連続的炭素-炭素結合形成反応を用いる新規有機合成反応の開発

広島大学大学院

医歯薬学総合研究科薬学専攻

武　田　　敬

２００２年４月２６日，金沢大学薬学部

Brook Rearrangement-Mediated Formation of Carbocycles

R3SiO

R1

CO2Me

5

R1

R3SiO

R2

OH

4

CO2Me

OSiR3

R1

6

OSiR3

R1

OH

R2

5

R1

R3SiO CO2Me

4

R1

R2

R3SiO OH3

O

R3SiO

R1

R2

7

O

R3SiO

R1

R2

8

R3SiO

O

R1

4

5

OSiR3

R1

CO2Me

CHO

8

環形成法

分子内環化法 (cyclization)

アニュレーション法 (annulation)[m + n] annulation

( )m ( )n

Brook Rearrangement

Brook, A.G. J. Am. Chem. Soc. 79, 4373 (1957)

R R'

O

+ Nu

R Nu

R'O

R SiR'3

O

+ Nu

R Nu

R'HO

R Nu

SiR'3O

R Nu

OSiR'3

reactions

Brook rearrangement

Reactions of Acylsilanes Bearing a Leaving Group with a NucleophileReactions of Acylsilanes with a Nucleophile Bearing a Leaving

Brook, A. G.; Limburg, W. W.; MacRae, D. M.; Fieldhouse, S. A. J. Am. Chem. Soc. 1967, 89, 704.Reich, H. G.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112, 5609-5617.Nakajima, T.; Segi, M.; Sugimoto, F,; Hioki, R.; Yokota, S.; Miyashita, K. Tetrahedron 1993, 37, 8343.

CH2 R'

CH

X

R

RSiR3

O

X

SiR3

O

R'

R

X

SiR3O

R' R

X

R'

OSiR3

R R'

OSIR3

H

+

X = N!N, PR3, SO2Ph, CN

+

Use of Ketone Enolate as a Nucleophile

Introduction of a Carbanion-Stabilizing Heteroatom

X SiR'3

O

X Nu

SiR'3O

X Nu+

OSiR'3

Nu

X = SPh, SiMe3, P(O)(OMe)2

R

SiR'3O

R"

O

R R"

OOSiR'3

R SiR'3

O

R"

O R

R'3SiO

R"

O

+

Reaction of α,β-Unsaturated Acylsilanes with Lithium Enolates

Takeda, K.; Nakatani, J.; Nakamura, H.; Sako, K.; Yoshii, E.; Yamaguchi, K. Synlett 1993, 841-843.

Ph

OMe3Si

R

O

Ph

Me3SiO

R

O

Ph SiMe3

O

R

OLi

SiMe2But

O

Me

THF

R

OLi

THF

MeR

TBSO

OH

Ph R

Me3SiO OH

O

Me3

SiO

R' R

SiMe2But

O

RO

Me

Ph R

HO OSiMe3

+

+

-80!° to-30 °C

+

-80!° to-30 °C

R = Et, n-Pr, i-Pr, t-Bu

30-40%

59-90%

21-53%

7-21%

+

Ph SiMe3

O

Li

Me

OLi

Me

SiMe3

O

Ph

SiMe3HO

OHMe3Si O

Me

Me

Ph

HMe3SiO

SM

+

50% 28%

+

-80 ° to-30 °C

THF

-80 ° to-30 °C

THF

41%55%

+

+

1,2-addition product Brook rearrangementproduct

1,2-addition product

Attempted Synthesis of Heteroatom-Substituted Carbonylsilanes

(MeO)2P SiR3

O

O

R'3Si SiR3

O

PhS SiR3

O

PhSO2 SiR3

O

X SiR3

O

X Nu

SiR3O

X Nu

OSiR3

X = anion-stabilizing heteroatom

Nu ++

Brook Rearrangement-Mediated [3 + 2] Annulation

Three-Carbon Unit Two-Carbon Unit

X

SiR3O

R'O X

OSiR3

R'O X

OSiR3

R'O

SiR3

O

X

O R'

OSiR3

X OH

R'

+

X = anion-stabilizing heteroatom

Brookrearrangement

allylicrearrangement

Reich, H. J.; Kelly, M. J.; Olson, R. E.; Holtan, R. C. Tetrahedron 1983, 39, 949-960.Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E. Org. Synth. 1999, 76, 199-213

Preparation of β-(Phenylthio)- and β-(Trimethylsilyl)Acryloylsilanes

EE = ethoxyethyl

OH OEE

•

OEEtBuMe2Si

SiMe2But

O

PhS

•

OEE

SiMe2But

O

Me3Si

SiMe2But

O

SPh

SiMe2But

O

SiMe3

•

OEEtBuMe2Si

2. PhSSPh

3. CF3COOH THF-H2O

2. Me3SiCl

3. CF3COOH THF-H2O

1. n-BuLi

2. tBuMe2SiCl

CH2=CHOEt

p-TsOH

1. n-BuLi

+

+

KOBut

(E) (Z)

(E) (Z)

Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351-9352.

