Alkylation of Metalated O-Silyl Cyanohydrins of β-Silyl-α,β-epoxyaldehydes

Takeda, K.;Kawanishi, E.;Sasaki, M.;Takahasi, Y.;Yamaguchi, K. Org. Lett. 2002, 4, 1511-1514.

1

tBuMe2Si

O

CN

OSiMe2But

H

tBuMe2SiO CN

OSiMe2But

H

tBuMe2SiO CN

OSiMe2But

H

tBuMe2Si

O

CN

OSiMe2But

tBuMe2Si CN

OSiMe2ButO

H

RXbase

-80 °C5 min

R = Me, Et, Pri, CH2CH=CH2, CH2Ph

base

LiNiPr2 (LDA)

LiN(SiMe3)2 (LHMDS)

NaN(SiMe3)2 (NHMDS)

KN(SiMe3)2 (KHMDS)

yield (%)

58 - 98

15 - 90

80 - 98

80 - 95

tBuMe2SiO CN

OSiMe2But

H

R

A Proposed Reaction Pathway2

Sasaki, M.;Kawanishi, E;Nakai, Y.;Matsumoto, T.;Yamaguchi, K.;Takeda, K. J. Org. Chem. 2003, 68, 9330-9339.

OSiR3NC

HH

R3Si

O

CN

R3SiO

HH

R3Si

O

OSiR3NC

H

SiR3

OH

M

SiR3H

H

H

NC OSiR3

O

CNHR3SiO

HO

SiR3

NC

OSiR3

HO

SiR3

H

CNR3SiO

H

SiR3

OH

R3SiO CN

OSiR3

1A

CN

OSiR3R3SiO

CN

OSiR3R3SiO

R

CN

OSiR3

R3SiO

R

N

R R

SiR3

H

H

H

R3SiO CN

O

1B

N

R R

E-isomer

Z-isomer

An Approach to New Acrolein β-Anion Equivalent3

O

ZR3SiR3Si

O

Zbase

El+

Z

H

R3Si

O

El+

ZR3SiO

El

H

desilylationelimination

O El

H

Z = leaving group

O

ZR3Si

Acrolein !-Anion Equivalent

H

O

Equivalents of the Acrolein β-Anion Synthon

4

Corey, E. J.; Erickson, B. W.; Noyori, R. J. Am. Chem, Soc. 1971, 93, 1724-1729.Chinchilla, R.; Nájera, C. Chem. Rev. 2000, 100, 1891-1928.

RX YRn-BuLior LDA RX YR

Li RX YREl

El

1. hydrolysis2. elimination

El

H

O

H

O X = Y = S or Se

X = S, Y = O

X = SO2, Y = O

MeS SMe

1. LDA2. n-C5H11Br

-75 °C, 2hr(90%)

MeS SMe

C5H11

HgCl2

50 °C, 4 hr(84%)

C5H11

H

O

MeS SMe

1. LDA

2. R1R2CO

-75 °C to rt(89-97%)

MeS SMe

R2

R1 OH

HgCl2

85 °C, 4 hr(41%)

H

O

R1 = C2H5; R2 = H

R1 = R2 = CH3

R1 = R2 = Ph

HO

R2R1

R1 = C2H5; R2 = H

An Approach to New Acrolein β-Anion Equivalent

5

O

ZR3SiR3Si

O

Zbase

El+

Z

H

R3Si

O

El+

ZR3SiO

El

H

desilylationelimination

O El

H

Z = leaving group

O

ZR3Si

Acrolein !-Anion Equivalent

H

O

New Acrolein β-Anion Equivalents6

Preparation of γ-(p-Toluenesulfonyl)-α,β-epoxysilane

tBuMe2Si

O

S

N

tBuMe2Si

O

S S

N

tBuMe2Si

O

S

N

O

Me3Si

O

SO2pTol

tBuMe2Si

O

OTf

tBuMe2Si

O

SO2pTol

tBuMe2Si OH tBuMe2Si OH

OmCPBA

Na2HPO4, CH2Cl2

(100%)

MsCl

Et3N, CH2Cl2

tBuMe2Si OMs

O NaI

acetone tBuMe2Si I

O

p-TolSO2Na

DMF tBuMe2Si SO2p-Tol

O

(72% 2 steps)

(80%) mp 76 °C

7

PhCH2Br

NHMDS, THF-80 ° to -40 °C

tBuMe2SiO SO2p-Tol

CH2Ph

PhO

n-Bu4NF, THF

-70 °C, 15 min

(88%) (85%)

tBuMe2Si SO2p-Tol

O

H(E/Z = 2.0)

