRh
Me
PhPh
t-Bu
t-Bu
OH
OH
53% yield
99% ee
N
NHBoc
Boc
F
N
NHBoc
Boc
Me
N
NHBoc
Boc
MeO
N
NHBoc
Boc
N
NHBoc
Boc
OMe
N
NHBoc
BocN
NHBoc
Boc
CF3
N
NHBoc
Boc
CO2Me
OMe
99% yield
97% ee
75% yield
99% ee
68% yield
99% ee
85% yield
68% ee
49% yield
84% ee
58% yield
86% ee
80% yield
50% ee
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Catalytic Enantioselective Deprotonation/Fragmentation ofmeso-Epoxides Mediated by chiral amides
Liu, D.; Kozmin, S. A. Angew. Chem. Int. Ed. 2001, 40, 4757.
Si
O
Ph Ph
NH
N5 mol%
H
LDA (200 mol%)
THF-DBU, -78 oC to 0 oC
Si
Ph Ph
OH
72% yield
91% ee
Mg, Ph2SiCl2
THF
Si
Ph Ph
mCPBA
CH2Cl2
98% yield82% yield
Si
Ph Ph
OH
mCPBA
CH2Cl2
96% yield
Si
Ph Ph
OH
O
RMgBr orRLi
CuCN
Si
Ph Ph
OHHO
R
R = Alkyl, vinyl, aryl, allyl
t-BuOOH, KH
DMF
70-79% yield72-91% yield
R
OH
OHOH
OH
Application to the Preparation of Tetraols
First Organocatalytic Asymmetric Deprotonation/Fragmentation of Cyclic Ketones
NH
HN
N
S
HN CF3
CF3
A
NH
OTIPS
N
B
MeO
HN
S
HNF3C
CF3
Jorgensen, K. A. et al., Angew. Chem. Int. Ed. 2009, 48, 6650.
O
EtO2C CO2Et
O
CH(CO2Et)2
10 mol% A
CH2Cl2
84% yield
96% ee
O
O
O10 mol% B
CH2Cl2
93% yield
90% ee
OH
O O10 mol% B
CH2Cl2
90% yield
97% ee
OMe Me Me
OHMe
Prostaglandins
Mechanism and Tandem Reactions
Jorgensen, K. A. et al., Angew. Chem. Int. Ed. 2009, 48, 6650.
O
HO
PhPh HN
S
NH
F3C
CF3
N
H
N
MeO
Mechanistic Proposal
O
O
O
OH
10 mol% thiourea
BnSH
CH2Cl2
90% yield
94% ee
BnS
O
OH
1. 10 mol% thiourea
dioxane/H2O (4:1)
82-94% yield
90% ee
2. 3 mol% [Rh(cod)Cl]2 10 mol% Cs2CO3
R
R
B(OH)2
R = Me, Ph
Tandem Reactions
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Asymmetric Ring Closing Metathesis:First Efficient Examples
Hoveyda, A. H.; Schrock, R. R. et al.,J. Am. Chem. Soc. 1998, 120, 9720.
See also: Grubbs, R. H. et al.,Org. Lett. 2001, 3, 3225.
(Chiral Ru complex; less efficient)
N
Mo
Ph
MeMe
Me Me
O
O
Catalyst
O
R1R1
O
R1
R1
R2R2 R2
3-5 mol% catalyst
toluene or benzene
-25 oC or rt
Substrate Product
O
MeMe
O
MeMe
O
Me
Me
% yield % ee
86 93
99 83
MeMe
O
Me
Me
MeMe Me
On-octyl
O
88 10
O
n-octyl
Me
84 73
O
Me
Asymmetric Ring Closing Metathesis:Formation of Six-Membered Rings
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 1999, 121, 8251.
O
O
Mo
N
O
iPr
iPriPr
iPr
iPr
iPr
Me
Me
Catalyst
OX
MeMe
5 mol% catalyst OX
Me
Me
benzene
60 oC
Substrate Product % yield % ee
98 >99
86 >99
O
Me2Si
Me
Me
O
Me
Me
O
Me2Si
MeMe
O
MeMe
Asymmetric Ring Closing Metathesis:Synthesis of Cyclic Amides and Amines
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2005, 127, 8526.
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
CHPh2
CHPh2 O
C
A
N
Mo
Ph
MeMe
O
O
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
CHPh2
CHPh2
B
Substrate Product Cat. % ee
84 93
94 90
91 >98
92 88
N
O
Me
Me
N
O
Me
MeA
N
O
Me
Me
N
O
Me
B
C
C
N
O
Me
Me
N
O
Me
Me
Me
N
O
N
O
% yield
Asymmetric Ring Closing Metathesis:Synthesis of Cyclic Amides and Amines
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2005, 127, 8526.
