diastereoselective construction of remote stereocenters...

Diastereoselective Construction of Remote Stereocenters:The use of Chiral Allylstannes & Claisen Rearrangements

Scott PetersonEvans' Group Friday Seminar

May 24, 2002

R R'

XY

01-Title 5/24/02 11:03 AM

Synthetic Strategies for the Construction of Remote Stereogenic Centers Across a Double Bond

Coupling of Chiral Fragments

Asymmetric Induction by Reagent Control

Asymmetric Induction by Substrate Control

Chirality Transfer Methodology

Useful references:

Warren, S. Perkin I. 1999, 1899

Thomas, E.J. Chemtracts. 1994, 7, 207

02-Overview 5/23/02 5:47 PM






Danishefsky, S.J. ACIEE 1996, 35, 2801

Me

OP

MeOP'

OMeMeO

S

N

MeOAc

I

Me

Me

OP

OP'

S

N

Me

i) 9-BBNii) PdCl2(dppf)2, Cs2CO3, Ph3As

Epothilone AOMe

OMeOAc

Me

03-Overview-Coupling-1 5/23/02 5:47 PM


Corey, E.J. J. Am. Chem Soc. 1987, 109, 7925





O

O

THPO

O

OH

O

THPO

O

9:1

N B

O

H PhPh

CH3

BH3•THF

04-Overview-Reagent-1 5/23/02 5:47 PM






Evans, D.A. J. Am. Chem. Soc. 2002, 124, 5654

Xp

OO

Me Me

OHMeOTBS

OPMB

Xp

OO

Me Me

OHMeOTBS

OPMB

13 913 9

N O

Me

OOO

Bn

Me

O

H

MeOTBS

OPMB

O

H

MeOTBS

OPMB

Cy2BCl, EtNMe2-78 °C

diastereoselection 55:45 diastereoselection 92:8

05-Overview-Substrate-1 5/23/02 5:49 PM






Mikami, K. J. Org. Chem. 1992, 57, 6105

OTBDPS

CH3

MeO2COTBDPS

OH CH3

MeO2CCHOSnCl4, -78 oC

O

H

TBDPSO

H

CH3

HH

OMeO SnCl4

1,5 syn:anti 94:676% yield







Bu3Sn

OBn

i.) SnCl4, 5 min, -78 oC

ii.) PhCHO, 1 hour

Ph

OH

OBn

1,5 syn:anti >98:2Z olefin formed exclusively

90% yield

Thomas, E.J. Tetrahedron Lett. 1990, 31, 6239


SnCl4 Catalyzed Allylstannane Reactions

SnCl4, -78 oC

Keck, G.E. Tetrahedron Lett. 1984, 25, 3927Keck, G.E. J. Am. Chem. Soc. 1989, 111, 8136Denmark, S.E. J. Am. Chem Soc. 1988, 110, 984

R

OH

CH3

Bu3Sn CH3

RCHO

syn and anti

R CH3

OH

E and ZR and S

Bu3Sn CH3

SnCl4

CH3

Cl3Sn

Cl3Sn CH3

RCHO RCHO RCHO

R

OH

CH3

R CH3

OH

R

OH

CH3

O

SnBu3H3C

H

RO

SnCl3H

R

CH3

08-SnCl4 Cat allylstannane 5/23/02 6:06 PM

1,5-Asymmetric Induction Using 4-Alkoxy-allylstannanes

Bu3Sn

OBn

i.) SnCl4, 5min, -78 oC

ii.) RCHO, 1 hourR

OH

OBn

1,5 syn favored

Aldehydes Yield

PhCHO

p-ClC6H4CHO

p-NO2C6H4CHO

p-MeOC6H4CHO

furfural

CH3CH2CH2CHO

(CH3)2CHCHO

(CH2)5CHCHO

PhCH=CHCHO

MeO2CCHO

90

77

77

77

72

84

84

78

64

68

1,5 syn : anti

98 : 2

94 : 6

95 : 5

97 : 3

95 : 5

95 : 5

93 : 7

92 : 8

95 : 5

95 : 5

Thomas, E.J. Tetrahedron Lett. 1990, 31, 6239Thomas, E.J. Chemtracts 1994, 7, 207

