エポキシドからカルバニオンへの不斉転写：

エポキシシランの連続的開環－転位反応を

利用するアルキル化反応

広島大学大学院医歯薬学総合研究科○佐々木　道子，川西　英治，中井　良雄　松本　龍弥，武田　敬

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.

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, i-Pr, 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

1

Methylation of Metalated O-Silyl Cyanohydrins of trans-β-Silyl-α,β-epoxyaldehydes2

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

Alkylation of Asymmetric O-Silyl Cyanohydrins of β-Silyl-α,β-epoxyaldehydes3

TBS

O

CN

OTBSH

TBS CN

OTBSO

H

TBSO CN

OTBS

H

TBS

O

CN

OTBS

R3SiO CN

OTBS

H

Electrophile

base

*

*

*

*

**

* TBSO CN

OTBS

H

*

El

Methylation of Metalated O-Silyl Cyanohydrins of trans-β-Silyl-α,β-epoxyaldehydes4

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 Selectivity5

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-Siloxyacrolein6

OTBSH

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

A Proposed Reaction Pathway7

OSiR3NC

HH

R3Si

O

CNR3SiO

HH

R3Si

O

OSiR3NC

H

SiR3

OH M

CNHR3SiO

HO

SiR3

NCOSiR3

H O

SiR3

H

CNR3SiO

H

SiR3

OH

R3SiO CN

OSiR3

CN

OSiR3R3SiO

O SiR3

HH

R3SiO CN

R'2N

M

1A

O SiR3

HH

NC OSiR3

R'2N

M

1B

O SiR3

H

H

HNC OSiR3

NR2

O SiR3

H

H

HR3SiO CN

NR21B1A

syn-elimination syn-elimination

anti-elimination anti-elimination

(Z)-5a (E)-5a

(E)-3

(Z)-3

R

RX

RX

R

(Z)-5b

(Z)-5c

(E)-5b

(E)-5c

1ALDA

E/Z = 2.5 1BLDA

E/Z = 22.0

Base-Promoted Ring-Opening of Cyanohydrins of β-Silyl α,β-Epoxyaldehyde8

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

A Proposed Reaction Pathway9

OSiR3NC

HH

R3Si

O

CNR3SiO

HH

R3Si

O

OSiR3NC

H

SiR3

OH M

CNHR3SiO

HO

SiR3

NCOSiR3

H O

SiR3

H

CNR3SiO

H

SiR3

OH

R3SiO CN

OSiR3

CN

OSiR3R3SiO

O SiR3

HH

R3SiO CN

R'2N

M

1A

O SiR3

HH

NC OSiR3

R'2N

M

1B

O SiR3

H

H

HNC OSiR3

NR2

O SiR3

H

H

HR3SiO CN

NR21B1A

syn-elimination syn-elimination

anti-elimination anti-elimination

(Z)-5a (E)-5a

(E)-3

(Z)-3

R

RX

RX

R

(Z)-5b

(Z)-5c

(E)-5b

(E)-5c

1ALDA

E/Z = 2.5 1BLDA

E/Z = 22.0

Substituent Effect of the Silyl Group on Rates of Ring Opening10

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

Methylation of Metalated γ-Silyl-β,γ-butyronitrile

11

TBS

O

CN TBSO CN

H

CH3I (1.2 eq)base (1.0 eq)

yield (%)

2

8

30

38

E/Z

5.7

E

238

18

base

LDA LHMDS

NHMDS

KHMDS

THF-80 °C!5 min

R2R1

9; R1= R2 = Me

10; R1= Me, R2 = H

11; R1= R2 = H

yield (%)

77

82

38

24

E/Z

9.7

8.4

3.8

1.2

yield (%)

8 0 5

21

E/Z

E

-

2.3

0.8

yield (%)

87 90 73

83

E/Z

11.0

9.3

6.7

2.4

9 10 11 total

8

Methylation of Metalated Cyanohydrins of δ-Silyl-γ,δ-epoxy-α,β-unsaturated Aldehyde

