Catalytic, Enantioselective Addition of Carbon...

Evans Group Friday Seminar

June 28, 2002

André Beauchemin

Catalytic, Enantioselective Addition of Carbon Nucleophiles to C=N Double Bonds

1. Background

2. Activation of the electrophile

2.1. Activation via bidentate complexation

– Basic sites present on imine (ex. Acylhydrazones)

– Basic sites present on substrate (ex. Imino esters)

2.2. Activation via single point binding

3. Activation of the nucleophile

4. Bifunctional catalysis

Keywords: Amines, Allylation, Asymmetric, Bifunctional Catalysis, Catalytic, Chiral, Enantioselective, Imine, Imine Aldol, Mannich, Nucleophilic Addition, Staudinger

01-Title 6/25/02 8:29 PM

"Asymmetric Synthesis of Amines by Nucleophilic 1,2-Addition of Organometallic Reagents to the CN-Double Bond"

Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946

Leading References

"Addition of Organometallic Reagents to C=N Bonds: Reactivity and Selectivity"

Bloch, R. Chem. Rev. 1998, 98, 1407-1438

"syn-anti Isomerizations and Rearrangements"

McCarty, C. G. in The Chemistry of the Carbon-Nitrogen Double Bond, Patai, S., Ed., John Wiley &

Sons (London), 1970, chapter 9.

"Catalytic Enantioselective Addition to Imines"

Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094

"Stereoselective Imine Aldol Reactions"

Tedrow, J. S. Evans Group Evening Seminar 1997

"Modern Variants of the Mannich Reaction"

Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045-1070

"Rearrangements and tautomerizations of enamines"

Huang, Z.-T.; Wang, M.-X. in The Chemistry of Enamines, Rappoport, Z., Ed., John Wiley & Sons

(London), 1994, chapter 16.

02-Leading References 6/26/02 6:33 PM

Me Me

O

H

O

Me

MeH2N OMe

Me

O HNPMP

Me

Me

Other Catalytic Enantioselective Synthesis of Chiral Amines

Direct 3-Component Mannich Reaction

+ +

90% yield, 93%ee

L-Proline (20-35 mol%)

Strecker Reaction

Ph H

N Ph

Ph

+ HCN

HN

NH

O

O

Ph

HN NH2

NH

(2 mol%)

Ph CN

HN Ph

Ph

97% yield, ≥99% ee

Reduction P

P

Et

Et

Et

Et

Ph Me

N

HN Ph

OPh Me

HN

HN Ph

O0.2 mol% [Rh]+, H2

95% ee

Ph

NHAc

MePh

NHAc

0.2 mol% [Rh]+, H2

95% ee

P P

Me

Me

Me

Me

• imines

• enamines

03-Chiral amines from catalysis 6/26/02 7:15 PM

R H (R')

O

R H (R')

NR''

R H (R')

NR'''R''

Comparison between C=O and C=N

E-Z geometry problem associated with C=N double bonds

Reduced electrophilicity of the C=N double bond

1.21 Å 1.28 Å 1.26-1.30 Å

173-181 kcal.mol–1C=X bond E: 143

+ 0.51Polarization (δ): + 0.33 + 0.54

XXX

Side reactions observed with organometallics

04-C=O vs C=N 6/25/02 4:44 PM

H N

R

n-Bu NHPMPCHO

n-Bu n-BuLi/THF

OMe

Tomioka: Imine Substituent Influences the Reaction Pathway

Tomioka et al. Tetrahedron 1994, 50, 4429For calculations (MOPAC PM3): J. Org. Chem. 2001, 66, 7051

n-BuLi/THF

(91%)(80%)

R = R =

OMeR =

i-Pr

i-Pr

CHO

Ph

PhLi/THF

Relative magnitude of the LUMO coefficients account for the regioselectivity

Conjugation is not possible (steric)

05-Tomioka-1,2 vs 1,4-addition 6/27/02 8:41 PM

Buchwald: Different Behavior of E and Z Isomers under Reaction Conditions

Buchwald et al. J. Am. Chem. Soc. 1994, 116, 8952; 11703Related hydrosilylation (Optimized) system: Buchwald et al. J. Am. Chem. Soc. 1996, 118, 6784

N

Me

Ph NH

Me

Ph

TiH

H2 (80-2000 psig), THF, 65 ˚C

Similar stereodivergent results were observed in the reduction of ketoximes ethers:Stoichiometric reduction: Sakito et al. Tetrahedron Lett. 1988, 29, 223

Didler et al. Tetrahedron 1991, 47, 4941Catalytic reduction: Bolm et al. Synlett 1994, 655

E:Z = 11:1 81% ee (~10:1 er)

• Reaction is stereodivergent: E imine gives R amine; Z imine gives S amine

• Reaction shows ee dependence on H2 pressure

• Z imine reacts faster than E imine; interconversion of imines is slow

• Best ee obtained at high temperature and pressure

(5 mol%)

06-E-Z impact 6/26/02 2:24 PM

Mechanisms of Interconversion between E and Z Imines

Equilibration via formation of N,O-acetal

Homolytic or Heterolytic π-Bond Cleavage

"Lateral Shift" Mechanism

R1 NR3

R2

R1 NR3

R2

R1 NR3

R2

R1

N

R2R1

NR3

R2

R3

R1

N

R2

R3

sp

• Eact estimated to be 50 kcal/mol or higher; lower energy pathways available• Equilibrium can be induced using hυυυυ

• Rates studies are consistent with this mechanism

"syn-anti Isomerizations and Rearrangements" McCarty, C. G. in The Chemistry of the Carbon-Nitrogen Double Bond, Patai, S., Ed., John Wiley & Sons (London), 1970, chapter 9.