09-initial allylstannane 1,5 5/23/02 6:08 PM

Mechanism for 1,5 Induction with 4-Alkoxy-allylstannanes

i.) SnCl4, -78 oC


Bu3Snii.) RCHO

SnCl4

CH3

OBnR

OH

CH3

OBn

syn : anti >95:5

Bu3SnCH3

OBn Cl3Sn OBn

CH3

R

OH

CH3

OBn

RCHO

SnO

H

R

OBn

H

H CH3

ClCl

Cl

SnO

H

R

OBn

H

H CH3

ClCl

Cl

RCHOH2O

10-1,5 mechanism 1 5/23/02 6:09 PM


Thomas, E.J. Chem. Commun. 1998, 8, 899

SnCl4Bu3SnCH3

OBn Cl3Sn OBn

CH3

Ph3SnCH3

OBn

i) SnCl4, -78 oC, 5 min

ii) PhLi

iii.)

H3C CH3

OBn

Ph3Sn

Ph3Sn OBn

CH3H3C

H3C CH3

H

HO

H3C H

H

CH3

O

Ph3SnLi

Ph3SnLi

H3C CH3

SnPh3

OH

H3C CH3

OH

Ph3Sn

H3C CH3

OH

Ph3Sn

H3C CH3

SnPh3

OH

NaH, BnBr

NaH, BnBr

N N

H H

11-1,5 mecanism allyltintric 5/23/02 6:11 PM



SnCl4Bu3SnCH3

OBn Cl3Sn OBn

CH3

Bu3Sn

OBn

H CH3

Cl3Sn

Cl

H

Cl

Favored: A1,3 minimized

H3C HH

OBn

Bu3Sn

Cl3Sn

Cl

ClA1,3

Disfavored

12-1,5 mecanism form allyltin 5/23/02 6:13 PM



Cl3Sn OBn

CH3

R

OH

CH3

OBn

RCHO SnO

H

R

OBn

H

H CH3

ClCl

Cl

Cl3Sn OCH3HO

OCH3 HO OCH3

SnO

H

H

OCH3

ClCl

Cl

H

CH2O

SnO

H

H

H

Cl ClCl

OCH3

∆E = 1.9 kcal•mol-1 ∆E = 12.0 kcal•mol-1

2.222

2.380

2.370

2.182

2.374

3.297

favored

(GAUSSIAN94 Calculation, split valence basis)