[3 + 2] Annulation Using Reaction of(β-Phenylthio)acryloyl)silanes and Lithium Enolates

SiMe2But

O

PhS

LiO R

SiR3O

PhS RO PhS RO

OSiR3

OSiMe2But

PhS OHR

OSiMe2But

PhS OHR

+

-80 ° to -30 °C

THF+

Et

Pr

i-Pr

n-octyl

5%

7%

19%

8%

70%

74%

55%

71%

(E,Z)

[3 + 2] Annulation Using Reaction of(β-Trimethylsilyl)acryloyl)silane and Lithium Enolates

SiMe2But

O

Me3SiLiO R

Me3Si RO

OSiR3

Et

n-Pr

i-Pr

Et

n-Pr

i-Pr

OSiMe2But

Me3Si OHR

OSiMe2But

Me3Si RO

H

+

-80 ° to -30 °C

THF+

17%

11%

14%

43%

57%

63%

E

48% (75)

55% (70)

51% (76)

Z

(E,Z)

16% (9)

22% (19)

21% (10)

Summary of the Reaction of β-Substituted-Acryloylsilaneswith Lithium Enolate of Methyl Ketones

-80 ° to -30 °C

THF

-80 ° to -30 °C

THF

-80 ° to -30 °C

THF

SiMe2But

O

PhS

LiO R

SiMe2But

O

Me3Si

SiMe2But

O

Me MeR

TBSO

OH

OSiMe2But

PhS OHR

OSiMe2But

Me3Si OHR

OSiMe2But

Me3Si RO

H

OSiMe2But

PhS OHR

+

+

30-40%

55-74% 5-19%

11-17%

48-55%

43-63%

16-22%

E

Z

E,Z

+

A Proposed Reaction Pathway for the [3 + 2] Annulation

SiMe2But

O

X

LiO R

X RO

SiR3O

PhS RO

OSiMe2But

OSiMe2But

PhS OH

R

X RO

OSiMe2But

X RO

OSiMe2But

OSiMe2But

Me3Si OH

R

R

X

O

tBuMe2SiO

Me3Si RO

OSiMe2But

H

R

Me

OH

tBuMe2SiO

+

X = Me, SiMe3

X = SiMe3

+

X = Me

X = SPhpath a

path b

vinylcyclopropane-cyclopentene rearrangement

Does the phenylthio group stabilize the α-carbanion more stronglythan does the trimethylsilyl group ?

Does the oxyanion accelerated vinylcyclopropane rearrangementoccur at low temperatures below -30 °C?

below -30 °C

THF

R

Me3Si

O

tBuMe2SiO

OSiMe2But

Me3SiOH

R

PhS RO

OSiMe2But

H

Me3Si RO

OSiMe2But

H

X ORO

OHtBuMe2Si

>

Kei Takeda, Haruka Ubayama, Ayako Sano, Eiichi Yoshii, Toru Koizumi Tetrahedron Lett.1998, 39, 5243-5246.

Comparison of the Rate of Base-Catalyzed Brook Rearrangement of β-Substituted α-Silyl Allyl Alcohol

X

S(O)Ph

SPh

Ph

SiMe3

product

B

B

B

B + C (~2 : 1)

t1/2 (min)

< 1

3.2

5.5

27.5

Cl (Z)

Br

A : C = 2.2 : 1 (25 h)

A : C = 4.5 : 1 (43 h)

X

OHtBuMe2Si

OBut

O

A

X

OBut

OtBuMe2SiO

H

H

B

X

OBut

OtBuMe2SiO

H

X

tBuMe2SiO

OBut

O

X

HtBuMe2SiO

OBut

O

C

DBU (0.2 eq)d6-DMSO

23 °C, 50 mM

+

Vinylcyclopropane-CyclopenteneRearrangement

Me3Si

R

tBuMe2SiO

O

OSiMe2But

OH

RMe3Si

below -30 °C

R ROCH2CH2Cl

n-BuLi

RO

THF-HMPA

25 °C, 1h

R OH

: CH2OCH2CH2Cl

Danheiser, R. L.; Davilla, C. M.; Auchus, R. J.; Kadonaga, J. T. J. Am. Chem. Soc. 103, 2443 (1981).

Me3SiO OSiMe3

Girard, C.; Amice, P.; Barnier, J. P. Conia, J. M. Tetrahedron Lett. 1974, 3329.