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
CHPh2
CHPh2 O
C
A
N
Mo
Ph
MeMe
O
O
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
B
Substrate Product Cat. % ee
98 95
50 87
63 75
94 97
A
B
C
B
% yield
NCbz
Me
Me
NCbz
Me
HMe
NH
Me
Me
NH
Me
HMe
NCbz
Me
Me
NCbz
Me
MeMe
Me
NCbz
Me
Me
NCbz
Me
Me
Asymmetric Ring-Closing Metathesis:Development of a Stereogenic at Mo Complex
Hoveyda, A. H.; Schrock, R. R. et al., Nature 2008, 456, 933.
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
MeCF3
F3C
Me
F3C
F3C
A
N
Mo R
i-Pr i-Pr
L
L
N
Mo R
i-Pr i-Pr
L
L
Chiral Complex
(non-stereogenic at Mo)
Chiral Complex
(stereogenic at Mo)
L: chiral ligand (same enantiomer)
L: achiral ligand
TwoPossibilities:
NH
NChiral Alkene Metathesis
Catalyst
NH
N
All existing chiral bidentate Ru or Mo catalysts are ineffective: very low conversion.
Alkylidene A is the most active catalyst.Structural rigidity of the diolates would lead to higher energy transition states and intermediates.
KEY: CHIRAL Mo CATALYST BEARING MONODENTATE LIGANDS
(+)-quebrachamine
Broadening of Substrate Scope
Hoveyda, A. H.; Schrock, R. R. et al., Nature 2008, 456, 933.
Substrate Product % ee
88 91
>98 92
86 93
% yield
N
MeMe
O
N
MeMe
O
N
MeMe
N
MeMe
Me
PhN
Me
PhN
Me
Me
N
Mo
Ph
MeMe
i-Pr i-Pr
O
ClTBSO
Cl
N
Me
Me
Catalyst
Conditions:
1-3 mol% Catalyst
benzene, rt
(+)-quebrachamine Synthesis
Hoveyda, A. H.; Schrock, R. R. et al., Nature 2008, 456, 933.Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2009, 131, 943.
NH
N1 mol% catalyst
NH
N
benzene, rt
5 mol% PtO2
1 atm H2, EtOH
NH
N
(+) quebrachamine97% yield84% yield
96% ee
N
Mo
Ph
MeMe
i-Pr i-Pr
O
ClTBSO
Cl
N
Me
Me
Catalyst
Mechanism
Hoveyda, A. H.; Schrock, R. R. et al., Nature 2008, 456, 933.For mechanistic details, see: Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2009, ASAP.
R
N
Mo
i-Pr i-Pr
L
L
N
Mo
i-Pr i-Pr
L
L
R
N
i-Pri-Pr
L
L
R
Mo
N
Mo
i-Pr i-Pr
L
L
R
RDouble inversion
at metal
Asymmetric Ring Opening Metathesis/Cross Metathesis:First Example of Catalytic AROM
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 1999, 121, 11603.Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2001, 123, 7767.
5 mol% catalyst
benzene, rt
OP
R
OPR
Catalyst
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
OMOM
96% yield
>98% ee
OMOMMeO
88% yield
>98% ee
OMOMF3C
80% yield
>98% ee
OTMSH
85% yield
>98% ee
OTBSH
57% yield
96% ee
Asymmetric Ring Opening Metathesis/Ring Closing Metathesis
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2000, 122, 1828.
N
Mo
Ph
MeMe
O
O
t-Bu
t-Bu
Catalyst
Substrate Product % yield % ee
10 98
69 92
76 98
O O
O O
Me Me
OO
O
Me
O
Me
OO O
H
HO
Conditions:
5 mol% catalyst
Asymmetric ROM/CM: Expanding the scope witnAdamantylimido Molybdenum Alkylidene Complex
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2003, 125, 2591.
N
Mo
Ph
MeMe
O
O
Catalyst
OTBSOTBS
BO
O
Me
Me
MeMe
benzene, rt
BO
O
Me
Me
MeMe
88 % yield
98% ee
5 mol% catalyst
5 mol% catalyst
benzene, rt
O
O O
20 % yield80 % yield
96% ee
Asymmetric Ring-Opening/Cross Metathesis:Development of a Recyclable Chiral Ru Catalyst
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2002, 124, 4954.Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2003, 125, 12502.