CN

O

OTBS

H

TBSTBSO CN

OTBSCH3

H

THF-80 °C, 5 min

CH3I (1.2 eq)base (1.1 eq)

yield (%) E/Zbase

LDA

LHMDS NHMDS

KHMDS

87

91

97

92

9.8

16.5

16.5

7.2

12 13

A Proposed Reaction Pathway12

OSiR3NC

HH

R3Si

O

CNR3SiO

HH

R3Si

O

OSiR3NC

H

SiR3

OH M

SiR3H

H

H

NC OSiR3

O

CNHR3SiO

HO

SiR3

NCOSiR3

HO

SiR3

H

CNR3SiO

H

SiR3

OH

R3SiO CN

OSiR3

1A

CN

OSiR3R3SiO

CN

OSiR3R3SiOR

CN

OSiR3

R3SiO

R

NR R

SiR3

H

H

H

R3SiO CN

O

1B

N

R R

E-isomer

Z-isomer

(Z)-5 (E)-5

Reactions of Enantiomerically Pure O-Silyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehyde with LDA in the Presense of Benzyl Bromide

13

1B93%ee

PhCH2Br

base

additive, solvent

-80 °C , 5 min1A

93%ee

1. AcOH, THF, H2O, 60 °C , 24 h2. NaBH4, EtOH

< 1% ee

base

LDA, LiHMDS, NaHMDS, KHMDS

solvent

THF, Et2O, toluene, hexane

additive

TMEDA

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBSBn

H

HO CN

OTBSBn

*

**

*

**

*

*

A Proposed Reaction Pathway14

OSiR3NC

HH

R3Si

O

CNR3SiO

HH

R3Si

O

OSiR3NC

H

SiR3

OH M

SiR3H

H

H

NC OSiR3

O

CNHR3SiO

HO

SiR3

NCOSiR3

HO

SiR3

H

CNR3SiO

H

SiR3

OH

R3SiO CN

OSiR3

1A

CN

OSiR3R3SiO

CN

OSiR3R3SiOR

CN

OSiR3

R3SiO

R

NR R

SiR3

H

H

H

R3SiO CN

O

1B

N

R R

E-isomer

Z-isomer

(Z)-5 (E)-5

Reactions of Enantiomerically Pure O-Silyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehyde with LDA in the Presense of Benzyl Bromide

15

1B

PhCH2Br

base

additive, solvent

-80 °C , 5 min1A

1. AcOH, THF, H2O, 60 °C , 24 h2. NaBH4, EtOH

< 1% ee

base

LDA, LiHMDS, NaHMDS, KHMDS

solvent

THF, Et2O, toluene, hexane

additive

TMEDA

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBSBn

H

HO CN

OTBSBn

*

**

*

**

*

*

Reactions of Enantiomerically Pure O-Carbamoyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehyde with LDA in the Presense of Alkylating Reagent

R3Si

O

CN

O

NR'2

O

RX

LiNR"2

R3SiO CN

H

O

O

Li

NR'2

R3SiO CN

O

NR'2

O

H

R*

*

*

*

Reactions of Enantiomerically Pure O-Silyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehyde with LDA in the Presense of Benzyl Bromide

16

TBSO

O O

NPri2

O O

NPri2

14B

PhCH2BrLDA

+

15 16

TBSOsolventTMEDA

-78 °C, 1 h H H

CNTBS CN

O

NPri2

OO H

TBS H

O

NPri2

OO CN

SM

14A

14B

14A

14B

14A

14B

14A

14B

14A

14B

solvent

THF

Et2O

toluene

yield (%)

30

52

6

23

8

39

11

26

25

49

(E)15 (Z)15

yield (%)

36

-

44

-

25

-

21

-

29

9

ee (%)

0

-

30.0

-

0

-

37.3

-

0

2.4

(E)-16

yield (%)

2

7

1

35

3

26

2

33

2

10

(Z)-16

yield (%)

7

-

11

-

18

-

11

-

9

-

yield (%)

75

59

62

58

54

65

46

59

65

68

total

TMEDA

(–)

(–)

(–)

(–)

(+)

(+)

(–)

(–)

(+)

(+)

CN

Bn

(E)-15, (E)-16, and (Z)-16 were inseparable. The !"#"tiomeric purity was determined by chiral HPLC using a CHIRALPAK AD®.