• Hammett ρ of 1.5 found for substituents on R3 = Ar (EWG at 4-position accelerate isomerization)• Rate enhancement increases with increasing size of ortho substituents (R3 = Ar)

• Pathway only available when H2O or ROH present

Tautomerization

• C-H bond must be present α to the imine group

07-Mechanism 6/26/02 5:59 PM

NB

NS S

Br

PhPh

O OO O

F3C

F3C

CF3

CF3

MeSt-Bu

O

St-Bu

OBR2*

MeSt-Bu

O

R1

NH

Me

R2

R1 H

NR2

Ph

Ph

1-naphthyl

(E)-PhCH=CH

Ph(CH2)2

Ph(CH2)2

Corey: First Example Usingan "External" Source of Chirality

Corey et al. Tetrahedron Lett. 1991, 32, 5287

1

PhMe/hexane

1, Et3N, –78 ˚C

R1 anti:syn ee (%)

>99:1

>99:1

>99:1

>99:1

97:3

92:8

90

92

>99

>99

90

90

R2

allyl

Bn

allyl

allyl

allyl

Bn

yield (%)

92

96

91

86

90

86

• Chair transition state with Z imine accounts for the results

08-Corey 6/26/02 6:09 PM

Me

N

R

Ph

R

NH

Ot-Bu

OOTMS

Ot-Bu

OTMS

Ot-Bu

N

TMS

Me

Ph NH

TMS

Ot-Bu

O

Me

Ph

O

OB OPh

Yamamoto: Synthesis of β-Amino Estersvia Double Stereodifferentiation

Yamamoto et al. J. Am. Chem. Soc. 1993, 115, 1151

1 (>1 equiv.)

CH2Cl2, –78 ˚C+

(50-60%)R = Ph, R-1R = Ph, S-1R = n-Pr, R-1R = n-Pr, S-1

92% de74% de94% de86% de

CH2Cl2, –78 ˚C+

(50-60%)

R-1: anti/syn = 40:1,dr (anti) = 99:1

S-1: anti/syn = 2:1,dr (anti) = 94:6

1

Me

Ph

1 (>1 equiv.)

09-Yamamoto1-Chiral Additive 6/28/02 8:04 AM

N

TMS

Me

PhMe

N

Ph

Ph

O BO

O

NH

H

MePh

Yamamoto: Effect of Lewis Acid on Imine Geometry


equiv. of (R)-1 Imine 2 Imine 3

E:Z ratio (–60 ˚C, CD2Cl2)

0

0.3

0.7

1.0

2.0

≥95:5

≥95:5

≥95:5

≥95:5

≥≥≥≥95:5

67:33

60:40

41:59

29:71

≤≤≤≤5:95

32

Observed imine geometry explains the stereochemical outcome of the reaction

10-Yamamoto2-Lewis Acid Effect 6/26/02 6:11 PM

R1

R2

NS

O

R1

R2

NH

S

OR3

i-Pr

Ph

Ph

n-Bu

Me

Me

n-Bu

Me

S

ON RL

RS

AlLi R

Ellman: Synthesis of Chiral Tertiary Amines

Ellman et al. J. Am. Chem. Soc. 1999, 121, 268

R3Li, Me3Al

R1 yield (%) dr

65

93

61

26

86

>99

93

94:6

97:3

99:1

99:1

98:2

99:1

89:11*

R2 R3

Ph

Ph

n-Bu

n-Bu

n-Bu

Me

Ph

Me3Al (equiv.)

0

1.1

1.1

0

1.1

1.1

1.1

Me3Al required for both high yield and diastereoselectivity

E isomer only

* E:Z ratio of imine in CDCl3 = 83:17

For a review on synthesis of chiral 2˚ amines using this auxiliary: Davis et al. Chem. Soc. Rev. 1998, 27, 13

11-Ellman 6/27/02 9:04 PM

1. Background

– E-Z geometry problem

– C=N reduced electrophilicity



– Basic sites present on azomethine group





12-Bidentate on imine 6/27/02 6:33 PM

OMe

OTMS

α-Nap OMe

ONH

20

20

20

10

5

2

N

α-Nap H

HO

Me

Me

Me Me

O

O O

OZr

OH

R

R

R

R

NN Me

R'

