Non-MacMillan Approaches Enantioselective Organic Catalysis · Enantioselective Organic Catalysis:...

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


O'Donnell, M. J., et al., J. Am. Chem. Soc., 1989, 111, 2353.


Phase Transfer Catalysis: Support for Stereochemical Model

O

NtBuO


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

+


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


! 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


! 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.

+


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


20 vol. %

+


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



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


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

+


23° C, 12 - 48 hours

Me

Me


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

+


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.

+


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


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


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


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.

Non-MacMillan Approaches Enantioselective Organic Catalysis · Enantioselective Organic Catalysis:...

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