350 °C, 1h

95%

Synthesis of the Vinylcyclopropanolate Intermediates

Me3SiMe

O

tBuMe2SiO

Me3Si

OTBS

Me3SiMe

O

tBuMe2SiO

CH3

CH3O

(CO)5CrMe

OAc

CH3Li(2 eq)

Me

OAc

Me3SiMe

O

tBuMe2SiOCH3

O

+

Synthesis of the Vinylcyclopropanolate Intermediates

Me3Si

TBSO

Me

OAc

Me3Si

OTBS

O

Me3Si

SiMe2But Li SPh

O O

(CO)5Cr

Me

OAc

CH2Cl2

CH2Cl2

OTBS

SiMe3 SiMe3

TBSO

Me

OAc

Me3Si

SiR3O

SO2Ph

SiMe3

TBSO

OAc

Me

Me3Si

TBSO

OAc

Me

Me3Si

OTBS

(E) (73%)(Z) (85%)

-80 ° to -30 °C

THF+

-40 ° to -20 °C

+

-40 ° to -20 °C

+

syn-(E) anti-(E)

anti-(Z)syn-(Z)

(E, Z)

(28%)

(58%)

1.3 : 1

1 : 1

+

+

Oxyanion Accelerated Vinylcyclopropane Rearrangement

Kei Takeda, Keiki Sakurama, Eiichi Yoshii Tetrahedron Lett. 38 (18), 3257-3260 (1997).

Me3SiMe

O

tBuMe2SiO

0

!63

!0

!54

!59

!76

!52

!76

1

!89

!34

!81

!31

!10

!14

!20

!16

3

1

2

3

4

5

6

7

8

OTBS

Me3Si MeO

Me3SiMe

OAc

tBuMe2SiO

OAc

M e

Me3Si

TBS O

Me3Si

TBS O

Me

OAc

SiM e3

TBSO

OAc

M e

S iM e3

TBSO

M e

OAc

OSiMe2But

Me3Si OHMe

OSiMe2But

Me3Si OHMe

tBuMe2SiO

Me

O

Me3Si

H

anti-Z

syn-Z

MeLi(2.2 eq)

THF+

31

anti-E

-80 °C, 30 min

-80 ° to -30 °C

-80 °C, 30 min

-80 ° to -30 °C

-80 °C, 30 min

-80 ° to -30 °C

-80 °C, 30 min

-80 ° to -30 °C

conditionsyield (%)

cyclopropyl acetateentry

syn-E

0

0

0

0

6

9

6

8

2

2

+

(1.1:1)

(only E)

(1.1:1)

(17:1)

(1.7:1)

(5.7:1)

(1.7:1)

(only E)

(E:Z)

A Proposed Reaction Pathway for the Vinylcyclopropane Rearrangement

Me

TBSO

O

SiMe3

Me

TBSO

O

Me3SiO

TBSO

Me

Me3Si

O

TBSO

Me

SiMe3

O

TBSO

Me

SiMe2Ph

O

TBSO

Me

Me3SiO

TBSO

Me

Me3Si

OTBS

Me3Si OH

Me

MeMe3Si

O

SiMe2PhO

[1,3] sigmatropicshift

syn-(E)

anti-(Z)syn-(Z)

anti-(E)

OTBS

LiO Me

R3SiH

OTBS

Me OLi

H

SiR3

OTBS

Me OLi

R3SiH

OTBS

LiO Me

H

SiR3

OLi

TBSO

Me

Me3SiMe

TBSO

OLi

Me3Si

OTBS

H

Me3Si Me

OH

OTBS

H

Me3Si OH

Me

OLi

TBSO

Me

SiMe3

Me

TBSO

OLi

SiMe3

OTBS

Me3Si

H OH

Me

OTBS

Me3Si

H Me

OH

si si

sisi

E-anti

Z-anti

E-syn

Z-syn

Me

PhMe2SiO

O

SiMe3

Me

TBSO

O

SiMe3

O

PhMe2SiO

Me

SiMe3

O

TBSO

Me

SiMe3

Me

R3SiO

OH

SiMe3

Me

SiMe3

O

SiMe2PhO

OSiR3

Me3Si OH

Me

OSiR3

Me

O

Me3Si

H

conditions

toluene-80 ° to -30 °C

7% 54%

30% 25%

THF-80 °C, 30 min

8% 31%

20% 35%

-

-

53%

21%

A Proposed Reaction Pathway for the [3 + 2] Annulation

SiMe2But

O

X

LiO R

X RO

SiR3O

PhS RO

OSiMe2But

OSiMe2But

PhS OH

R

X RO

OSiMe2But

X RO

OSiMe2But

OSiMe2But

Me3Si OH

R

R

X

O

tBuMe2SiO

Me3Si RO

OSiMe2But

H

R

Me

OH

tBuMe2SiO

+

X = Me, SiMe3

X = SiMe3

+

X = Me

X = SPhpath a

path b

vinylcyclopropane-cyclopentene rearrangement

Oxyanion-Accelerated Vinylcyclopropane Rearrangement (2)