Kobayashi: Optimization of the Reaction Procedure

Kobayashi et al. J. Am. Chem. Soc. 1997, 119, 7153

+(X mol%)

CH2Cl2, –15 ˚C

X (mol %) yield (%) ee (%)

>99

80

73

>99

>99

75

34

70

90

92*

91

86*

Additive (X mol%)

–

NMI

NMI

NMI

DMI

NMI

R

H

H

Br

Br

Br

Br

* Reaction was carried out at –45 ˚C

R' = H :R' = Me :

NMIDMI

• Imine prepared from aniline or 2-methoxyaniline showed almost no chiral induction

13-Kobayashi1-Zr-Optimization 6/27/02 7:15 PM

R3

OTMS

Ph

4-(Cl)C6H4

Ph

1-naphthyl

2-furyl

c-C6H11

R2

R2

O

O O

OZr

Br

Br

Br

BrN

R1 H

HO

R1 R3

ONH

R2 R2

OH

Kobayashi: Scope of the Zr-Catalyzed Addition

Kobayashi et al. J. Am. Chem. Soc. 1997, 119, 7153J. Am. Chem. Soc. 2000, 122, 8180

+ (5-10 mol%)

NMI (5-30 mol%)CH2Cl2, –45 ˚C

R1 yield (%) ee (%)

70

86

78

>99

89

56

87

83

88

>98

89

80*

R2

Me

Me

H

H

H

H

R3

OMe

OMe

SEt

SEt

SEt

SEt

* Imine prepared using 2-amino-3-methylphenol

Substitution of –Br for –CF3 at the 6,6' positions of BINOL increase catalyst efficiency (2 mol%)

14-Kobayashi2-Zr-Scope1997 6/27/02 8:46 PM

Oi-Pr

OTMS

OTBS

O

O O

OZr

Br

Br

Br

Br

N

Ph H

Ar

Ph Oi-Pr

ONHAr

DMI

DMI

Ar

HO

OTBS

Oc-C6H11

OTMSN

α-Nap H

Ar

α-Nap Oc-C6H11

ONHAr

OBn

BnO

Kobayashi: Scope of the Zr-Catalyzed Addition-2


+

1

>99% yield, syn/anti = 96/4, 99% ee (syn)65% yield, syn/anti = >99/1, 96% ee (syn)

+ 1 (10 mol%)

PhMe, –78 ˚C

91% yield, syn/anti = 6:9480% ee (anti)

1 (10 mol%)

PhMe, –78 ˚C

E – OTBS:Z – OTBS:

15-Kobayashi3-Zr-Scope1998 6/27/02 7:06 PM

R2

OTMS

R1 H

N

HO

ZrO

O

O

O

L

L

ZrO

O

O

OO

N

R1

H

ZrO

O

O

OO

N

R1

R2

OTMS

ZrO

O

O

OTMS

O

N

R1

R2

O

R2

O

N

R1

Ar

TMS

R2

O

NH

R1

OTMS

Kobayashi: Mechanism of the Zr-Catalyzed Addition

Kobayashi et al. J. Am. Chem. Soc. 1997, 119, 7153J. Am. Chem. Soc. 2000, 122, 8180

Tetrahedron 2001, 57, 861

• No mention of the role of DMI as possible TMS shuttle• Silyl crossover observed if imine is reacted with 2 different thiosilylketeneacetals

16-Kobayashi4-Zr-Mechanism 6/25/02 4:38 PM

Ph

2,3-(MeO)2C6H3

2-furyl

Ph

2,3-(MeO)2C6H3

2-furyl

H

R2

O

O Ot-Bu

Ot-BuZr

N

R1 H

HO

R1

NH

OH

SnBu3

R2

Br

Br

Me

Me

Me

H

H

H

Kobayashi: Scope of the Zr-Catalyzed Addition

Kobayashi et al. Angew. Chem., Int. Ed. 2001, 40, 1896

+

(10 mol%)

PhMe, 0 ˚C

R1 yield (%) ee (%)

84

72

76

77

80

68

93

91

92*

96**

87**

96**

R2

* 3,3'-Cl2BINOL-derived catalyst was used** Catalyst prepared with 2 equivalent of MeOH in THF; then 0.1 mmHg

syn:anti> 95:5

OH

OH

O

N

R1 H

Zr

OO

O

Me

SnBu3

*

• Replacement of CH2OH for Me or CH2OTBS results in enantioselection (~55% ee)

17-Kobayashi5-Zr-Allylation 6/26/02 6:43 PM

R1 O R1 NH

Et

Ph

2-furyl

3-pyridyl

n-Bu

i-Bu

c-C3H5

TBDPSOCH2

NH

HN

O

NH

O

n-Bu

PhOH

MeO

H2N

OMeOMe

H

Hoveyda & Snapper: Three-Component Catalytic Asymmetric Synthesis of Aromatic and Aliphatic Amines

Hoveyda, Snapper et al. J. Am. Chem. Soc. 2001, 123, 984 J. Am. Chem. Soc. 2001, 123, 10409

+

R1 ee (%)

91

83

85

97

95

98

>98

yield (%)

92

98

>98

69

58

83

48

Zr(Oi-Pr)4•i-PrOH (10 mol%)Et2Zn (6 equiv.)