13-1,5 mecanism calculations 5/23/02 6:15 PM


Bu3Sn

CH3


ii.) RCHO, 1 hourR

OH

CH3

Aldehydes Yield

PhCHO

p-ClC6H4CHO

p-MeOC6H4CHO

CH3CH2CHO

(CH3)2CHCHO

86

67

65

70

81

1,5-anti : 1,5 syn

96 : 4

96 : 4

96 : 4

95 : 5

95 : 5

Thomas, E.J. Synlett 1992, 585

OBn OBn

1,5 anti

14-init 5-o-allylstannane 1,5 5/23/02 8:06 PM


Bu3Sn

CH3


ii.) RCHO, 1 hourR

OH

CH3


OBn OBn

1,5 anti

SnCl4Bu3Sn

CH3

R

OH

CH3

RCHO

SnO

H

R

HH3C

ClCl

Cl

RCHOH2O

OBnOBn

Cl3Sn OBn

CH3

BnOSn

O

H

R

HH3C

ClCl

Cl

BnO

15-mech 5-o-allylstan 1,5 5/23/02 8:07 PM


Bu3Sn

CH3

i.) Lewis Acid, -78 oC

ii.) PhCHO, -78 oCPh

OH

CH3

Lewis Acids Yield

SnCl4BuSnCl3SnBr4

Bu2SnCl2TiCl4BF3•OEt2AlCl3•i-PrOH

86

40

75

low

low

low

low

1,5-anti : 1,5 syn

96 : 4

95 : 5

99 : 1

--

--

--

--


OBn OBn

1,5 anti

16-LA Screen 5-o-allylstan 1,5 5/23/02 8:07 PM


Bu3Sn

CH3

i.) SnCl4, -78 oC

ii.) PhCHO, -78 oCPh

OH

CH3

R Yield

p-MeOC6H4CH2

MOM

SEM

SiMe2tBu

SiPh2tBu

80

66

71

60

61

1,5-anti : 1,5 syn

80 : 20

81 : 19

80 : 20


OR OR

1,5 anti

95 : 5

93 : 7

17-OP - 5-o-allylstan 1,5-cor 5/24/02 8:45 AM


Bu3Sn

CH3

i.) SnCl4, -78 oC

ii.) RCHO, -78 oCR

OH

CH3

Thomas, E.J. Perkin Trans. I ,1993, 2863

OP OP

1,5 anti : syn >99:1yield >70%

CH3

CH3

P=MOM, H, Bn R=Ph, Aliphatic

H CH3

OBnCl3Sn

Bu3Sn

H3CH3C

H CH3

OBnCl3Sn

Bu3Sn

E-isomer Z-isomer

E or Z

18-2 sub 5-o-allylstan 1,5 5/24/02 8:42 AM

1,5-Asymmetric Induction with Imines

Bu3Sn

OBn

i.) SnCl4, -78 oC

ii.)

Yield

CHPh2

CMe2Ph

OBn

(1)

ent - (1)

79

75

67

72

73

anti : syn

90 : 10

90 : 10

90 : 10

90 : 10

96 : 4

Thomas, E.J. Chem. Commun. 1995, 6, 657Thomas, E.J. Tetrahedron. Assym. 1995, 4, 2575

BuO2C

NX BuO2C

HN OBnX

1,5 anti, E olefin

X

BuO2C

N

Me

Ph

(1)

Mismatched

Matched

19-initial 1,5 4-O imine 5/23/02 8:15 PM

1,5-Asymmetric Induction with Imines

Bu3Sn

OBn

i.) SnCl4, -78 oC

ii.)

Thomas, E.J. Chem .Commun. 1995, 6, 657

BuO2C

NRr BuO2C

HN OBnR

1,5 anti, E olefin

Cl3Sn OBn

CH3

BuO2C

N

CH3

Ph

N

SnCl3

BuO2C OBnH

Me

H

Ph

CH3Cl3Sn OBn

CH3H

NCO2BuHH

H3C

Ph

20-mech 1,5 4-O imine 5/23/02 8:15 PM

Limitations of the Allylstannane Chemistry

i.) SnCl4, -78 oC

Thomas, E.J. Tet rahedron Assym. 1995, 6, 2579

Bu3Snii.) PhCHO

SnCl4

CH3

OTBSPh

OH

CH3

OTBS

Bu3SnCH3

OTBS Cl3Sn OTBS

CH3

R

OH

CH3

OTBS

RCHO

Ph CH3

HO OTBS

1: 2 product ratio

SnCl4

CH3

OTBS

Cl3Sn

H SnCl3O

H

Ph

OTBS

CH3

H

RCHO

Ph CH3

HO OTBS

21-1,5 limitations, TBS-1 5/23/02 8:17 PM


Yield

CHPh2

(S)-CHMePh

(R)-CHMePh

CHPh2

(S)-CHMePh

(R)-CHMePh

79

73

72

74

76

93

1,5-anti : 1,5 syn

90 : 10

96 : 4

90 : 10

25 : 75

25 : 75

33 : 67

Thomas, E.J. Tet rahedron Assym. 1995, 6, 2579

Bn

Bn

Bn

TBS

TBS

TBS

i.) SnCl4, -78 oCBu3Sn

ii.)