PhSMe

O

tBuMe2SiO

84

85

87

!87

!50

!48

48

48

1

2

3

4

5

6

7

8

OTBS

PhS MeO

1

PhSMe

OAc

tBuMe2SiO

PhS

TBSO

OAc

Me

PhS

TBSO

Me

OAc

SPh

TBSO

OAc

Me

SPh

TBSO

Me

OAc

OSiMe2But

PhS OHMe

OSiMe2But

PhS OHMe

MeLi(2.2 eq)

THF+

21

anti-Z

syn-Z

anti-E-80 °C, 30 min

-80 ° to -30 °C

-80 °C, 30 min

-80 ° to -30 °C

-80 °C, 30 min

-80 ° to -30 °C

-80 °C, 30 min

-80 ° to -30 °C

conditions

2

3

1

2

39

39

35

40

2

yield (%)cyclopropyl acetateentry

anti- : syn-E = 1 : 1.1

A Proposed Reaction Pathway for the [3 + 2] Annulation

SiMe2But

O

X

LiO R

X RO

SiR3O

PhS RO

OSiMe2But

OSiMe2But

PhS OH

R

X RO

OSiMe2But

X RO

OSiMe2But

OSiMe2But

Me3Si OH

R

R

X

O

tBuMe2SiO

Me3Si RO

OSiMe2But

H

R

Me

OH

tBuMe2SiO

+

X = Me, SiMe3

X = SiMe3

+

X = Me

X = SPhpath a

path b

vinylcyclopropane-cyclopentene rearrangement

Low-Temperature Quenching of the [3 + 2] Annulation (1)

LiO Me

SPh

SiMe2But

O

SPh

SiMe2But

O

OSiMe2But

PhS OH

Me

PhS

OHButMe2Si

MeO

OSiMe2But

PhS OH

Me

PhS

OSiMe2But

H

O Me

+

27 29 30

31 32

+ +

+ +

-80 °C, 10 min

-80 ° to -70 °C

-80 ° to -60 °C

-80 ° to -50 °C

-80 ° to -30 °C

27 (E:Z)

23 (1:1.4)

20 (1:1.2)

12 (1:1.2)

-

-

29

14

-

-

-

-

30

12

17

24

-

-

31

33

53

48

63

68

32

-

-

1

1

2

(E,Z)-27

28

yield (%)

27

E

E

E

E

E

27 (E:Z)

73 (1:1.9)

66 (1:1.2)

38 (1:1.2)

24 (1:1.3)

-

29

-

-

-

-

-

30

3

9

12

8

-

31

8

21

40

42

73

32

2

2

2

2

5

27

Z

Z

Z

Z

Z

conditionsyield (%)

Reaction of (E)-1,2-Adduct (SPh) with LDA

PhS MeO

OHtBuMe2Si

SPh

SiMe2But

O

PhS

OSiMe2But

H

O Me

PhS

OHButMe2Si

MeO

OSiMe2But

PhS OH

Me

+

+ +

8% (E:Z = 1:1.3) 13%

52% 20%

LDA(1.05 eq)

THF -80 °C10 min

(E:Z = 1:12.8)

E

PhS MeO

OSiMe2Bu

t

?

Low-Temperature Quenching of the [3 + 2] Annulation (2)

35

2

3

7

6

7

20

35

30

35

35

35

34

34

(E:Z)

(1:1.8)

(1:1.5)

(1.7:1)

(3.5:1)

(5.6:1)

(6.2:1)

(E:Z)

(1:1.9)

(1:1.8)

(1.3:1)

(2.0:1)

(E)

(E)

(Z)-10a

65

61

56

57

32

-

33

11

9

6

4

-

-

36

6

7

12

16

42

60

36

6

9

12

15

17

19

37

-

-

-

3

5

6

37

-

-

-

-

-

-

(Z)-34

12

14

-

3

-

-

(E)-34

31

18

8

-

-

SiMe3

SiMe2But

O

LiO Me

SiMe3

SiMe2But

O

Me3Si

OSiMe2But

H

O Me

Me3Si

SiMe2But

OH

OSiMe2But

Me3Si OHMe

Me3Si

OHButMe2Si

MeO

OSiMe2But

Me3Si OHMe

+

10a 33

35 36 37

+ +

+

(E,Z)-10a

conditionsyield (%)

10a

E

E

E

E

E

E

10a

Z

Z

Z

Z

Z

Z

-80 °C, 10 min

-80 ° to -70 °C

-80 ° to -60 °C

-80 ° to -50 °C

-80 ° to -30 °C

-80 ° to 0 °C

+

(E,Z)-34

28

yield (%)

Reaction of (E)-1,2-Adduct with LDA

Me3Si

OHButMe2Si

MeO

Me3Si

SiMe2But

O

Me3Si

SiMe2But

OH

Me3Si

OSiMe2But

H

O Me

Me3Si

OHButMe2Si

MeO

OSiMe2But

Me3Si OH

Me

LDA

(1.05 eq)

