Enantioselective Organic Catalysis:
Non-MacMillan Approaches
Jake Wiener
8 November 2000
I. Catalytic Antibodies and Multi-Peptide Catalysis
II. Phase Transfer Catalysis
III. Bifunctional Organic Catalysis
IV. Phophoramide Catalysts
V. Catalysis via Enamine Intermediates
VI. Catalysts as Nucleophilic Triggers
VII. Ketone Catalyzed Epoxidations
VIII. Amine Catalyzed Epoxidations
Catalytic Antibodies and Multi-Peptide Catalysis
! Antibodies have been used to catalyze a range of specific transformations
Recent review, containing pertinent references: Hilvert, D., Annu. Rev. Biochem., 2000, 69, 751.
Slightly older review: Hsieh-Wilson, L. C., Xiang, X., Schultz, P. G. Acc. Chem. Res., 1996, 29, 164.
! Molecules consisiting of multiple linked peptides have been used to catalyze a range of reactions, including azide conjugate
additions, asymmetric acylations, the Strecker synthesis, expoxidations, and HCN additions. These reactions cuurently lack
clear mechanistic understandings.
Relevant Articles:
Miller, S. J., et al., Angew. Chem. Int. Ed. Engl., 2000, 39, 3635.
Miller, S. J., et al., J. Am. Chem. Soc., 1999, 121, 11638.
Miller, S. J., et al., J. Org. Chem., 1998, 63, 6784.
Miller, S. J., et al., J. Am. Chem. Soc., 1998, 120, 1629.
Lipton, M., et al., J. Am. Chem. Soc., 1996, 118, 4910.
Itsuno, S., et al., J. Org. Chem., 1990, 55, 6047.
Inoue, S., et al., J. Org. Chem., 1990, 55, 181.
Phase Transfer Catalysis: Alkylation
Lead to the first practical asymmetric synthesis of !-amino acids
! Initial report: O'Donnell
Corey, E. J., et al., J. Am. Chem. Soc., 1997, 119, 12414.
RO
O
N
Ph
Ph
Br
20 mol% catalyst
17% aq. NaOH
CH2Cl2
RO
O
N
Ph
Ph
60 - 90% yield
14 - 56% ee
R = PhCH2, 4-NO2-C6H4-CH2, 4-MeO-C6H4-CH2
Ph2CH, 1-naphthyl-CH2, Me, Et, Me2CH, Me3C
Me3CCH2, Et3C
N
H
Cl
H
OH
N
Cinchonine catalyst
! Slam Dunk: Corey
O
N
Ph
Ph
RX
10 mol% catalyst
CsOH H2O
CH2Cl2
O
N
Ph
PhR
68 - 91% yield
92 - 99.5% ee
N
H
Br
H
O
N
Cinchonine-derived catalyst
O'Donnell, M. J., et al., J. Am. Chem. Soc., 1989, 111, 2353.
tBuO
Allylic, benzylic, propargylic bromides
Alkyl iodides
Electrophile
tBuO
O
N
Ph
Ph
O
N
Ph
Ph
O
N
Ph
Ph
R X
O
N
Ph
PhR
Cs
Phase Transfer Catalysis: Mechanism of Alkylation
tBuO tBuO
Organic Phase Aqueous Phase
aq. CsOH
R*4N Br
tBuO
R*4N
Organic Phase
tBuO
R*4N XCatalyst is regenerated and returns to aqueous phase
Corey, E. J., et al., J. Am. Chem. Soc., 1998, 120, 13000.
O'Donnell, M. J., et al., J. Am. Chem. Soc., 1989, 111, 2353.
Corey, E. J., et al., J. Am. Chem. Soc., 1997, 119, 12414.
Phase Transfer Catalysis: Support for Stereochemical Model
O
NtBuO
Corey, E. J., et al., J. Am. Chem. Soc., 1998, 120, 13000.