Reaction of γ-Methalated γ-Sulfonyl-α,β-epoxysilane with Electrophile Followed by Desilylation with Concomitant Elimination of the Sulfonyl Group (I)

1. BnBr (1.0 eq), NHMDS (1.0 eq), -80 ° to -60 °C, 40 min2. TBAF (1.1 eq), THF (0.1 M), -80 ° to -60 °C, 30 min

1. BnBr (1.0 eq), NHMDS (1.0 eq), -80 ° to -60 °C, 30 min2. EtOH (1.0eq), TBAF (1.1 eq), THF (0.08 M), -85 ° to -80 °C, 10 min

1. BnBr (1.05 eq), NHMDS (1.0 eq), -80 ° to -60 °C, 30 min2. EtOH (3.0eq), TBAF (1.1 eq), THF (0.08 M), -85 ° to -70 °C, 15 min

29

61

85

41

9

-

conditionsyield (%)

2 3

1. PhCH2Br, NHMDS2. n-Bu4NF

tBuMe2SiO SO2p-Tol

CH2Ph

PhO tBuMe2Si SO2p-Tol

O

2 31

+

Reaction of γ-Methalated γ-Sulfonyl-α,β-epoxysilane with Electrophile Followed by Desilylation with Concomitant Elimination of the Sulfonyl Group (II)

8

tBuMe2Si SO2p-Tol

O 1. El (1.05 eq), NHMDS (1.0 eq) -80 ° to -50 °C

H El

O

El

Br

I(CH2)7CH3

product

H (CH2)7CH3

O

yield (%)

8482

H

O85

H (CH2)4OTBS

O

68

CO2EtI

OHC(CH2)4CH3

H

O

74

H

O

(CH2)4CH3 77

CO2Et

OH

I(CH2)4OTBS

El product yield (%)

2. TBAF (1.0 eq), EtOH (3.0 eq) -80 ° to -70 °C

Br (CH2)4CH3

H

(CH2)4CH3

O

An Approach to New Acrolein β-Dianion Equivalent9

R3Si

O

SO2p-Tolbase

El1

desilylationelimination

O El2

H

Acrolein !-Dianion Equivalent

H

O

SO2p-TolR3SiO

El1

H

base

El2SO2p-TolR3SiO

H

El2El1

El1

H

tBuMe2Si SO2p-Tol

O 1. NHMDS (1.0 eq), R1X (1.1 eq), -80 ° to -40 °C

2. NHMDS (4.0 eq), R2X (1.3 eq), -80 ° to -55 °C

3. TBAF (1.0 eq), EtOH (3.0 eq), -80 ° to -70 °C H

O

THF

R2

R1

product yield (%)

I(CH2)7CH3

I(CH2)7CH3

R1X

H

O Et

(CH2)7CH3

H

O (CH2)7CH3

(CH2)7CH3

52

76

R2X

IEt

I(CH2)7CH3

Application of the Epoxysilane Rearragement to Wittig-Type Olefination Reaction

10

tBuMe2Si

O

IPPh3

R3Si

O

PPh3 I

conditions benzene, reflux ether, rt CH2Cl2, rt

tBuMe2Si I

O

80%

P(OMe)3 tBuMe2Si P(OMe)2

O O LDA, CH3(CH2)4CHO

tBuMe2SiO P(OMe)2

O

C5H11HO

38%THF-80 ° to 10 °C

R3Si

O

P(OR)2

O

R3Si

O

PPh2

O

R3SiO

R'

R

Horner-Wadsworth-Emmons Reaction

R3Si

O

PPh3Wittig ReactionX

tBuMe2Si

O

XtBuMe2SiO XtBuMe2Si

O

XBase

RCOR'

Wittig-Horner Reaction

Preparation of γ-Phosphinoyl-α,β-epoxysilane

11

Reactions of γ-Phosphinoyl-α,β-epoxysilane with Cyclohexanone

tBuMe2Si PPh2

O O1. base, -80 °C, 10 min

2. cyclohexanone tBuMe2SiO PPh2

OHO

2

tBuMe2SiO

tBuMe2SiO PPh2

OH

base

n-BuLi

n-BuLi

NaN(SiMe3)2

NaN(SiMe3)2

KN(SiMe3)2

additive

-

HMPA

-

HMPA

HMPA

3

-

13

20

15

-

2

31

3

-

-

-

1

29

26

28

31

53

yield (%)KHMDS, THF

-80 °C, 15 min

3

1

tBuMe2Si OH tBuMe2Si Br

NBS, Me2S

CH2Cl255% (4 steps)