THF

-80 °C10 min

+

9%

56%

5%

5%

++

E E

Reaction of (Z)-1,2-Adduct with LDA

SiMe3

Me

OOHB utMe2Si

SiMe3

SiMe2But

O

OSiM e2But

Me3Si OH

MeMe3Si

OSiMe2But

H

O Me

SiMe3

Me

OOHButMe2Si

OSiM e2But

Me3Si OH

Me

63%

4%

4%

16%

+

+ +

1%

LDA

(1.05 eq)

THF

-80 °C

10 min

A Proposed Reaction Pathway for the [3 + 2] Annulation Using (β-(Phenylthio)acryloylsilanes

PhS RO

OSiR3

OSiR3

PhS OH

RPhS RO

SiR3O

OSiR3

PhS OH

R

SiR3

O

PhS

R

O

SiR3O

SPh

LiO R

SiR3

O

SPh

+

+

E

+

Z

Kei Takeda, Kenji Yamawaki, Noriaki Hatakeyama J. Org. Chem. 67, 1786-1794 (2002)

A Proposed Reaction Pathway for the [3 + 2] Annulation Using (β-(Trimethylsilyl)acryloylsilanes

O

R3SiO

R

SiMe3

SiR3

O

Me3Si

LiO R

Me3Si RO

SiR3O

SiR3

O

SiMe3

R

O

Me3Si

O

SiR3

RO

SiR3O

SiMe3

R

O

O

SiR3

SiMe3

OSiR3

Me3Si OHR

E

Z

E

Z

syn -(E)

syn-(Z)

anti-(Z)

+

+

1. Takeda, K.; Nakayama, I.; Yoshii, E. Synlett 1994, 178.2. Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351-9352.3. Takeda, K; Kitagawa, K.; Nakayama, I.; Yoshii, E. Synlett 1997, 255-256.

Application of the [3 + 2] Annulaton to the Synthesis of Biologically Important Molecules

O

OH

CH2(CH2)14CH3

CO2Me

O

OH

COOMe

O

OAc

COOMe

OAc

O

OAc

COOMeAcO

O

OH

MeSCO2Me

O

OH

SCO2Me

N

Untenone A1Chromomoric acid DII methyl ester

2

Clavulone I I3

(Claviridenone c)

Clavulone II I3

(Claviridenone b)

Total Synthesis of Clavulones (Claviridenones) Using the [3 + 2] Annulation

O

PhS

SiMe2But

O

OH

LiO

O

OAc

COOMe

OAc

CO2Me

OAc

O

O

OH

COOMe

OAc

OH

PhS

OSiMe2But

OH

Ac2O (3 eq)

DMAP (5 eq)pyridine

1. LDA (2.1 eq)

2.

Clavulone II(Claviridenone c)

+

-98 ° to -30 °C

n-Bu4NF

CH2Cl2

[3 + 4] Annulation Using Reaction of Acryloylsilaneswith the Lithium Enolate of Alkenyl Methyl Ketones

SiR'3

X

O

OLi

R

R'3SiO

O

X

R

O

O

R'3Si

X

R

O

R'3SiO R

X

O

X

RR'3SiO

O

R'3SiO R

X

+

O

X

RR'3SiO

anionic oxy-Cope

intramolecularMichael

[3 + 4] Annulation Using (E)-(β-(Trimethylsilyl)acryloyl)silane

OLi

(CH2)2CH3

O

TBSO

SiMe3

(CH2)2CH3

OLi

CH3

CH3

O

TBSO

SiMe3

CH3

CH3

OLi

(CH2)4CH3

O

TBSO

SiMe3

(CH2)4CH3

OLi O

TBSO

SiMe3OLi O

TBSO

SiMe3OLi

Br

O

TBSO

SiMe3OLi

CH3H3C

O

TBSO

SiMe3

CH3

CH3

84%

67%

ketone enolate product yield ketone enolate

30%84%

73%

82%

73%

product yield

O

tBuMe2SiO

SiMe3

R

OLi

R

SiMe2But

Me3Si

O

+

-80 ° to -30 °C

THF5

6

[3 + 4] Annulation Using (Z)-(β-(Trimethylsilyl)acryloyl)silane

OLi

(CH2)4CH3

O

TBSO

SiMe3

(CH2)4CH3

29%(55%)

OLi

CH3

CH3

O

TBSO

SiMe3

CH3

CH3

OLi

Br

O

TBSO

SiMe3

11%(59%)

0%(77%)

OLi

(CH2)2CH3

O

TBSO

SiMe3

(CH2)2CH3

OLi

CH3H3C

O

TBSO

SiMe3

CH3

CH3

18%(31%)

31%(56%)

ketone enolate product ketone enolate product

yield(recovery of acylsilane)

yield(recovery of acylsilane)