X
X
The intermediacy of a contact ion pair is supported by varying electronics of the enolate aryl substituents
R*4N!p
ee
X
-0.15
81%
H
0
67%
tBu OMe NMe2
-0.28
91%
-0.63
96%
! As the value of ! becomes more negative, the aryl substiuents become more electron-donating.
! As the aryl substituents become more electron donating, electron density on the enolate oxygen increases.
! More electron density on the enolate oxygen results in a tighter contact ion pair, bringing the substrate further into the
chiral cavity, thereby accentuating the effect of the sterics in the cavity on bond formation higher % ee
R
O
X KOCl
R
O
X
O
C6H5
C6H5
C6H5
n-C5H11
C6H5
C6H5
X
H
F
Br
H
F
F
H
F
H
H
F
H
C6H5O
H
X
N
MeH
Br
H
O
N
Ph
Phase Transfer Catalysis: Epoxidation of ",#-Unsaturated Ketones
Corey, E. J., et al., Org. Lett., 1999, 1, 1287.
10 mol % catalyst
toluene, -40° C
cyclo-C6H11
cyclo-C6H11
#-naphthyl
2,4-Br2-C6H3O
% yield % ee
93
98
93
94
95
91
94
95
94
92
98.5
95
93
98
93
96
93
92
90
97
90
85
87
70
94
94
70
89
90
87
% yield % ee
Cinchonine-derived catalyst
4-NO2-C6H4
4-NO2-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-CH3O-C6H4
R R
Phase Transfer Catalysis: Stereochemical Rationale for Epoxidation of !,"-
Unsaturated Ketones
O
F KOCl
10 mol % catalyst
toluene, -40° C
O
F
O
N
O
N
F
O
O
Cl
! Nuclephilic oxygen of ClO is proximate to " carbon of ketone
! 4-fluorophenyl group wedged between ethyl and quinoline substituents
! Carbonyl oxygen is placed close to N+Me
Negative charge on O in TS is stabilized by proximate N+
charge acceleration of nucleophilic attack
Corey, E. J., et al., Org. Lett., 1999, 1, 1287.
Analogous michael reactions have been performed: Corey, E. J., et al., Org. Lett., 2000, 2, 1097; Corey, E. J., et al., Tetrahedron Lett., 1998, 39, 5347.
Cinchonidine-derived catalysts have been used in aldol and nitroaldol reactions: Corey, E. J., et al., Tetrahedron Lett., 1999, 40, 3843. Corey, E. J., et al., Angew. Chem. Int. Ed. Engl., 1999, 38, 1931.
Conjugate additions of thiol have been reported: Wynberg, H., J. Am. Chem. Soc., 1981, 103, 417.
A Diels-Alder reaction has been reported: Kagan, H. Tetraheron Lett., 1989, 30, 7403.
R1
O
R2 R1 R2
OH NPh
Ph
OHP
O
MeO
MeO
Br
OH
Me
OH OH
Me
OH
MeMe
OH
OH
Ph Ph Ph PMP Napthyl
Cl
OH
Ph
ClCl
Me
OH
Me
OH
PhPh
OH
OH
Ph
OH
Ph
OH
Me
MeMe
ArCl
OHCl
OH
BnO
X
Bifunctional Enantioselective Organic Catalysts: Ketone Reduction
Wills, M., et al., J. Org. Chem., 1998, 63, 6068.
10 mol % catalyst
BH3SMe2
toluene, 40 - 110° C
89% yield
93% ee
83% yield
88% ee
76% yield
77% ee
89% yield
90% ee
82% yield
90% ee
81% yield
82% ee
81% yield
56% ee
87% yield
67% ee
65% yield
86% ee
83% yield
>90% ee
71% yield
>90% ee
Ar = Ph: 83% yield
75% ee
Ar = 4-F-Ph: 68% yield
83% ee
X = H: 86% yield
94% ee
X = CH2OBn: 84% yield
93% ee
Phosphinamide catalyst
Bifunctional Enantioselective Organic Catalysts: Stereochemical
Rationale for Ketone Reduction
Wills, M., et al., J. Org. Chem., 1998, 63, 6068.