CH3

ORBuO2C CH3

NHX OR

N

BuO2C

X BuO2C CH3

NHX OR

1,5-anti 1,5-syn

Imine (X)Stannane (R)



Yield

CHPh2

(S)-CHMePh

(R)-CHMePh

CHPh2

(S)-CHMePh

(R)-CHMePh

78

82

73

77

80

74

1,5 syn : 1,5-anti

95 : 5

98 : 2

90 : 10

80 : 20

67 : 33

75 : 25

Thomas, E.J. Tetrahedron Assym. 1995, 6, 2579

Bn

Bn

Bn

SiMe2tBu

SiMe2tBu

SiMe2tBu

i.) SnCl4, -78 oC

ii.) BuO2C CH3

NHX OR

N

BuO2C

X BuO2C CH3

NHX OR

1,5-anti1,5-syn

Imine (X)Stannane (R)

Bu3Sn

CH3

OR


1,5-Asymmetric Induction with 4/5-Alkoxy-allylstannanes

Bu3Sn

CH3

i.) Lewis Acid, -78 oC

ii.) RCHO, -78 oCR

OH

CH3

OP OP

1,5 anti selective, Z olefin

R'

Bu3Sn

OP

i.) Lewis Acid, -78 oCR

OH

OP

1,5 syn selective, Z olefin

ii.) RCHO, -78 oC

SnCl4 or SnBr4

Chelating protecting group on oxygen is necessary Other heteroatoms are also effective (N, S)

2-Substitution on the olefin is acceptable SM olefin geometry is not important

High selectivities for a range of aldehydes and imines Generally >95:5 diastereoselctivity

R'

24-general 1,5 aldehyde 4,5-O 5/24/02 8:43 AM


Bu3Sni.) SnBr4, 10 min, -78 oC

ii.) R'CHO, 1 hourR'

OH

Thomas, E.J. Tet rahedron Lett. 1993, 24, 3935

CH3 CH3

1,6 syn >90:10yields >70%

OR OR

R=Me, H R'=aromatic, aliphatic

(3:2 E:Z)

SnBr4 RCHO

SnO

H

R

ClCl

Cl

RCHOH2O

Br3Sn OH

O

Bu3Sn CH3

OH

CH3

H

Br3Sn

H

CH3O

H HH3C

HSn

O

H

R

ClCl

Cl

O

HH3C

H

R'

OH

CH3

OR

25-init 5-o-allylstannane 1,6 5/23/02 8:27 PM


Bu3Sni.) SnBr4, 10 min, -78 oC

ii.) RCHO, 1 hourR

OH


1,7 syn >90:10yield >50%

OH

CH3

OH

Bu3SnCH3

OHBr3Sn

OH

CH3

SnBr4 RCHO

R

OH

CH3

OH

Sn OHOBr Br

Br

H3C

H

RSn OHO

Br BrBr

H3C

H

RBr3Sn O CH3

H

R=aromatic, aliphatic

26-mech 6-o-allylstan 1,7 5/23/02 8:28 PM






Ph

OBn

O

O

OP

Ph OCH3

OBn OP

O

I

OP OP OP

OP

OP

i) LiHMDS, TMSClii) TMSCHN2, MeOH

C1 - C16 - Amphidinol 3

27-Overview-Transfer 5/23/02 8:30 PM

2-Step 1,8-Asymmetric Induction via Chirality Transfer (Ireland-Claisen Rearrangement)