1. LiPPh2, THF

2. H2O2

tBuMe2Si PPh2

O

tBuMe2Si PPh2

OOmCPBA

CH2Cl2

85%

78%

OEE3 steps

mp 108 °C

Reactions of γ-Phosphinoyl-α,β-epoxysilane with Ketones and Aldehydes

12

tBuMe2Si PPh2

O O1. n-BuLi, THF -80 °C, 10 min

2. ketone (aldehyde) -80 ° to -70 °C3. NaN(SiMe3)2 (3 eq) -80 °C to r.t.

tBuMe2SiO

R'

R

tBuMe2SiO

tBuMe2SiO

CH2CH3

CH3

tBuMe2SiO

CH(CH3)2

CH3

tBuMe2SiO

H

CH(CH3)2

tBuMe2SiO

H

yield (%) yield (%)

80

52

57

54

60

tBuMe2SiO

H

C5H1124

Preparation and Reactions of γ-Phosphonio-α,β-epoxysilane

13

tBuMe2Si

O

OH

Tf2O,pyridine

R3Si

O

PPh3

OTf

CH2Cl2

tBuMe2Si

O

OTf

PPh3

Et2O

86% (2 steps) mp 123 °C

tBuMe2Si PPh3

O 1. n-BuLi, THF -80 °C, 20 min

2. ketone (aldehyde) -80 ° to -30 °C

tBuMe2SiO

R'

R

tBuMe2SiO

tBuMe2SiO

H

tBuMe2SiO

H

Ph

tBuMe2SiO

H

yield (%) yield (%)

36

5174

63

tBuMe2SiO

H

C5H1159

OTf

Reactions of γ-Phosphonio-α,β-epoxysilane with Ketones and Aldehydes

14

tBuMe2Si PPh3

O 1. n-BuLi, THF/toluene (1 : 1) -80 °C, 20 min

2. ketone (aldehyde) -80 ° to -30 °C

tBuMe2SiO

R'

R

tBuMe2SiO

tBuMe2SiO

H

tBuMe2SiO

H

Ph

tBuMe2SiO

H

yield (%) yield (%)

54(-80 °C to rt)

77

76

69

tBuMe2SiO

H

C5H1173

OTf

Summary15

tBuMe2Si PPh3

O 1. n-BuLi

2. RCOR'

tBuMe2SiO

R'

R

tBuMe2Si PPh2

O O

1. n-BuLi

2. RCOR'

3. NaN(SiMe3)2 (3 eq)

OTf

El

tBuMe2Si SO2p-Tol

OH

O1. NHMDS, El

2. n-Bu4NF, EtOH

1. NHMDS, El1

2. NHMDS, El2

3. n-Bu4NF, EtOH

El2H

O El1

Reaction of γ-Methalated γ-Sulfonyl-α,β-epoxysilane with Electrophile Followed by Desilylation with Concomitant Elimination of the Sulfonyl Group (II)

16

tBuMe2Si SO2p-Tol

O1. El+ (1.05 eq), NHMDS (1.0 eq)2. TBAF (1.0 eq), EtOH (3.0 eq)

H El

O

El+

Br

(CH2)4CH3Br

I(CH2)7CH3

conditions

1. -80 ° to -50 °C, 40 min2. -80 ° to -70 °C, 20 min

product

H (CH2)7CH3

O

yield (%)

84

1. -80 ° to -50 °C, 30 min2. -80 ° to -70 °C, 15 min H

O

(CH2)4CH3 82

1. -80 ° to -60 °C, 30 min2. -80 ° to -70 °C, 15 min H

O

85

I 1. -80 to -40 °C, 45 min2. -80 ° to -70 °C, 15 min H

O

OTBS OTBS 68

Reaction of γ-Methalated γ-Sulfonyl-α,β-epoxysilane with Electrophile Followed by Desilylation with Concomitant Elimination of the Sulfonyl Group

17

tBuMe2Si SO2p-Tol

O

1. NHMDS (1.0 eq)2. El+ (1.05 eq), 3. TBAF (1.0 eq), EtOH (3.0 eq)

H El

O

El+

CO2EtI

conditions

1. -80 °C, 5 min2. -80 ° to -40 °C, 40 min3. -80 ° to -70 °C, 20 min

product

H

O

yield (%)

74

H

O

(CH2)4CH3 77

CO2Et

1. -80 °C, 5 min2. -80 ° to -60 °C, 20 min then CH3COOH (1.0 eq)3. -80 ° to -70 °C, 15 min

OH

OHC(CH2)4CH3

THF

OHC 1. -80 °C, 5 min2. -80 ° to -60 °C, 20 min then CH3COOH (1.0 eq)3. -80 ° to -70 °C, 15 min

