何玉萍 20120609

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何何何 20120609 Total synthesis of (+)-vinblastine M eO CO 2 Me N N H OAc Me OH N H N M eO 2 C OH (+)-vinblastine (1)

description

何玉萍 20120609. Total synthesis of (+)-vinblastine. ◆. ◆. ◆. ◆. ◆. ◆. ◆. Fukuyama’ synthesis of indoles from quinolines. ◆. ◆. Clasisen rearrangement. - PowerPoint PPT Presentation

Transcript of 何玉萍 20120609

Page 1: 何玉萍 20120609

何玉萍20120609

Total synthesis of (+)-vinblastine

MeO

CO2Me

N

NH

OAcMe

OH

NH

N

MeO2C

OH

(+)-vinblastine (1)

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NMsO

1) CSCl2Na2CO3

2) NaBH4

3) DHP,CSA72% (3 steps)

MsO N C S

THPOCO2Bn

CO2Bn

NaH

THF

96%MsO N

H

THPO

S

CO2Bn

CO2Me

1) Bu3SnH, AIBN

tol, refulx

2) Boc2, Et3N

DMAP, CH2Cl2

83%(2 steps)

MsO CO2Bn

CO2Me

N

Boc

OTHP

MsO CO2H

CO2Me

N

Boc

OTHP

H2, Pd/C

EtOH

HCHO

AcOH, NaOAc

EtOH

85% (2 steps)MsO

CO2Me

N

Boc

OTHP

CSA

MeOH

97%

MsO CO2Bn

CO2Me

N

Boc

OH

17 18 19

20 21

22 23

THF.H2O

Me2NH.HCl

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HO

OH

OHH+

heat

ONH2

R

NH

R

O

NH

R

OH

H+

-H2O

NH

R[O]

N

R

Skraup quinoline synthesis

Fukuyama's modified approach

N

O

RTs

3N HCl/THF1:1, 80oC

NRTs

KOH, DMSO

80oC to 140oCNR

5:1 to 14:1

regioselection ◆

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NMsO

Cl Cl

S

NMsO

S ClCl-OH- NMsO O-

S Cl

NC

S

O

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Fukuyama’ synthesis of indoles from quinolines

Bu3SnH, AIBN

MsO NH

THPO

S

R

MsO NH

THPO

RSSnBu3

MsO NH

RSSnBu3

OTHPH5-exo cyclization

MsO N

OTHPH

R

-HSSnBu3

-HSSnBu3

MsO N

THPO

R MsO N

OTHPH

RMsO N

H

OTHP

R ◆

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MsO CO2H

CO2Me

N

Boc

OTHP

MsO

CO2Me

N

Boc

OTHP

MsO

CO2Me

N

Boc

OTHP

N Cl-

MsO

CO2Me

N

Boc

OTHP

22

21

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CHOPhMgBr

THFOH

Ph

OBuHg(OAc)

NaOAc

refulx

72%(2 steps)

OHC

Ph

H

1) NaCNAcOH

2) Ac2O, Py

95% (2 steps) Ph

HNC

OAc

lipase PS

THF-H2O

44% (97% ee) Ph

HNC

HOH

O3

Me2S

87%

O

H

OHNC

MsCl

Et3N

toluene

66%

ONC

1) LiAlH4, THF

2) DNsCl, PyNO2

NO2

O2SNH

O

2728 29

30 31

32 3326

OPh

Me

Clasisen rearrangement

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NO2

NO2

O2SNH

O

MsO

CO2Me

N

Boc

OH

23 26

DEADPPh3

Benzene,rt

89%

MsO

CO2Me

N

Boc

N

DNsO

34

TFAMe2S

CH2Cl2rt

MsO

CO2Me

NH

NH

O

OH MsO

CO2Me

NH

NH

NH

MeCNMeOH

rt, 5 min

35 36

60oC

2h MsO

CO2Me

NH

NOH

MsO

CO2Me

NH

NOH

H

37 38

72% (3steps)

OHCHO

Me

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AcONa

Ac2O, rt

91%MeO

CO2Me

N

NH

OAcMe

OH

2:(-)vindoline

PPh3, CCl4MeCN, 70oC

HO

CO2Me

NH

N

H

39

1)