OH

CH3

OSEM

1,5 syn : anti 96:4

O

CH3

OSEM

O

BnO

[3,3]CH3

OSEM

CH3O

O

OBn

CH3

OSEMO

HTMSO

BnO

H

1,8 anti

28-initial 1,8 5/23/02 8:37 PM

2-Step 1,8-Asymmetric Induction Synthesis of (±)-Patulolide


OH

CH3

OSEM

1,5 syn : anti 96:477% from (±)-stannane

O

CH3

OSEM

O

BnO

CH3

OSEM

CH3O

O

OBn

1,8 anti : syn 86:14

BnOCH2COCl

Et3N, DMAP84%

i) LiHMDS, -78 oC

ii) TMSCl, -78 to RTiii)TMSCHN2

80%

i)

ii) H2 / Pdiii) TBDPSCl, imid

71%

CH3O CH3

OSEM

OTBDPS

ON N

H H

O

O

OH

H3C

29-1,8-claisen-pat-1 5/24/02 8:47 AM

CH3O CH3

OSEM

OTBDPS

O i) DIBAl-H

ii) Swerniii) PH3P=CHCO2Me

72%

CH3

OSEM

OTBDPS

MeO2C

i) MgBr2, BuSH, K2CO3ii) LiOH, MeOH-H2O

81%

CH3

OH

OTBDPS

HO2C

i) , Et3N

ii) DMAP, ∆ (separate isomers)iii) TBAF, THF

27%

O

O

OH

H3C

(±)-Patulolide

15 steps from stannane

Cl

OCl

ClCl

1,8 syn:anti 86:14

2-Step 1,8-Asymmetric Induction Synthesis of (±)-Patulolide


O

O

OH

H3C

30-1,8-claisen-pat-2 5/24/02 8:49 AM

2-Step 1,8-Asymmetric Induction via Chirality Transfer (2,3 Wittig Rearrangement)


OH

CH3

OSEM

1,5 syn : anti 96:4

O

CH3

OSEM

CH3

OSEMOH

1,8 syn : anti 90:10

PhPh

NaH, cinnamyl-Br

Bu4NI

70% 74%

-78 oC

n-BuLi

CH3

OSEM

OH

Ph

H

31-1,8-wittig-1 5/23/02 8:40 PM

2-Step 1,8-Asymmetric InductionSynthesis of (±)-Epipatulolide


i) SmI2ii) O3, DMSiii) PH3P=CHCO2Me

34%

CH3

OSEM

OTBDPS

MeO2C

22 %

O

O

OH

H3C

(±)-Epipatulolide

14 steps from stannane

PhCH3

OOTBDPS

OSEM

CH3

OSEMOH

Ph

5 steps

i) VO(acac)2, tBuOOH

ii) TBDPSCl, imid

iii)N N

H H1,8 syn : anti

90 : 10

32-1,8-wittig-2 5/23/02 8:42 PM

2-Step 1,8-Asymmetric Induction Syntheses of Epothilones B and D


IOO

DMPU, nBuLi

CH3

PhSO2

OO

CH3

SO2Ph

i) Amberlyst

ii) TBDMSCl, imidiii) Bu3SnH

TBSO

OH

CH3

SnBu3

1:1 E:Z

86 %53 %

i) SnBr4

ii)

H CH3

O

Me OH

CH3

1,6 anti 85:1560% of desired

OH

HO

iii) TBAF

CH3 O

CH3

O

O

i)