14A

H

[3 + 2] Annulation Using Reaction of(β-(Trimethylsilyl)acryloyl)silanes and Lithium Enolate of Methyl Ketones

17

Reaction of β-Silyl-α,β-epoxyacylsilanes with Ketone Enolates

SiR3O

Me3Si RO

SiMe2But

O

Me3Si

LiO R R

R3SiO

O

Me3Si

OSiMe2But

Me3SiOH

R

+

-80 ° to

-30 °C

THF

1. Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351-9352.2. Takeda, K.; Yamawaki, K.; Hatakeyama, N. J. Org. Chem. 2002, 67, 1786-1794.3. 武田　敬，大西裕司，未発表データ

SiMe2But

O

ButMe2Si

O

tBuMe2SiO

R3Si

Pri

O

OH

R3SiO

ButMe2SiO

OH

Pri

R3Si

O

Pri

O

SiMe2But

O

R3SiOPr

iO

OSiMe2But

H

LiO Pri

+

THF

-80 °C to rt

32%

12%

* *

OSiMe2But

R3SiO OH

R

EWG

R3Si

O

H

Preparation of O-Silyl Cyanohydrins of trans-β-Silyl-α,β-epoxyaldehydes18

OEE

tBuMe2Si OH

tBuMe2Si O

O

OH

tBuMe2Si

R3Si

O

CN

OSiMe2But

H

tBuMe2Si OH

O

R3Si

O

CN

OSiMe2But

H

mCPBA

Na2HPO4, CH2Cl2(89%)

SO3!pyridine

DMSO, CH2Cl2NEt3

(82%)

tBuMe2SiCN

n-Bu4PBr - KCN CH2Cl2

A (less polar)

43%

EE = 1-ethoxyethyl

1. LDA, THF2. tBuMe2SiCl

3. p-TsOH H2O, acetone

Red-Al®

Et2O, 0 °C

(88%)

(87%)

B (more ploar)

44%

Preparation of Enantiomerically Pure O-Carbamoyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehydes

19

TBS OH

TBHP, MS4A

Ti(OPri)4, D-(-)-DIPT

CH2Cl2, -20 °C, 3 days85%

TBS OH

O

SO3·pyridineDMSO, Et3N

CH2Cl2, 0 °C, 1 h 93%

TBSCHO

O

TMSCN, KCN

Bun4PBr

CH2Cl20 °C ! rt, 2 h

TBS

O

CN

OTMS H2SiF6

rt, 0.5 h 89%

TBS

O

CN

OH

93% ee

pyridine90 °C, 8 h

TBS H

OCl

OH

31%

36%

O

NPri2

TBS H

O O

NPri2

O

DBU

CH2Cl20 °C, 1 h

55%

ClCONPri2

CN

TBS CN

OCl

OH

O

NPri2

H DBU

CH2Cl20 °C, 1.5 h

52%

CN

TBS CN

O O

NPri2

O H

14B

14A

OH

TBS

Red-Al"

Et2O, rt, 2 h92%

An Explanation for the Enhanced Z-Selectivity in Less-Polar Solvents20

baseor 9

8

(E)- 17

(Z)-17

(Z)- 18(E)- 18

CH3I

CH3I

base

8 or 10M = Li, Na, K

(Z)- 9(Z)-10

(Z)- 11

R3Si CN

O

R3SiO CN

CN

R3SiO M

CN

R3SiO

R3SiO M

CN

CH3

CN

R3SiO CH3CH3

R3SiO CN

CH3

CN

R3SiO CH3

An Explanation for the Enhanced Z-Selectivity in Less-Polar Solvents21

CN

O

OSiR3

H

R3Si

R3SiO CN

OSiR3

H H

R3SiO CN

OSiR3

R

H

RX

base

-80 °C

5 min

R3Si CN

OSiR3O

HH

O

R3Si CN

OSiR3

H

R3SiO CN

OSiR3

H H

R3SiO CN

OSiR3

H H

CN

OSiR3

H H

R3SiO M

12 13

Rates of Brook Rearrangement of α-Silyldiphenylcarbinol22

HNEt2

CH3Cl, 27.5 °CH C

SiR3

SiPh3

SiPh2Me

SiPhMe2

SiMe3

k2 ( l mole-1 s-1)

6.10 !10 -3

0.98 !10 -3

0.15 !10 -3

0.25 !10 -4

CR3Si

O

Ph

Ph

Ph

OSiR3

PhR3Si C

Ph

OH

Ph

Brook, A. G.; LeGrow, G. E.; MacRae, D. M. Can. J. Chem. 1967, 45, 239-253.