R1
O
R2
10 mol % catalyst
BH3SMe2
toluene, 40 - 110° CR1 R2
OH
NPh
Ph
OHP
O
MeO
MeO
Phosphinamide catalyst
N
H
Ph
Ph
OH2B
P O
Ph
Ph
BH2
O
H
Ph
X!"
!"
!+
!+
Lewis base
Lewis Acid
! High temperatures are required to facilitate catalyst
turnover after reduction (to break the numerous B–O bonds)
! 11B and 31P NMR studies indicate no decomposition of catalyst
! Anhydrous conditions not required
O
H
R
OH
R
Me
N
P
N
O HHO
Ph
P O
O
ZnEt2
Zn
O
Et Ar
H
N
N
Ph
Et
Bifunctional Enantioselective Organic Catalysts: Diethyl Zinc Addition
Buono, G., et al., Tetrahedron Lett., 1998, 39, 2961.
5 mol % catalyst
Et2Zn
THF, 20° C
Diazaphopholidine catalyst
R
H
NMe2
Cl
CN
% yield
98
98
84
91
% ee
73
71
86
>99
! Electron withdrawing substituents result in increase in enantioselectivity
Possible transition state
!+
!"
!"
!+
Ar Ar
HN
CN
Ph
PhN
Ph
Ph
H3O+
Ar
NH3
O
O
N
N NH
Bifunctional Enantioselective Organic Catalysts: Strecker Synthesis
Corey, E.J., et al., Organic Lett., 1999, 1, 157.
10 mol % catalyst
HCN
toluene, -40° C
8 - 72 hours
C2-symmetric Guanidine catalyst
!-amino nitrile !-amino acid
Ar
Ph
p-tolyl
3,5-xylyl
o-tolyl
4-tBu-Ph
4-TBSO-Ph
4-MeO-Ph
4-F-Ph
4-Cl-Ph
1-naphthyl
% yield
96
96
96
88
80
98
99
97
88
90
% ee
86
80
79
50
85
88
84
86
81
76
! No background reaction below 10° C
! N-methyl derivitive of catalyst is inactive
Bifunctional Enantioselective Organic Catalysts: Mechanism and
Stereochemical Rationale for Corey's Strecker Synthesis
Corey, E.J., et al., Organic Lett., 1999, 1, 157.
Ar
10 mol % catalyst
HCN
toluene, -40° C
8 - 72 hours Ar
HN
CN
Ph
PhN
Ph
Ph
N
N NH
C2-symmetric Guanidine catalyst!-amino nitrile
N
NH
N
PhPh
H C N
N
NH
N
PhPh
H
C
N
Ph2HCN
Ar
N
N N
PhPh
HH
N
Ar
Ph2HC C
N
Ar CN
NH
Ph2HC
! Catalyst Cycle
N
N
HN
HH
H N
N C
! Pre-transition state assembly predicts outcome
"-stacking
si face blocked by phenyl ring
ONO2
R1 R2
O
NO2
R1
R2
NH
CO2H
Me Me
NO2 NO2 NO2
MeNO2 Me NO2
NO2
NH
NH
HN
NH
Me
Me
Bifunctional Enantioselective Organic Catalysts: Conjugate Addition
Hanessian, S., et al., Organic Lett., 2000, 2, 2975.
n
+
3 - 7 mol % catalyst
CHCl3, 23° C
n
catalystn = 1,2,3
nucleophile
30 - 88% yield
71 - 93% ee
1:1 dr where relevant
! n = 2 (cyclohexenone) affords best ee
! Numerous basic additives tried: basicity and structure have large effect on ee
86% ee 4% ee
! This work is an extension of Yamaguchi's work using Rubidium prolinate salts:
Yamaguchi, M., et al., Tetrahedron, 1997, 53, 11223.