PhMe/THF (7:1), –40 ˚C

(10 mol%)

No examples of functionalized dialkylzincs

18-Hoveyda-Snapper 6/26/02 1:36 PM

R3

OTMS

R1 R3

OHN

Ph(CH2)2

C6H13

Ph

ClCH2

N

R1 H

NH

O C6H4(CF3)-4

NH

C6H4(CF3)-4O

R2

R2R2 R2

O

O O

OZr

Br

Br Br

Br

Kobayashi: Zr-Catalyzed Addition to Acylhydrazones

Kobayashi et al. Chem. Lett. 1998, 1131

+ (20 mol%)

PhMe, 0 ˚C

R1 yield (%) ee (%)

66

42

60

39

59

59

86

88

96

87

81*

93

R2

Me

H

Me

H

Me

Me

R3

OMe

SEt

OMe

SEt

OMe

OMe

* 50 mol% catalyst was used

19-Kobayashi5-Zr-Acylhydra 6/25/02 1:21 PM

R1 NPPh2

O

R1 NH

PPh2

ONO2

MeNO2

Ph

4-(Cl)C6H4

4-(Me)C6H4

2-furyl

2-(HS)C6H4

Yb

O O

K

O O

OHOH

Shibasaki: Catalytic Asymmetric Nitro-Mannich-Type Reaction

Shibasaki et al. Angew. Chem., Int. Ed. 1999, 38, 3504

+

R1 ee (%)

91

87

89

83

69

yield (%)

79

93

85

57

41

PhMe/THF (7:1), –40 ˚C

from: (R)-binaphthol,KOt-Bu, Yb(OTf)3

(3:1:1)

(20 mol%)

* *

*

20-Shibasaki-Nitro 6/25/02 1:23 PM

1. Background





– Basic sites present on azomethine group





21-Bidentate on substrate 6/27/02 6:33 PM

N

EtO

O

H

Ts

Ph

OTMS

Ph

NHTs

EtO

O

O

P

P

R

R

MLn

R

R

AgSbF6

Pd(ClO4)2

CuClO4

CuClO4

Ni(SbF6)2

+2-10 mol%

THF or CH2Cl2, T

MLn T (˚C) ee (%)

– 80

– 40

–

– 78

0

–

90

67

80

89

98

30

R

Ph

Ph

Ph

4-(Me)C6H4

Ph

Lectka: Catalytic Enantioselective Alkylation of Imino Esters

Lectka et al. J. Am. Chem. Soc. 1998, 120, 4548J. Am. Chem. Soc. 2002, 124, 67

22-Lectka1-Metal 6/27/02 10:06 AM

N

EtO

O

H

Ts

R'

NHTs

EtO

O

P

P

R

R

CuClO4

R

R

R1

OTMS

Ph

OTMS

OTMS

+2-10 mol%

THF or CH2Cl2

Nuc anti/syn ee (%)yield (%)

Lectka: Scope of the Alkylation Reaction

Lectka et al. J. Am. Chem. Soc. 1998, 120, 4548J. Org. Chem. 1998, 63, 6090

J. Am. Chem. Soc. 2002, 124, 67

Nuc

86 25:1 98

82 >9920:1

R1 = OPh

Ph

3-(NO2)C6H4

4-(MeO)C6H4

t-Bu

83

95

87

94

65

–

–

–

–

–

72

98

94

86

90

R= 4-(Me)C6H4

23-Lectka2-Scope 6/27/02 11:22 AM

N H

O OEt

Ts

P

R'R'

Cu

PR'

R'

N H

O OEt

Ts

P

R'R'

Cu

PR'

R'

N

O OEt

Ts

P

R'R'

Cu

PR'

R'

P

R'R'

CuClO4

PR'

R'

RO

TMS

N

EtO

O

R

O

R

OTMS

Ts TMS

N

H

O

EtO

Ts

Lectka: Proposed Mechanism

Lectka et al. J. Am. Chem. Soc. 2002, 124, 67

Re Attack

ComplexFormation

Silyl transfer

24-Lectka3-Mechanism 6/20/02 10:44 PM

N

EtO

O

H

Ts

R2

NHTs

EtO

O

P

P

R

R

CuClO4

R

R

+(2-10 mol%)

PhCF3, rt

Olefin ee (%)yield (%)

Lectka: Scope of the Ene Reaction

Lectka et al. J. Am. Chem. Soc. 1998, 120, 11006J. Am. Chem. Soc. 2002, 124, 67

See also: Jørgensen et al. J. Chem. Soc., Chem. Commun. 1998, 2547 (CuPF6 catalyst)