O

tBuMe2SiO

SiMe3

R

OLi

R

SiMe2But

SiMe3

O

+-80 ° to -30 °C

THF 5

6

[3 + 4] Annulation Using (β-(Alkyl)acryloyl)silanes

O

TBSO

R

n-C5H11

O

TBSO

R

OMe

O

DPSO n-C5H11

O

DPSO Pri

O

DPSOMe

Me

O

DPSO OMe

O

DPSO

O

DPSO

82%

59%

54%

51%

51%

68%

R = i-Pr, n-Pr, t-Bu, c-C6H11

65-77%

44-70%

O

tBuMe2S iO

R

R'

OLi

R'

5

6SiR3

R

O

+

-80 ° to -30 °C

THF

SiR3 = SiM e2But (TBS), SiMe2Ph (DPS)

Mechanistic Studies of the [3 + 4] Annulation

O

TBSO

HH

SiMe2But

nBu3Sn

O OLi

Br

nBu3Sn

TBSO

OH

Br+

-80 ° to-45 °C

THF

(24%) (18%)

LDATHF

-30 °C10 min

O

TBSO

SiMe3

Me6

5

OAc

SiMe3

TBSO

Me

SiMe3

TBSO

O

Me

MeLi (2.2 eq)

-80 °C, THF

EZ

5,6-cis5,6-trans

OLi

C5H9

SiMe2But

PhS

OOTBS

PhS OHC5H9 PhS O

OTBS

C5H9

+

LDATHF

-80 ° to-30 °C

(34%)

Takeda, K.; Takeda, M.; Nakajima, A.; Yoshii, E. J. Am. Chem. Soc. 1995, 117, 6400-6401.Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T. J. Am. Chem. Soc. 1998, 120, 4947-4959.Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E. Org. Synth. 1999, 76, 199-211.

A Reaction Mechanism of the [3 + 4] Annulation Using the Reaction of Acryloylsilaneswith the Lithium Enolates of Alkenyl Methyl Ketones

O

TBSO R

XE

XZ

5

6

SiMe2But

X

O

O

O

R3Si

X

R

R3SiO

O

X

ROLi

RXE

XZ R

OO

R3Si

O

TBSO

XE

XZ

R

(E,Z)

+

EZ

5,6-cis5,6-trans

anionic oxy-Coperearrangement

X = SiMe3, SnBun

3, alkyl

Kei Takeda, Daisuke Nakane, Mika Takeda Org. Lett. 2, 1903-1905 (2000)

Synthesis of the Tricyclic Skeleton of CyathinsUsing Brook Rearrangement-Mediated [3 + 4] Annulation

Pri

Me

O

OSiMe2R

SiMe3

H

H

Pri

Me

SiMe3

O

O

SiMe2R

Pri

Me

OH

OSiMe3

SiMe3

H

H

Pri

Me

OH

O

H

H

Pri

Me

OLi

Pri

Me

O

OSiMe2R

SiMe3

RMe2Si

O

Me3Si

+

THF

-80 ° to 0 °C

DIBAL

Et2O, -80 °C(72%)

1. NBS, THF

2. n-Bu4NF (72%)

Pri

Me

OHMe

CHO

Allocyathin B2

Formation of Eight-Membered Carbocycles by [3 + 4] Annulation (1)

R3SiOO

R'

R3SiO

R'

O

O

R3SiO

R'

HO

CH2CO2R

R3SiO

R' Y

X

OLi

SiR3O

R'

OLi

[3 + 4] Annulation

8

Formation of Eight-Membered Carbocycles by [3 + 4] Annulation (2)

TBSO

O

R

R

OOR'3Si

SiMe2But

O

R

OMTHF

O

R

SiMe3

SiMe2But

i-Pr

t-Bu

c-C6H11

R

HOR'3Si

O

H

LiO

TBSO

H

R

H

conditions

-80 °C, 30 min

-80 ° to 0 °C

-80 °C, 30 min

-80 ° to 0 °C

-80 ° to 0 °C

yield (%)

66

65

45

84

45

+

LDA orNaN(SiMe3)2

α-Hydroxylation of Bicyclo[2.2.2]decenones

TBSOO

R

TBSOO

R

OHH

TBSO

OM

R

NO

PhSO2 Ar

R

SiMe3

SiMe3

t-Bu

t-Bu

base

LDA

NaN(SiMe3)2

LDA

NaN(SiMe3)2

Vedejs !

52

66

Davis !