OO O
OO O
R10 mol% catalyst
THF, rt
R
OO O
Ph
OO O
n-C5H11
OO O
Cy
71 % yield
80% ee
57 % yield
>98% ee
60 % yield
>98% ee
O
N N
RuCl
Oi-Pr
Me
Me
Me
Catalyst
10 mol% catalyst
THF, rt
Ph
Ph
76 % yield
>95% ee
O
OMeO
OMe
Asymmetric Ring-Opening/Cross Metathesis:Application to the Synthesis of (+)-africanol
Hoveyda, A. H.; Schrock, R. R. et al., Proc. Natl. Acad. Sci. 2004, 101, 5805.
Catalyst
N
Mo
Ph
MeMe
i-Pr i-Pr
O
O
Ar
Ar O
Ar = 2,4,6-(i-Pr)3C6H3
OLi
Me Me
1. THF, -78 oC
2. TBSOTf, lutidine
CH2Cl2
TBSO
Me
Me
Me
MeOTBS
H
Me
MeOH
H
Me
Me
3 mol% catalyst
pentane
(+)-africanol
Asymmetric Ring-Opening/Cross Metathesis:Enantioselective Synthesis of Piperidines
Hoveyda, A. H.; Schrock, R. R. et al., Angew. Chem. Int. Ed. 2007, 46, 4534.Synthesis of THPs: Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2004, 126, 12288.
NMe
OTBS
95% yield
94% ee
NMe
OTBS
92% yield
89% ee
OMe
NMe
OTBS
88% yield
64% ee
CF3
NCbz
OTBS
93% yield
90% ee
NCO2Et
72% yield
90% ee
CF3
Catalyst
N
Mo
Ph
MeMe
O
O
PN
OTBS
5-10 mol% catalyst
Rbenzene, rt
NP
OTBS
R
Asymmetric Ring-Opening/Cross Metathesis:Overcoming the Challenge of Z-Selectivity
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2009, 131, 3844.For a Review, see: Cordova, A.; Rios, R. Angew. Chem. Int. Ed. 2009, Early View.
N
Mo
Ph
MeMe
O
BrTBSO
Br
N
Me
Me
Catalyst
N
Mo
R
Pyr
OR
R2
N
Mo
R
Pyr
RO
R1
R1
R2
small
large
N
Mo
R
Pyr
OR
R2 R1
Asymmetric Ring-Opening/Cross Metathesis:Overcoming the Challenge of Z-Selectivity
Hoveyda, A. H.; Schrock, R. R. et al., J. Am. Chem. Soc. 2009, 131, 3844.For a Review, see: Cordova, A.; Rios, R. Angew. Chem. Int. Ed. 2009, Early View.
N
Mo
Ph
MeMe
O
BrTBSO
Br
N
Me
Me
Catalyst
O
OP
1-2 mol% catalyst
Ar
O
OP
Ar
neat, rt
O
OTBS
80% yield
94% ee
Z:E 95:5
OMe
O
OTBS
67% yield
96% ee
Z:E 98:2
CF3
O
OTBS
50% yield
98% ee
Z:E 89:11
Br
O
OTBS
80% yield
92% ee
Z:E 89:11
OMe
O
OBn
80% yield
84% ee
Z:E 91:9
O
OBn
45% yield
68% ee
Z:E 95:5
OTBS
Non-Enzymatic Catalytic EnantioselectiveDesymmetrization Reactions
Introduction
Alcohol Protection
Cyclic Anhydride Alcoholysis and Alkylation
Oxidation Reactions
Ring Opening of Epoxides and Aziridines
Ring Opening of Bridged Systems
Deprotonation Reactions
Olefin Metathesis
Aldol Reactions
Hajos-Parrish and Wieland-Miescher Ketones: Two EarlyEfficient Examples of Asymmetric Desymmetrization
Buchschacher, P.; Furst, A.; Gutzwiller, J. Org. Synth. 1990, Coll. Vol. 7, 368.Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
Hajos, Z. G.; Parrish, D. R. Org. Synth. 1990, Coll. Vol. 7, 363.Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
NH
COOH
DMF, 16 oC
3 mol%
Me
O
Me
O
O
O
O
Me
OH
92% ee
O
O
Me
76% yield
99% ee
H2SO4
DMF, 95 oC
Recristallyze
NH
COOH
DMSO, 16 oC
5 mol%
Me
O O
57% yield
''enantiomerically pure''
101 g
Recristallyze
O
OMe Me
O
Hajos-Parrish ketone:
Wieland-Miesher ketone:
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