H

O

OH

49

Methylation of Metalated O-Silyl Cyanohydrins of trans-β-Silyl-α,β-epoxyaldehydes

18

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBSCH3

H1B

SM

40

CH3I (1.2 eq)base (1.1 eq)

diastereomer

1A 1B

1A 1B 1A 1B 1A 1B

yield (%)

82 84

44 83

91 92

84 87

E/Z

2.522.0

23.031.0

40.047.0

0.9 9.7

base

LDA(in hexane/THF)

LiN(SiMe3)2 (1.0M in THF)

NaN(SiMe3)2 (1.0M in THF)

KN(SiMe3)2 (0.5M in toluene)

THF-80 °C !"5 min 2

R3Si

O

CN

OSiR3

H

R3Si CN

OSiR3O

R3Si

O

CN

OSiR3

Hbase

R3Si C

OSiR3O

N

base

1A 1B

1A

Solvent Effect on E/Z Selectivity

19

TBS

O

CN

OTBSH

TBSO CN

OTBSR

H1B

RX (1.2 eq)

Base (1.1 eq)

solvent/HMPA

-80 °C!"5 min 3

S#

1A 1B

1A1B

1A1B

1A1B

yield (%)

93 78

84 77

86 83

85 84

E/Z

1.5 6.0

1.928.0

1.024.0

28.052.0

solvent

hexane

ether

toluene

THF

1A

CN

OSiR3

CNR3SiO

OSiR3

CN

R3SiO OSiR3R

R3SiO Li

base

LDA

KHMDS

S#

1A 1A

1B1B

1A 1A

1B1B

HMPA

(–)(+)

(–)(+)

(–)(+)

(–)(+)

yield (%)

8261

8485

8492

8784

E/Z

2.528.0

22.0E

0.915.0

9.7E

SM (%)

-26

-8

--

--

Base: NHMDS, RX: BnBr solvent: THF, RX: CH3I

TBS

O

H

OTBSCN

CNR3SiO

OSiR3R

Alkylation of O-Silyl Cyanohydrins of β-Siloxyacrolein

20OTBS

H

CNTBSO

OTBSH

TBSO

CN THFH

CN

OTBSCH3

TBSO1.Base, 2.CH3I

-80 °C, 5 min(Z)-4

Base

LDA

LHMDS

NHMDS

KHMDS

LDA

LHMDS

NHMDS

KHMDS

yield (%)

76

46

81

75

41

0

30

76

E/Z

58.0

E

E

E

0.01

-

0.02

0.01

yield (%)

-

47

6

8

18

87

59

8

SM2

(E)-42

SM

E

E

E

E

Z

Z

Z

Z

or

CN

OSiR3

CNR3SiO

OSiR3

CN

R3SiO OSiR3

R

R3SiO Li

CNR3SiO

OSiR3

R

Base-Promoted Ring-Opening of Cyanohydrins of β-Silyl α,β-Epoxyaldehyde

21

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBSCH3

1B2

35

26

E/Z

6.6

25.0

1

40

67

A:B

1.00:0.70

1.00:0.76

HMPA

(–)

(+)

1A:1B = 1.00:1.04

CH3I (0.5 eq)LDA (0.5 eq)

2

THF-80 °C, 5 min

+

1

+

yield (%) yield (%)

H

O SiR3

HH

R3SiO CN

R'2N

M

1A

O SiR3

HH

NC OSiR3

R'2N

M

1B

syn-elimination

O SiR3

H

H

HNC OSiR3

NR2

O SiR3

H

H

HR3SiO CN

NR21B1A

anti-elimination

1A

TBS

O

H

OTBSCN

A-value: OTMS = 0.7 CN = 0.2

Substituent Effect of the Silyl Group on Rates of Ring Opening

22

1B 1B2

6B

ButPh2SiO CN

OTBSCH3

6B7

CH3I (0.7 eq) Base (0.7 eq)

THF -80 °C, 5 min

ButMe2SiO CN

OTBSCH3

O SiR3

H

H

HR3SiO CN

NR21B

!"

1B

24.4

18.1

19.4

6B

39.1

39.8

29.8

2

18.8

21.5

22.1

7

6.0

6.7

14.8

7 (TBDPS)/2 (TBS)

0.32

0.31

0.67

yield (%) yield (%)

base

LiNEt2

LDA

LTMP

ButMe2Si

O

H

OTBSCN

ButPh2Si

O

H

OTBSCN

ButMe2Si

O

H

OTBSCN

ButPh2Si

O

H

OTBSCN

LTMP =N

TBS = ButMe2Si

TBDPS = ButPh2Si