76

71

base MoOPH

or

yield (%)

Tandem [3 + 4] Annulation /α-Hydroxylation

TBSOO

R

OH

TBSO

OM

R

SiMe2But

O

R N

O

PhSO2 Ar

R

SiMe3

SiMe2Ph

SiMe2But

i-Pr

t-Bu

base

NaN(SiMe3)2NaN(SiMe3)2NaN(SiMe3)2LDA

LDA

OM

O

NaN(SiMe3)2

+

yield (%)

48

72

58

50

62

THF

-80 °C to rt

base

Tandem [3 + 4] Annulation /α-Hydroxylation

TBSOO

R

OHTBSO

CO2Me

CHOR

3 4

8Pb(OAc)4

Benzene-MeOH

R

SiMe3

SiMe2Ph

SiMe2But

i-Pr

t-Bu

yield (%)

95

96

95

97

93

Kei Takeda, Yuji Sawada, Koichi Sumi Org. Lett. 4, 1031-1033 (2002)

[3 + 2] Annulation Using a Double Brook Rearrangement (1)

ButMe2SiO RO

OSiMe2But

H

SiMe2But

O

ButMe2Si

O

ButMe2Si

O

SiMe2But

O

ROBu

tMe2Si

O

RO

OSiMe2But

LiO R

+

OSiMe2But

ButMe2SiO OH

R

*

*

* **

[3 + 2] Annulation Using a Double Brook Rearrangement (2)

SiMe2But

O

ButMe2Si

O

tBuMe2SiO

R3Si

Pri

O

OH

R3SiO

ButMe2SiO

OH

Pri

R3Si

O

Pri

O

SiMe2But

O

R3SiO Pri

O

OSiMe2But

H

LiO Pri

+

THF

-80 °C to rt

32%

12%

OSiMe2But

ButMe2SiO OH

Pri

Reaction of Acryloylsilanes with KCN/18-crown-6 in the Presense of MeI

Kei Takeda, Yuji Ohnishi Tetrahedron Lett. 41, 4169-4172 (2000).

CH3I

Me3Si CN

SiR3O

Me3Si SiMe2But

O

CH3I (5 eq)

Me3Si CN

OSiMe2ButCH3

+KCN (1.1 eq)

18-crown-6CH2Cl2 65%

Reaction of Metalated β-Silyl-α,β-epoxides with Electrophiles

R3Si

O

EWG

H

R3SiO EWG

El

H

R3SiO EWG

H

R3Si

O

EWG

R3SiO EWG

H

R3Si EWG

O

H

El+

base

R3Si

O

CN

OSiR'3H

Preparation of β-Silyl-α,β-epoxyaldehyde Cyanohydrins

OEE

tBuMe2Si OH

tBuMe2Si O

O

R3Si

O

CN

OSiMe2But

H

OH

tBuMe2Si

tBuMe2Si OH

O

R3Si

O

H

OSiMe2But

CN

mCPBA

Na2HPO4, CH2Cl2

(89%)

SO3!pyridine

DMSO, CH2Cl2NEt3

(82%)

tBuMe2SiCN

ZnI2, CH2Cl2

A (less polar)

46%

EE = 1-ethoxyethyl

1. LDA, THF

2. tBuMe2SiCl

3. p-TsOH

H2O, acetone

Red-Al®

Et2O, 0 °C

(88%)

(87%)

B (more ploar)(X-ray)

27%

+

Reaction of Cyanohydrins of β-Silyl-α,β-epoxyaldehyde with LDA in the Presence of Alkylating Agents

TBS

O

CN

OTBSH

RX

MeI

EtI!

i-PrI!

PhCH2Br

CH2=CHCH2Br

1 (yield, %)

82

76

58

97

83

diastereomer A

2 (yield, %)

-

-

12

-

-

TBSO CN

OTBSR

1 (yield, %)

84

74

74

98

87

diastereomer B

2

-

-

-

-

-

TBSO CN

OTBSH

RX (1.2 eq)LDA (1.1 eq), THF

-80 °C5 min

+

E/Z

2.5

2.9

2.8

2.7

3.4

E/Z

22.0

28.0

31.0

47.0

40.0

1 2A, B

H

Reaction of Cyanohydrins of β-Silyl-α,β-epoxyaldehyde with MN(SiMe3)2 in the Presence of Alkylating Agents

MN(SiMe3)2

RX, THF-80 °C, 5 min

RX

MeI

EtI

i-PrI

PhCH2Br

CH2=CHCH2Br

ButMe2Si

O

CN

OSiMe2But

LHMDS

44 (23.0)

24 (16.0)

15 (14.0)

56 (30.0)

45 (31.0)

KHMDS

84 (0.9)

76 (0.7)

42 (2.1)

83 (0.8)

80 (1.1)

NHMDS

96 (40.0)

90 (42.0)

80 (62.0)

98 (65.0)

91 (39.0)

LHMDS

83 (31.0)

64 (28.0)

44 (37.0)

75 (82.0)

80 (89.0)

ButMe2SiO CN

OSiMe2But

H

R

KHMDS

87 ( 9.7)

81 (16.0)

73 (83.0)

88 (13.0)

83 (14.0)

NHMDS

98 ( E)

89 (42.0)

89 (75.0)

99 (67.0)

92 (41.0)

yield (%) (E/Z)

from A from B

A, B

Kei Takeda, Eiji Kawanishi, Michiko Sasaki, Yuji Takahashi, Kentaro Yamaguchi Org. Lett. in press.