Olefin

94 99

85 89

R1 = Ph

SPh

92

85

99

98

Product

R1

O

N

Ts

R1EtO2C

NHTs

EtO2C

NHTs

EtO2C

NHTs

EtO2C

NHTsO

EtO2C

NHTsN

Ts

85 95

90 85

R= 4-(Me)C6H4

25-Lectka4-Ene 6/27/02 3:43 PM

N

EtO

O

H

Ts

R2

NHTs

EtO

O

P

P

R

R

CuClO4

R

R

+(2-10 mol%)

Allylsilane ee (%)yield (%)

Lectka: Scope of the Allylation Reaction

Lectka et al. J. Am. Chem. Soc. 2002, 124, 67See also: Jørgensen et al. J. Org. Chem. 1999, 64, 4844

Allylsilane

85 75

88 92

88 72*

Product

91 94

88 87

TES

CH2Cl2, – 78 ˚C

EtO2C

NHTs

TMS

EtO2C Ph

NHTs

Ph

TMS

EtO2C Ph

NHTs

PhMe

Me

EtO2C

NHTsTMS

anti:syn

–

20:1

–

–

10:1

TMS EtO2C

NHTs

Ph

Ph

R= 4-(Me)C6H4

* Can be improved to 80% ee by using CuPF6 catalyst and tri(n-butyl)allylstannane (Jørgensen)

26-Lectka4-Allylation 6/27/02 3:49 PM

N

EtO

O

H

Ts

TsHN OEt

O+

Johannsen, Jørgensen: Catalytic Enantioselective Friedel-CraftsReactions of α-Imino Esters

Jørgensen et al. Angew. Chem., Int. Ed. 2000, 39, 4114

THF, – 78 ˚CNH

NH

P

P

R

R

CuClO4

R

R

(2-10 mol%)

R= 4-(Me)C6H4

Johannsen, M. J. Chem. Soc., Chem. Commun. 1999, 2233

89% yield, 96% ee

NCO2Et

EtO

O

H

HN

OEt

O

+ THF, – 78 ˚C

P

P

R

R

CuPF6

R

R

(2-10 mol%)

R= 4-(Me)C6H4

75% yield, 96% ee

CO2Et

N

N

27-Friedel-Crafts 6/28/02 8:06 AM

O

EtON R1

OR2

OTMS

Ph

NH

Ph

NH

α-Napα-Nap CuTfO OTf

R2

O

EtO

O

NH

O

R1

C11H23

Me

Ph

Kobayashi: Reaction of N-Acylimino Esters using Cu(II)-Catalyst

Kobayashi et al. Org. Lett. 2002, 4, 143

+ (10 mol%)

CH2Cl2, T, 18h

R1 yield (%) ee (%)

92

97

88

85

79

81

76

94

92

93

94

97

96

90

R2

Ph

4-(MeO)C6H4

4-(Cl)C6H4

Ph

Ph

OMe

SEt

T (˚C)

0

0

0

0

–78

–78

–78

• Reaction is also efficent with methyl enol ethers, to afford the parent "internal" methyl enol ether in similar yields and ee• Proposed: [4+2]-cycloaddition

N

O

OTMS

R1EtO2C

R2

28-Kobayashi-Cu 6/26/02 6:30 PM

O

EtON

R1

OTMS

Ph

NH

Ph

HN

PhPh

R1

O

EtO

O

NH

Ph

Ph

4-(Cl)C6H4

4-(Me)C6H4

4-(MeO)C6H4

Ph

i-Pr

NHBz

BzHN

R2

R2

H

H

H

H

H

Me

Me

Kobayashi: Reaction using Zn(II)-Catalyst in Aqueous Media


+

(10 mol%)

TfOH (1 mol%)H2O:THF (1:9), 0 ˚C

R1 syn:anti ee (%)

—

—

—

—

—

96:4

90:10

90*

92

89

91

91

91

30

R2

ZnF2 (50 mol%)

(3 equiv.)

yield (%)

19

89

88

82

63

91

30

* Reaction run without TfOH

29-Kobayashi-Zn 6/25/02 1:37 PM

1. Background





– Basic sites present on imine





30-Single Point binding 6/27/02 6:36 PM

Ph

2-naphthyl

4-(Me)C6H4

3-pyridyl

3,4-(OCH2O)C6H3

O

OTi

N

R H

Bn

Murahashi: Titanium-Catalyzed Enantioselective Addition to Nitrones

Murahashi et al. J. Am. Chem. Soc. 2002, 124, 2888

+(10 mol%)

PhMe, –78 ˚C

R yield (%) ee (%)

99

94

66

90

74

92

88

88

80

80

O

O t-BuO

OMe

OTBS

OMe

O

R

NHO Bn

• Reaction exhibit a positive nonlinear relationship

• Biphenoxide catalyst affords the opposite enantiomer (55% ee, R = Ph)

31-Murahashi 6/28/02 1:09 PM

1. Background










32-Electrophile activatio copy 6/27/02 6:38 PM

Ph H

N

Ph Me

HN

OMe OMe

Tomioka, Denmark: Catalytic Asymmetric Addition of Organolithium Reagents

Tomioka et al. Tetrahedron Lett. 1991, 32, 3095Tetrahedron 1994, 50, 4429

+PhMe, –100 ˚C

(30 mol%)