ONO2
R1 R2
O
NO2
R1
R2
NH
CO2H
HN
NH
Me
Me
O
NCO2H
NCO2 N
CO2
NO2
R1
R2
O
NO2
R1
R2
NH
CO2H
Bifunctional Enantioselective Organic Catalysts: Possible Mechanism of
Conjugate Addition
Hanessian, S., et al., Organic Lett., 2000, 2, 2975.
n
+
3 - 7 mol % catalyst
CHCl3, 23° C
n
catalystn = 1,2,3
Nuc
Ionic complex blocks top face
Nucleophile approaches bottom face
+
! Possible iminium ion intermediate
Nonlinear effect of catalyst ee on product ee suggests
oligomeric TS Potential H bonding of prolinate-
iminium ion aggregate to nitroalkane resulting in greater
TS organization
Alternately
H2NR2 H2NR2
Enantioselective Catalysis by Phosphoramides: Aldehyde Allylation
H
O
R
R1
R2
SiCl3+
10 - 20 mol% catalyst
THF, -60° C
72 - 168 hours
R
OH
R1 R2
N
P N
H
O
NPrPr
catalyst
% yield % ee
C6H5
2-MeC6H4
C6H5
C6H5
2-MeC6H4
4-tBuC6H4
H
H
Me
H
Me
Me
H
H
H
Me
H
H
83
86
80
90
78
72
syn:anti
--
--
98:2
2:98
>99:1
95:5
88
81
77
83
83
82
Iseki, K., et al., Tetrahedron, 1997, 53, 3513.
! Unlike Lewis acid catalyzed addition of crotylsilanes and crotylstannanes, this reaction allows access to both
syn and anti homoallylic alcohols
For a review of Phosphorus reagents in enantioselective catalysis, see: Buono, G., et al., Synlett, 1999, 377.
Me
H
O
R
R2
R1
SiCl3
R
OH
R1 R2
N
P N
H
O
NPrPr
R
OH
R1 R2
Si O
H
R
Cl
Cl
Cl
OPN
N
H
N
Me
R1
R2
Enantioselective Catalysis by Phosphoramides: Mechanism of Aldehyde
Allylation
+
10 - 20 mol% catalyst
THF, -60° C
72 - 168 hours
catalyst
Iseki, K., et al., Tetrahedron, 1997, 53, 3513.
! Chair-like transition state accounts for observed diastereo- and enantioselectivity
PM3 Calculation
! Hexacoordinate silicate proposed
! Larger N(alkyl)2 of phosphoramide leads to higher ee's
R R1 R2
Enantioselective Catalysis by Phosphoramides: Acetate Aldol Reaction
Denmark, S. E., et al., J. Org. Chem., 1998, 63, 918.
R
OSiCl3
H
O
Ph
+R
O
Ph
OH5 mol % catalyst
CH2Cl2, -78° C
! Variation in the trichlorosilyl enol ether component
R = Me, nBu, iBu, iPr, tBu, Ph, CH2OSiMe3tBu
93 - 98% yield
49 - 87% ee
Bu
OSiCl3
H
O
R
+Bu
O
R
OH5 - 10 mol % catalyst
CH2Cl2, -78° C
! Variation in the aldehyde component
R = cinnamyl, !-methylcinnamyl, naphthyl, 4-phenyl-phenyl, cyclohexyl, tBu
79 - 95% yield
84 - 92% een n
P
N
N
Me
Me
Ph
Ph
O
N
The catalyst
! Trichlorosilyl enol ethers are prepared from the corresponding trimethylsilyl enol
ethers by treatment with SiCl4 and catalytic Hg(OAc)2
Ph
OSiCl3
H
O
R Ph
O
R
OH
OSiCl3
H
O
R
O
R
OH
P
N
N
Me
Me
Ph
Ph
O
N
Me
Me
Enantioselective Catalysis by Phosphoramides: Syn and Anti Aldol
Reactions
Denmark, S. E., et al., J. Am. Chem. Soc., 1996, 118, 7404.