E/Z Ratios of the Alkylation Products Depending on the Bases Used

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBS

CH3

H

A (less polar)

B (more ploar)

SM

40

CH3I (1.2 eq)

base (1.1 eq)

diastereomer

A

B

A

B

A

B

A

B

yield (%)

82

84

44

83

91

92

84

87

E/Z

2.5

22.0

23.0

31.0

40.0

47.0

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

Increased Z-Selectivity in Less-Polar Solvents

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBSBn

H

diastereomer

A B

A B A B

A B

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

BnBr

NHMDS

(1.0M inTHF)

-80 °C, 5 min

solvent

A

B

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

OSiR3H

R3Si

O

CN R3Si

O

CN

OSiR3

R3SiO CN

OSiR3

H

R3SiO CN

OSiR3

M

CN

OSiR3

MR3SiO

R3Si CN

OSiR3O

H

R3SiO CN

OSiR3

El

CN

OSiR3

ElR3SiO

Z

E

Chelation-Assisted Syn-Elimination Mechanism for a Base-Promoted Ring Opening of Epoxides

HO CN

OCN

H

OCN

H

O H

Li N

R

R

CN

O

CN

Li

!"#$%&'('#)*'+#LDA

-78$°C, 5 min

LDA

-78$°C, 30 min

E1CB-like

Comparison of the Relative Rates of Ring Opening of the Diasetereomers

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBS

O

CN

OTBSH

TBSO CN

OTBSCH31A (less polar)

1B (more ploar)

base

LDA

NHMDS

2

35

26

40

45

E/Z

6.6

25.0

41.0

108.0

1

40

67

52

39

A:B

1.00:0.70

1.00:0.76

1.00:0.79

1.00:0.78

HMPA

(-)

(+)

(-)

(+)

1A:1B = 1.00:1.04

CH3I (0.5 eq)base (0.5 eq)

2THF

-80 °C, 5 min

+

1

+

yield (%) yield (%)

Plausible Mechanisms for the Base-Promoted Ring Opening of O-Silyl β-Silyl-α,β-epoxyaldehydes

O SiR3

H

H

H

NC OSiR3

O SiR3

H

H

HR3SiO CN

NR'2 NR'2

!"#$%&'$($"!#$)"

A (more stable)

*+"%&'$($"!#$)"

B (more stable)

B (less stable)

A (less stable)

O

H

H

NC OSiR3

R3Si

H

Li

NR'2O

H

H

R3SiO CN

R3Si

H

Li

NR'2

An Explanation for Relatively Favorable Formation of (Z)-Derivatives from Diastereomer A

O SiR3

H

H

HR3SiO CN

NR2

O SiR3

H

H

HNC OSiR3

NCOSiR3

H

O

SiR3

H

Li

OSiR3NC

HH

R3Si

O

CNR3SiO

HH

R3Si

O

R3SiOCN

H

O

SiR3

H

NR2

R3SiO M

OSiR3NC

OSiR3

MR3SiOCN

R3SiO M

OSiR3NC

OSiR3

MR3SiOCN

B (more stable)

A (less stable)

Summary

tBuMe2SiO CN

OSiMe2But

H

El

O SiR3H

H

HNC OSiR3

NR2

tBuMe2SiO CN

OSiMe2But

H

O SiR3H

H

HR3SiO CN

NR2

tBuMe2Si CN

OSiMe2ButO

H

tBuMe2SiO CN

OSiMe2But

H

EI

base

Brookrearrangement

BA

Prof. Emeritus Eiichi Yoshii The Late Prof. Toru Koizumi

[1 + 2] AnnulationKoichi Sako

Hitoshi NakamuraJunko Nakatani

[3 + 2] AnnulationTomoko MakinoMasato FujisawaKeiki Sakurama

Ayako SanoNoriaki Hatakeyama

Haruka UbayamaEmi Ando

Kenji Yamawaki

Yasushi OkamotoEmi IzumiKoichi SumiYuji SawadaHidekazu Haraguchi

Mika TakedaAkemi NakajimaYasuhiro OhtaniYasushi OkamotoKoichi Sumi

Synthesis of Natural Products

Ichiro NakayamaKanji KitagawaDaisuke Nakane

Tadashi Tanaka

[3 + 4] Annulation

Tandem Brook-Michael

Yuji Ohnishi

Reduction of Acylsilanesand Reactions with Cyanides

Grant-in-Aid for Scientific ResearchThe Research Foundation for Pharmaceutical SciencesThe Takeda Science Foundation

The Uehara Memorial FoundationThe Chiba-Geigy Foundation (Japan)

The Hoan-sha Foundation

Eight-Membered Rings

Alkylation of Epoxysilanes

Yuji OhnishiYuji TakahashiMichiko SasakiEiji Kawanishi

Prof. Kentaro Yamaguchi (Chiba University) for X-Ray