MeO OMe

ii) O

HOOPMB

O

OPMB

DIC, DMAP

66 %

33-Epothilone-1 5/23/02 8:42 PM

2-Step 1,8-Asymmetric Induction Syntheses of Epothilones B and D


Me O

Me

O

O

O

OPMB

i) LiHMDS, TMSCl

ii) TMSCHN2

Me

O

O

Me

CO2Me

OPMB

i) MCPBAii) H2/PtO2iii)KSeCN

78 %

Me

O

O

OPMBMe

CO2Me

i) DDQ

ii) LiAlH4iii) NaIO4, NaBH4

68 %

46 %

Me

O

O

Me

OH

O

Me

Me

Me

OH

MeS

N

Me

O O

OH

34-Epothilone-2 5/23/02 8:45 PM

1,9-Relationship Constructed by 1,7 InductionFollowed by a Claisen Rearrangement

Bu3Sn

i.) SnBr4, 10min, -78 oC

ii.) PhCHO, 1 hour

Ph

OH

Thomas, E.J. Tetrahedron. 1999, 55, 3723

1,7 syn 90:10yield 64%

OHOH

i) TBDPSCl, imidii) NaH, PMBCliii) TBAFiiii) Ac2O, NEt3

Ph

OPMB

O

49 %

i) LDA, TBSCl

ii) CH2N2Ph

OPMB

OCH3

OCH3

73 %1,9 anti:syn 90:1060% ee

CH3

CH3

CH3

60% ee

CH3

O

35-initial 1,9 5/23/02 8:56 PM

Fe(CO)3 Complexes as Chiral Transfer Groups

Takemoto, Y. Chem. Commun. 2000, 15, 1445

R'

R

HO

FeOC

COCO

R'FeOC

COCO

R

HOOO

R'FeOC

COCOR

HO

OH

[1,3]

RR'

OH

OH

1,8 anti diol

Fe(CO)3 moiety shifts to the electron deficient olefin

Hydride is delivered from opposite face of Fe complex

[R] H

[O]

base

36-FeCO3 1,3 shift initial 5/23/02 8:57 PM

Fe(CO)3 Complexes as Chiral Transfer Groups: Formal Synthesis of Epipatulolide


HH3C

TBSO

FeOC

COCO

H3C

TBSO

OH

H3C

OTBS

OH

HH3C

TBSO

O

O

OPMB

HWE

54%

i) KHMDS

ii) NaBH4

51%

i) H2O2, NaOHii) H2, Pt

OPMB

OPMB

H3C

OH

OTBDPS

CO2Me i) TBDPSCl, imid

ii) DDQiii) Swerniv) Ph3P=CHCO2Mev) AcOH, THF, H2O

24 %

O

O

OH

H3C

Epipatulolide C

>98:2 dr86%ee


89%

FeOC

COCO Fe

OCCO

CO

86% ee

15 steps from aldehyde

37-FeCO3 1,3 shift epipat 5/23/02 9:01 PM

Fe(CO)3 Complexes as Chiral Transfer Groups

Ley, S.V. Perkin Trans. I 1997, 3299

R CH3

OO Fe2(CO)9

RH

CH3

OO

O

Fe(CO)3

HR

CH3

OO

O

Fe(CO)3

HR

CH3

OHO

O

Fe(CO)3

R''

X2AlR''

endo : exo 4:1

dr >99:1yield >70%

CH3

OH

R''R

Fe(CO)3

X2AlR'' = Me3AlEt3AlBu3Al

AlMe2Bu

BuAlMe2

Ba(OH)2, MeOH

38-Ley-1,5 5/23/02 9:02 PM

Possibility for 1,10-Asymmetric Combining the Work of Ley and Takemoto

OFe2(CO)9

Ba(OH)2, MeOH

R

OP

CH3

O

R

OH

OP

CH3

OR

PO

FeOC

COCO

CH3

OR

PO O

O

Fe(CO)3

39-Ley-1,5-PROP 5/23/02 9:04 PM

Possibility for 1,10-Asymmetric Induction Using Fe(CO)3 Complexes

CH3

O

C5H11

TBSO

CH3

OH

C5H11

TBSO

H

C5H11CH3

TBSO

OH

KHMDS

70 %

NaBH4

72 %

(S)

Stereochemistry determined by Mosher Ester Analysis

i) H2O2, NaOH

89 %

ii) H2, Pt


CH3

OC5H11

TBSO

FeOC

COCO

FeOC

COCO

FeOC

COCO

40-1,10-proposal-1 5/23/02 9:04 PM






Bu3Sn


ii.) RCHO, 1 hour R

OH

CH3 CH3

OR

n

OR

n

1,5 to 1,9Induction

R'

R

HO

FeOC

COCO

O

RR'

OH

OH

i.) B-

ii) [R]iii.) [O]

1,8 & 1,10Induction

41-Summary 5/23/02 9:05 PM

diastereoselective construction of remote stereocenters...

Documents