Denmark, S. E., et al., J. Am. Chem. Soc., 1997, 119, 2333.
+
15 mol % catalyst
CH2Cl2, -78° C
6 - 8 hours
! Propionate aldol with various aldehydes
89 - 97% yield
3:1 - 18:1 syn:anti
84 - 96% ee
+
! Enforced E-enol silane aldol reaction: anti selective
R = cinnamyl, naphthyl, phenyl, tolyl, crotyl
The catalyst
The uncatalyzed reaction at 0° C is very syn selective (5:1 - 49:1)
10 mol % catalyst
CH2Cl2, -78° C
2hours
R = cinnamyl, !-methylcinnamyl, naphthyl, phenyl
94 - 98% yield
61:1 - 99:1 anti:syn
94 - 98% ee
The uncatalyzed reaction at 0° C is slightly anti selective (2:1)
Enantioselective Catalysis by Phosphoramides: Mechanism of the Aldol
Reactions
Iseki, K., et al., Tetrahedron, 1997, 53, 3513.
! Chair-like transition state accounts for observed diastereo- and enantioselectivities
O
Si O
H
R
Cl
Cl
Cl
OPN
N
N
R1
R2
Hexacoordinate silicate proposed
R
OSiCl3
H
O
R3
+R
O
R3
OH
catalyst
CH2Cl2, -78° CR1
R2R2
R1
R
R
O
R3
OH
R2R1
P
N
N
Me
Me
Ph
Ph
O
N
The catalyst
Me
Me
Ph
Ph
O
O
Me
O
Me
O
OH
Me
O
OMe
O
O
O
Me
O
Me
OMe
O
O
O
MeMe
O
Catalysis Involving Enamine Intermediates: Robinson Annulation
! Initial report: Hajos
3 mol% (S) - proline
DMF (anhydrous)
23° C, 20 hours
TsOH
Benzene
(Dean-Stark)
92% yield88% ee
Hajos, Z. G., J. Org. Chem., 1974, 39, 1615.
! Extension to one-pot annulation: Barbas
49% yield76% ee
Barbas III, C. F., Tetrahedron Lett., 2000, 41, 6951.
+
35 mol% (S) - proline
DMSO (anhydrous)
35° C, 89 hours
Catalysis Involving Enamine Intermediates: Mechanism of the Robinson
Annulation
O
OH
Me
O
Hajos, Z. G., J. Org. Chem., 1974, 39, 1615.
OH
N
OMe O
O H
! Chair-like transition state accounts for observed stereochemistry
List, B., et al., J. Am. Chem. Soc., 2000, 122, 2395.
Agami, C., et al, , Tetrahedron, 1984, 40, 1031.
O
Me
Me
O
OMe
O
Me O
O
Me
N
Me
HO2C
N
N
CO2H
CO2H
O
OH
Me
N
CO2H
NH
CO2H
OO
Me
Me Me
O
H
O
RMe R
O OH
NO2
H
Br
Cl
Me
Me
OH
NR
OO HH
Me R
O OH
Catalysis Involving Enamine Intermediates: Acetate Aldol Reaction
List, B., et al., J. Am. Chem. Soc., 2000, 122, 2395.
20 vol. %
+
30 mol% (S) - proline
DMSO
23° C, 2-8 hours
% yield % ee % yield % ee
68
62
74
97
94
54
76
60
65
96
69
77
! Enamine intermediate is proposed, in analogy to the Robinson annulation
Chair-like TS
R R
Cl
Me
Me
MeO
O
tBu
Me
O
H
O
RMe R
O OHHO
OH
Catalysis Involving Enamine Intermediates: Anti Aldol Reaction
List, B., et al., J. Am. Chem. Soc., 2000, 122, 7386.