MeLi

97% yield, 90% ee

Ph H

N

Ph Bn

HN

Et Et

N

O

N

O

t-But-Bu

OMe OMe

Denmark et al. J. Am. Chem. Soc. 1994, 116, 8797J. Org. Chem. 2000, 65, 5875

+DMF, 0 ˚C

(10-20 mol%)

BnLi

62% yield, 81% ee

Me Me

MeO

O

Bn

Me2N

N.B. The best results obtained by the authors are shown on this slide

33-Chiral ligands 6/28/02 8:09 AM

4-(CF3)C6H4

4-(MeO2C)C6H4

4-(F)C6H4

Ph

Ar1

Hayashi: Rhodium Catalyzed Arylation of Imines

Hayashi et al. J. Am. Chem. Soc. 2000, 122, 976

ee (%)

96

96

92

92

92

82

yield (%)

90

89

90

69

86

31

Ar1 H

NNs

+ Ar2-SnMe3

Me

OMe

Me

Ph2P (6 mol%)

Rh(acac)(C2H4)2 (3 mol%),LiF, dioxane, 110 ˚C

Ar1 Ar2

HNNs

Ph

4-(MeO)C6H4

Ph

Ph

4-(MeO)C6H4

4-(CF3)C6H4

Ar2

Reactions with bidentate phosphines were very slow

(5 equiv.)

34-Hayashi 6/25/02 1:48 PM

R1 NR2

R1 NH

R2

Me

Et2Zn

Ph

4-(MeO)C6H4

4-(Cl)C6H4

2-(Cl)C6H4

2-furyl

N

OPPh2Me

MeMe

BnBn

Ts

Ms

SES

Ms

Ms

Ms

SES

Tomioka: Copper-Amidophosphine Catalyst for Asymmetric Addition of Diethylzinc to Imines

Tomioka et al. J. Am. Chem. Soc. 2000, 122, 12055

+

R1 ee (%)

93

94

90

92

94

92

93

yield (%)

98

97

98

83

95

95

98

Cu(OTf)2 (1-8 mol%),PhMe, 0 ˚C

(1-10 mol%)

R2

35-Tomioka 6/26/02 1:58 PM

OBz

N

N

H

O

ClR

N

HOEt

O

Ts

N

R CO2Et

TsO

NMe2 NMe2

Lectka: Catalytic Asymmetric Staudinger Reaction

Lectka et al. J. Am. Chem. Soc. 2000, 122, 7831

+(10 mol%)

Catalyst plays two distinct roles: base (ketene generation) and nucleophilic catalyst

, PhMe, –78 ˚C to rt

cis:trans ee (%)

99:1

99:1

99:1

>99:1

99:1

96

99

99

98

95

yield(%)

65

57

45

61

56

R

Ph

Et

OPh

OAc

OBn

OMe

36-Lectka-Staudinger 6/26/02 5:45 PM

Fe

MeMe Me

MeMe

R3 H

NTs

NO

R3

Ts

R1

R2

N

N

O

C

R1 R2

Fu: Catalytic Asymmetric Staudinger Reaction

Fu et al. J. Am. Chem. Soc. 2002, 124, 1578

+

(10 mol%)

PhMe, rt

cis/trans ee (%)

–

–

–

8:1

10:1

9:1

10:1

81

91

94

98

95

95

98

R2

i-Bu

i-Bu

Et

Et

R1

Ph

Ph

Ph

Ph

R3

Ph

(E)-PhCH=CH2

c-C6H11

Ph

(E)-PhCH=CH2

2-furyl

c-C3H5

yield (%)

84

91

76

88

95

97

98

–(CH2)6–

–(CH2)6–

–(CH2)6–

37-Fu-Staudinger 6/27/02 3:20 PM

Fe

MeMe Me

MeMe

N

N

O

C

R R

catalyst*

O

R

R

catalyst*

O

R1

N

R R

Ts

NTs

R1H

N

R1

O Ts

R

R

Fu: Mechanism of the Staudinger Reaction

Fu et al. J. Am. Chem. Soc. 2002, 124, 1578

38-Fu-Staudinger-Mechanism 6/25/02 1:42 PM

N

N

O

N

O

PhPhO

Ar1 HHPh Ar1

Ph

NHAr2

Ar2-NH2

Me

Me Ph

NHO Bn

HMe

Me

NO Bn

Ph

H

Me Me

N

O

N

O

PhPh

Carreira, Li: Catalytic Asymmetric Addition of Metal Acetylides

For more on Catalytic Additions of M-acetylides: Janey, J. Evans Group Friday Seminar 2002

Li et al. J. Am. Chem. Soc. 2002, 124, 5638

+ +(10 mol%)

CuOTf (10 mol%),H2O or PhMe

48-93% yield,78-96% ee

Carreira et al. Acc. Chem. Res. 2000, 33, 373

+(cat.)