Enantioselective Lithiation-Substitution Sequence23

X Y

H H

X Y

H Li·L*

X Y

H Ediastereoenriched

E

Asymmetric Deprotonation

RLi/L*

RLi X Y

H Li

racemic

Asymmetric Substitution

1) L*2) E

X Y

H H RLi

X Y

H Li

X Y

H E

Ligand

E

Ligand

N

N

H

H

L* : ( - )-sparteine

Chiral Homoenolate Equivalent (1)24

Ahlbrecht, H. ; Beyer, U. Synthesis 1999, 365-390.

R2X

TBME, !"#

R2X

THF/HMPA,

-78 #

NO

R1C6H5

NO

R1C6H5

N

OLi

C6H5 H

t-BuLi

C6H5 R1

NO

R2

C6H5 R1

R2 NO

H3OC6H5 R1

R2 O

C6H5 R1

R2 O

H3O

Chiral Homoenolate Equivalent (2)25

Hoppe, D. ; Hense, T. Angew. Chem. Int. Ed. Engl., 1997, 36, 2282-2316.

n-BuLi,

(-)-sparteine

toluene, -78 !

Ph O

H Li O

NPri2

N N

S

Ph

OCb

R

RX

Ph O

H H O

NPri2

Ph

OCb

RC

O

NPri2

Ph O

H Li O

NPri2

N N

R

+

Cb =

Reactions of Enantiomerically Pure O-Carbamoyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehyde with Bases in the Presense of Benzyl Bromide : Effect of Bases

26

O O

NPri2

14B

PhCH2Brbase

15 16

TBSOsolvent

-78 °C, 1 h

H

CNTBS CN

O

NPri2

OO H

TBS H

O

NPri2

OO CN

Base

LHMDS

NHMDS

KHMDS

SM

7A

7B

7A

7B

7A

7B

7A

7B

7A

7B

7A

7B

solvent

Et2O

toluene

Et2O

toluene

Et2O

toluene

yield (%)

22

51

49

46

39

53

47

59

50

23

47

60

(E)-15 (Z)-15

yield (%)

35

-

6

-

33

-

27

5

24

-

21

6

ee (%)

22.6

-

0

-

4.3

-

2.5

0

0

-

1.8

0

(E)-16

yield (%)

3

12

4

-

-

19

-

-

-

40

-

-

(Z)-16

yield (%)

4

-

-

7

-

-

-

-

-

-

-

-

yield (%)

64

63

59

53

69

72

74

64

74

63

68

66

total

14A

O O

NPri2

TBSO

H

CN

Bn H+

Reactions of Enantiomerically Pure O-Carbamoyl Cyanohydrins of β-Silyl-α,β-Epoxyaldehyde with LDA in the Presense of Benzyl Bromide : Effect of Temperature

27

TBSO

O O

NPri2

O O

NPri2

14B

PhCH2BrLDA

+

15 16

TBSOsolvent

1 h

H H

CNTBS CN

O

NPri2

OO H

TBS H

O

NPri2

OO CN

SM

7A

7A

7A

7A

7B

7B

7A

7A

7A

7B

solvent

Et2O

toluene

yield (%)

-

6

8

7

24

23

11

8

8

26

(E)-15 (Z)-15

yield (%)

6

44

46

44

-

-

21

32

36

-

ee (%)

27.8

30.0

27.8

0

-

-

37.3

15.9

5.6

-

(E)-16

yield (%)

9

1

2

3

37

35

2

3

2

33

(Z)-16

yield (%)

61

11

11

16

-

-

11

16

16

-

yield (%)

76

62

67

70

61

58

46

59

62

59

total

temp (°C)

-110

-78

-40

0

-110

-78

-78

-40

0

-78

CN

Bn

14A

H