% yield % ee % yield % ee
60
38
40
62
95
51
>99
>97
>97
>99
67
>95
anti:syn anti:syn
>20:1
1.5:1
>20:1
>20:1
1.7:1
2:1
20 vol. %
+
20 - 30 mol% (S) - proline
DMSO
23° C, 24 - 72 hours
Me
O
H
O
RMe R
O OHHO
OH
OH
NR
OO HH
Me R
O OHHO
OH
Me
N
OH
CO2H
Me
NCO2H
OHH
H
HN
OO H
Me R
O OHHO
OH
OR
H H
Catalysis Involving Enamine Intermediates: Mechanistic Aspects of the
Anti Aldol Reaction
List, B., et al., J. Am. Chem. Soc., 2000, 122, 7386.
20 vol. %
+
20 - 30 mol% (S) - proline
DMSO
23° C, 24 - 72 hours
! Chair-like transition state is proposed
! E-enamine geometry due to minimization of A(1,3) strain
A(1,3) strain
Z-enamine
Minimization of A(1,3) strain
E-enamine
! Boat-like transition state explains origin of syn
isomer for less hindered and !-oxygenated aldehydes
anti syn
R R
Catalysis Involving Enamine Intermediates: Mannich Reaction
List, B. J. Am. Chem. Soc., 2000, 122, 9336.
Me Me
O
H
O
R
+
35 mol% (S) - proline
23° C, 12 - 48 hours
Me
Me
% yield % ee % yield % ee
50
35
82
56
90
74
94
96
75
70
93
73
solvent
NH2
OMe
+
Me R
O HNPMP
Me
Me
Me
NO2
O
Ph
Me
O
H
O
+
35 mol% (S) - proline
DMSO
23° C, 12 hourssolvent
NH2
OMe
+
Me R
O HNPMP
! Hydroxy acetone can be used in place of acetone
HO
OH
57% yield17:1 anti:syn65% ee
Me
Me
Me Me
O
H
O
R
NH2
OMe
Me R
O HNPMP
HN
OO H
Me R
OX
X
NR
H H
R'
HNPMP
Me R
O
X
HNPMP
N H N
O
O
H
H
R
R'X
NH
NR
OO HH
XR'
Me R
O
X
HNPMP
NH
NR
OO HH
XR'
Catalysis Involving Enamine Intermediates: Mechanistic Aspects of the
Mannich Reaction
List, B. J. Am. Chem. Soc., 2000, 122, 9336.
+
35 mol% (S) - proline
23° C, 12 - 48 hours
solvent
+
boat-like TS
X = H or OH
chair-like TS
X = H or OHZ-enamine when X = OH allowed due to H-bonding
Chair-like TS of aldol reaction disfavored
destabilizing transannularinteractions
not observed
destabilizing A(1,3) interactions in minor resonance contributor
! Opposite sense of stereoinduction observed compared to proline-catalyzed aldol reactions
! Two potential transition states proposed
R R
Catalyst as Nucleophilic Trigger: Baylis-Hillman Reaction
Hatakeyama, S., et al., J. Am. Chem. Soc., 1999, 121, 10219.
O
O
CF3
CF3R
O
H
+10 mol % catalyst
DMF, -55° C R O
OH O
CF3
CF3
N
Me
O
N
OH
Quinidine-derived catalyst
R
p-NO2Ph
Ph
cinnamyl
Et
(CH3)2CHCH2
(CH3)2CH
cyclohexyl
tBu
time (hours)
1
48
72
4
4
16
72
72
% yield
58
57
50
40
51
36
31
NR
% ee
91
95
92
97
99
99
99
--
! Me ester is less reactive, requiring higher temperatures, resulting in lower ee's
O
OR1
R OR1
OH O
N
Me
O
OR1
ON
OH
R
O
H
N
Me
O
OR1
ON
O H
H
RO
H
CO2R1
H
HH
YX
O
NN
O H
N
Me
O
N
OH
Catalyst as Nucleophilic Trigger: Mechanism of the Baylis-Hillman
Reaction
Hatakeyama, S., et al., J. Am. Chem. Soc., 1999, 121, 10219.