Zn(OTf)2 (cat.),i-Pr2NEt (cat.)

85% yield, 88% ee

39-Acetylides 6/26/02 1:16 PM

1. Background










40-Bifunct catalysis 6/27/02 6:40 PM

Ph

4-(MeO)C6H4

(E)-PhCH=CH

R1 H

NR2

Sn(n-Bu)3

R1

HNR2

Me

Me

ClPdPd

Cl

Bn

PMB

Ph

n-Pr

Bn

Bn

Yamamoto: Catalytic Asymmetric Allylation of Imines

Yamamoto et al. J. Am. Chem. Soc. 1998, 120, 4242J. Org. Chem. 1999, 64, 2614

R1 yield (%) ee (%)

62

50

74

30

48

68

81

80

0

70

78

61

R2

+DMF, 0 ˚C

(5 mol%)

Running the reaction with allylsilane also possible under the following conditions:5 mol% cat., allyltrimethylsilane (2 equiv.), TBAF (0.5 equiv.), n-hexane/THF, 0 ˚C

(similar yields and ee)

41-Yamamoto 6/27/02 3:15 PM

R1 H

NR2

(n-Bu)3Sn

R1

NR2

Me

Sn(n-Bu)3

Pd

Me

Pd

Me

Pd N

n-Bu3SnCl

N

R2

R1

H

R2

R1

(n-Bu)3Sn

Yamamoto: Catalytic Asymmetric Allylation of Imines


Dimer

42-Yamamoto - Mechanism 6/24/02 12:02 PM

NPMP

i-PrO

O

H R

OTMS

R

HN

i-PrO

O

O

P

P

R

R

Pd

R

RP

P

R

R

Pd

R

RHO

OH

Sodeoka: Catalytic Enantioselective Alkylation of Imino Esters

Sodeoka et al. J. Am. Chem. Soc. 1998, 120, 2474J. Am. Chem. Soc. 1999, 121, 5450

+5 mol%

Solvent, rt, 5-19 h

R ee (%)yield (%)

Ph

2-naphthyl3,4-(Cl)2C6H4

2-(MeO)C6H4

3-(NO2)C6H4

Me

9560458280876279

9067*53*8384716053

2+2 BF4

–

Solvent

DMFTHF

CH2Cl2DMFDMFDMFDMFDMF

* Reaction required 4.5 days

PMP

R = Tolyl

43-Sodeoka1-Scope 6/26/02 1:29 PM

Pd

HO

PdP

P

P

POH L

Pd

HO

PdP

P

P

PO

R1

PdP

P O

L

R1

PdP

P O

N

R1

CO2R2

R3H

P

P

N

CO2R2

R1O

Pd

R3

PdP

P OH

L

Pd

HO

PdP

P

P

P OH – TMSOH

R1

OTMS

R1

OTMS

–TMSOHH2O

HN

CO2R2R1

OR3

Sodeoka: Proposed Mechanism

Sodeoka et al. J. Am. Chem. Soc. 1999, 121, 5450

2+ 2+

2+

L

L

X– = BF4–

2+

2+

2+

2+

44-Sodeoka2-Mechanism 6/27/02 6:44 PM

N

CO2Et

PMP

H

O2NCO2Et

HN

R

PMP

Me Me

N

O

N

O

PhPhCu

H

Me

Et

n-C5H11

Bn

Ph

Jørgensen: Catalytic Asymmetric Aza-Henry Reaction

Jørgensen et al. Angew. Chem. Int. Ed. 2001, 40, 2992 See also: J. Am. Chem. Soc. 2001, 123, 5843 (silyl nitronates: in Appendix)

+ (10-20 mol%)

Et3N (10-20 mol%), CH2Cl2, rt

R syn/anti ee, syn (%)

–

70:30

95:5

93:7

95:5

55:45

87

97

97

97

95

74

yield (%)

38

61

81

52

80

59

TfO OTf

Me

MeN

O

NO

Cu

O NN

PMPEt

O OEt

H

O

Ph

R NO2

45-Jorgensen-Nitro 6/28/02 11:25 AM

N

EtO

O

H

TsNHTs

OEt

O

+(10 mol%)

Jørgensen: Catalytic Enantioselective DirectMannich Reaction of α-Imino Esters

Jørgensen et al. Angew. Chem., Int. Ed. 2001, 40, 2995

CH2Cl2, rt, 20-40h

N

O

N

O

Me Me

PhPhCu

TfO OTfO

EtO2C

R R

EtO2C

O

yield (%) ee (%)