+
X = R
Y = H
Minimizes steric interations, and so is favored thermodnamically
reversible addition
Catalyst as Nucleophilic Trigger: [3+2] Cycloaddition
Zhang, X., et al., J. Am. Chem. Soc., 1997, 119, 3836.
C
H
H H
OOR1
R2
R3 H
O
OR4
+10 mol % catalyst
benzene, 23° C
CO2R4
R2
R3
CO2R1 CO2R1
CO2R4
R2 R3
+
A BR1 = Et, tBu
R2 = H, CO2Et
R3 = H, CO2Me
R4 = Et, iBu, Me, tBu
P
Ph
R
R
H
H
R = Me, iPr
Phophabicyclic catalysts
% yield = 13 - 92
A:B = 94:6 - 100:0
% ee (A) = 36-93
! Size of R4 alters enantioselectivity
! Rigid catalyst structure is important for enantioselectivity
! Best case:
CO2iBu C
CO2Et
CO2Et
CO2iBu
+
88 % yield
100:0 = A:B
93 % ee
CO2iBu
C
CO2Et
CO2Et
PR3
CO2Et
PR3
CO2iBu
CO2EtR3P
CO2iBu
CO2EtR3P
CO2iBu
CO2Et
P
R
R
Ph
EtO2C
H
HH
BuO2C
Catalyst as Nucleophilic Trigger: Mechanism of [3+2] Cycloaddition
Zhang, X., et al., J. Am. Chem. Soc., 1997, 119, 3836.
i
! Concerted bond rearrangement
! Concerted mechanism supported by preservation of olefin geometry
! Achiral version of this reaction reported by Xiyan Lu: J. Org. Chem., 1995, 60, 2908.
PR3
Chiral Ketone Catalyzed Alkene Epoxidation: Initial Report from Shi
R3
R2
R1
O
O
OMe
MeO
O
O
Me
Me
catalyst
30 mol % catalyst
Oxone
H2O-CH3CN
R1
R2
R3
O
! Catalyst works well with trans disubstituted olefins and trisubstituted olefins
! Reaction tolerates alkyl, aryl, heteroatom-containing substituents
35 - 94 % yield
91 - 99 % ee
! Representative examples:
PhPh
78 % yield
99 % ee
PhMe
94 % yield
96 % ee
83 % yield
95 % ee
OTBSMe Ph
O
OMe
76 % yield
91 % ee
Ph
94 % yield
98 % ee
Me
PhMe
89 % yield
97 % ee
C10H21
Me
97 % yield
87 % ee
Me
BuMe
35 % yield
91 % ee
Me
t
Shi, Y., et al., J. Am. Chem. Soc., 1997, 119, 11224.
Chiral Ketone Catalyzed Alkene Epoxidation:
Mechanism of the Shi Epoxidation
R3
R2
R1
O
O
OMe
MeO
O
O
Me
Me
catalyst
30 mol % catalyst
Oxone
H2O-CH3CN
R1
R2
R3
O
Shi, Y., et al., J. Am. Chem. Soc., 1997, 119, 11224.
O
O O
Me Me
OO
MeMe
O
O
R1
R2R3
! Proposed spiro TS
R1
O
R2
R1
R2O
O
HSO5
HSO4
R
R
R
RO
! Catalytic Cycle
Catalyst system also works for conjugated dienes: J. Org. Chem., 1998, 63, 2948.
hydroxy alkenes: J. Org. Chem., 1998, 63, 3099.
conjugates enynes: J. Org. Chem., 1999, 64, 7646.
2,2-disubstituted vinylsilanes: J. Org. Chem., 1999, 64, 7675.
kinetic resolution of racemic cyclic olefins: hydroxy alkenes: J. Am. Chem. Soc., 1999, 121, 7718.
Chiral Ketone Catalyzed Alkene Epoxidation: cis Olefins with Shi's Catalyst
R2
R1
O
O
OMe
MeO
O
NBoc
catalyst
15 - 30 mol % catalyst
Oxone
H2O-CH3CN R2
R1
O
! Reaction requires either R1 or R2 have !-electrons or a heteroatom
! Reaction tolerates cyclic and acyclic alkenes
47 - 91 % yield
77 - 97 % ee
! Representative examples:
Ph
87 % yield
91 % ee
88 % yield
84 % ee
61 % yield
97 % ee
82 % yield
91 % ee
Me
Shi, Y., et al., J. Am. Chem. Soc., 2000, ASAP.
O
Me
PhO
O
O
O O
Me Me
ONBoc
O
O
R(!)R
! Proposed spiro TS
O
R3
R2
R1R1
R2
R3
O
PhPh
PhtBu
OO
OO
O
Chiral Ketone Catalyzed Alkene Epoxidation: Initial Report from Yang
10 mol % catalyst
Oxone/NaHCO3
H2O-CH3CN
! Catalyst works with trans disubstituted olefins and trisubstituted olefins
! Reaction tolerates alkyl, aryl substituents
70 - 99 % yield
33 - 87 % ee
! Representative examples:
99 % yield
47 % ee95 % yield
76 % ee
83 % yield
33 % ee
Yang, D., et al., J. Am. Chem. Soc., 1998, 120, 5943.
tBu
catalyst
Chiral Ketone Catalyzed Alkene Epoxidation: Developments by Yang
10 mol % catalyst
Oxone/NaHCO3
H2O-CH3CN
Yang, D., et al., J. Am. Chem. Soc., 1998, 120, 5943.
! Modifications to catalyst increase ee of stilbene reactions
O
O
Br
Cl
tBu
tBu
tBu
tBu
O
X % ee
90
91
95
! Stereochemical Rationale for Yang
Epoxidation (Macromodel)
OO
OO
O
O
! More ketone catalyzed epoxidation: Denmark, et al., J. Org. Chem., 1997, 62, 8288.
Armstrong, A., et al., Chem. Commun., 1998, 621.
OO
OO
O
catalyst
XX
Amine Catalyzed Alkene Epoxidation
! Stilbenes and disubstiuted aliphatic alkenes do not react
Ph Ph
O
5 mol% amine
Oxone (2 eq.)
CH3CN:H2O (95:5)
NaHCO3 (10 eq.)
pyridine (0.5 eq.)
NH
Ph
Ph
Me
Amine Catalyst
96% yield (1H NMR)
57% ee
Me
O
90% yield (1H NMR)
15% ee
20% yield (1H NMR)
25% ee
O
Me
O
65% yield (1H NMR)
15% ee
O
21% yield (1H NMR)
13% ee
Me
O
93% yield (1H NMR)
9% ee
! The hit parade:
Adamo, M. F., et al., J. Am. Chem. Soc., 2000, 122, 8317.
NH
Radical Cation Intermediates: Amine Catalyzed Alkene Epoxidation
R
KHSO51O2
NH
R
NR
R2
R3R4
R1
R2
R3R4
R1
H
KHSO5KHSO4
R2
R3R4
R1
O
SET
NH
R
SET
R2
R3R4
R1
O
Proposed catalytic cycle for the alkene epoxidation
Adamo, M. F., et al., J. Am. Chem. Soc., 2000, 122, 8317.
Ph
N
Ph
Ph
Me
face of epoxidation
OPh
Ph
Rationale for Observed Stereochemical Outcome
In Conclusion
! Many reactions are catalyzed enantioselectively by organic molecules.
! These reactions can be grouped by the mode of catalysis, deriving from the fact that numerous, quite different
approaches to organic catalysis have been developed.
! Despite much success, often the organocatalyzed reactions lack generality (low yields, low ee's, and/or poor
substrate scope).
! As well, the modes of catalysis often lack generality -- rarely has a catalyst system been applied successfully
to several different reactions.
! Consequently, vast room for improvemet remains; these examples may act as food for thought.