70

89

98

94

79

89

>98

94*

97

78

R

H

Me

Me

Bn

Br

syn:anti

–

>10:1

>10:1

>10:1

>10:1

* 5 mol% catalyst was used

Me

MeN

O

NO

Cu

ON

PMPR

O OEt

HPh

H

OOEt

46-Jorgensen-Direct 6/27/02 5:23 PM

Et2Zn

Ph

3-(Cl)C6H4

4-(Cl)C6H4

4-(MeO)C6H4

2,6-(Cl)2C6H3

4-(t-Bu)C6H4

OHN

Me

Ph

Me

ArMe

HN

O

H

Ar SO2Tol

HN

O

H

Ar H

N

O

H

Ar

Bräse: Catalytic Asymmetric Addition of Dialkylzincs

Bräse et al. J. Am. Chem. Soc. 2002, 124, 5940

ee (%)

95

93

89

95

95

75

yield (%)

>99

99

>99

97

98

>99

Et2Zn (3 equiv.),hexane, 0-20 ˚C

(2-5 mol%)

47-Brase 6/26/02 2:04 PM

Conclusion

– Great progress has been made over the past 5 years in the development of catalytic, enantioselective additions to C=N double bonds

– Catalysis via nucleophile activation was achieved

– Catalysis via electrophile activation was achieved

– Bifunctional catalysis was achieved

– However, most systems have poor generality with regards to

aromatic vs. aliphatic (C=N)

nucleophile

nitrogen protective group

– No catalytic, enantioselective approaches to tertiary amines reported to date...

48-Conclusion 6/26/02 5:24 PM

HN

EtO

O

P

P

R

R

CuClO4

R

R

+ 2-10 mol%

THF or CH2Cl2

ee (%)yield (%)

Lectka: Reaction with N,O- and N,N-Acetals and Hemiacetals

Lectka et al. J. Org. Chem. 1999, 64, 2168Tetrahedron 1999, 55, 8869

93

85

81

90

89

78

95

90

76

95

87

96

R3

OTMS

R3

OR1

R2

NHR1

EtO

O

R3

Ph

TMSCH2

OPh

Ph

Ph

Ph

R2

OH

OH

OH

NTs

OEt

OH

R1

Ts

Ts

Ts

Ts

Ns

SES

• First equivalent of enol ether leads to formation of the iminoester (alternatively, 1

equiv. of TMSCl can be used, followed by 1 equiv. of enolsilane)

• Desilylated material is isolated after the reaction (no need for F–) in contrast with

parent reaction with iminoester

• If R1 = Bz, exclusive formation of the ethyl glyoxylate adduct!!!

(2 equiv.)

49-Lectka-NOacetals 6/27/02 11:49 AM

R1 NPPh2

O

R1 NH

PPh2

OEtEt2Zn

Ph

2-furyl

3-pyridyl

(4-MeO)C6H4

(4-Me)C6H4

(4-Cl)C6H4

NPh

PhOH

Ph

H

Andersson: Chiral Aminoalcohol-Promoted Addition of Diethylzinc

Andersson et al. Tetrahedron 2001, 57, 1615

+

R1 ee (%)

98

89

87

98

97

95

yield (%)

75

92

70

91

70

67

PhCl, rt, 18h

(1 equiv.)

(3 equiv)

Attempts to make this process catalytic failed

Many other reports of chiral promoters for the same transformation (aminoalcohols)

50-Andersson-Et2Zn 6/20/02 10:51 PM

N

R1

TMSO O N

CO2Et

PMP

H

O2NCO2Et

HN

R1

PMP

R3 R3

N

O

N

O

Ph

R2

Ph

R2

MLn

Et

Me

n-C5H11

Bn

Jørgensen: Catalytic Asymmetric Aza-Henry Reaction

Jørgensen et al. J. Am. Chem. Soc. 2001, 123, 5843

+ (20 mol%)

THF, –100 ˚C

R1 syn/anti ee (%)

3:1

18:1

10:1

25:1

5:1

39:1

32:1

90

89

97

95*

>98

83*

88

R2

H

H

Ph

Ph

H

Ph

Ph

MLn

Cu(I)ClO4

Cu(II)(OTf)2

Cu(I)PF6

Cu(II)(SbF6)2

Cu(I)ClO4

Cu(II)(SbF6)2

Cu(I)ClO4

yield (%)

90

67

68

94

67

87

93

* CH2Cl2 was used as solvent

R3

Me

Me

H

H

Me

H

H

51-Jorgensen-Nitro-Silyl 6/27/02 5:48 PM

N

PMP

HO2N

CO2Et

HN

Et

PMP

Me

MeN

O

NO

Cu

O OEt

(R)-PhBox-Cu

N

Et

TMSO

O

H

O NN

PMPEt

O OEt

H

O

Ph

– TMS

Jørgensen: Proposed Mechanism and Transition State Model

Rapid equilibrium between the E and Z form of the copper nitronate is assumed(TMS nitronate = ca. 10 kcal/mol: Dunitz, Seebach et al. Helv. Chim. Acta 1980, 63, 697)

No clear statement about the dissociation of the TMS group...

Jørgensen et al. J. Am. Chem. Soc. 2001, 123, 5843

52-Jorgensen-Nitro-rationale 6/28/02 11:26 AM

Catalytic, Enantioselective Addition of Carbon...

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