2) KOH, MeOH

t-BuOKMeI, THF

65%(3 steps) MeO

CO2Me

NH

N

H

40

(PhSeO)2O

PhH, 80oC

H2O, 80oC MeO

CO2Me

NH

N

H

OH

41

m-CPBAMeOH/CH2Cl2

sat.aq. NaHCO3

0oC 5 min

MeO

CO2Me

NH

NH

O

MeO N

N

OH

H

CO2Me

1) HCHO, NaCNBH3

HCl/MeOH 0oC

2)NaHSO3

64%(3 steps)

MeO

CO2Me

N

NH

OH

OHOH Me

OH

4243

O

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Et CO2H

PivCl, Et3NEt2O 0oC

N

O

Bn

O

Li

THF, -78oC

89%

Et

O

N

O

Bn

O

i-PrOTiCl3i-Pr2NEt

CN

CH2Cl20oC

82%

O

N

O

Bn

O

NC

Et

NaBH4

THF-H2O

92%

OHNC

Et

TBDPSClimidazole

DMF

92%

NC

Et

OTBDPS 1) DIBALCH2Cl2-78oC

2) H2NOH.HClNaOAC

EtOH

OTBDPS

NaOCl

CH2Cl2rt

58%(3 steps)

44 45

46 47

48 49

NOH

Et

OTBDPS

Et

N+-O

nitrile oxide 1,3-polar cycloaddition

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NO

OTBDPS

H

Et

Zn

AcOH

66%

OTBDPS

H

HO

OEt

m-CPBA

AcOHO

OTBDPS

O EtOH

K2CO3

MeOH

80%(2 steps)

OH

OH

Et

MeO2COTBDPS

OTES

OTMS

Et

MeO2COTBDPS

TESCl, imid, rt

TMSCl, rt

DMF

92%

50 51 52

5354

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LDA, THF

OTHP

NCS 55

-78oC to 0 oC

THPO

NH

S

OTES

EtOTMS

OTBDPSMeO2C

Et3B

toluenert

87%

NH

THPO

MeO2COTBDPS

OTES

OTMSEt

NBoc

HO

OTBDPS

OH

OHEt

CO2Me

1) Boc2, DMAP

CH2Cl2, rt

2) AcOH-H2O

80oC82%(2 steps)

78%

NBoc

HO

OTBDPS

OTs

OHEt

CO2Me

TsCl, Et3N

Bu2SnO

CH2Cl2, rt

84%

56 57

58 59

Bu3SnH

Page 13: 何玉萍 20120609

NaHCO3

DMF 80oC

90%NBoc

HO

OTBDPS

Et

CO2Me

O NsNH2

DEAD, PPh3

toluene rt

88%NBoc

HN

OTBDPS

Et

CO2Me

O

Ns

K2CO3

DMF 90oC

85%NBoc

OTBDPSCO2Me

N

Ns

OHEt

TFA

CH2Cl2

85%NH

OHCO2Me

N

Ns

OHEt

6160

62 63

1) TsCl

Me2N(CH2)3NMe2

toluene, MeCN

2) TFAA, Py

CH2Cl279%(2 steps)

NH

OTsCO2Me

N

Ns

OTFAEt

3

Page 14: 何玉萍 20120609

MeO

CO2Me

N

NH

OAcMe

OH

2:(-)vindoline

NH

OTsCO2Me

N

Ns

OTFAEt

t-BuOCl

CH2Cl20oC

NH

OTsCO2Me

N

Ns

OTFAEt

Cl

MeO

CO2Me

N

NH

OAcMe

OH

(-)-vindoline

TFA, CH2Cl2

0oC to rt

NHMeO2C

N

Ns

OTFAEt

1) Et3N, MeOH

2) HSCH2CH2OH

DBU, acetone

76%(2 steps) MeO

CO2Me

N

NH

OAcMe

OH

NHMeO2C

HN

OHEt

OTsOTs

MeO

CO2Me

N

NH

OAcMe

OH

NH

NaHCO3

i-PrOH, H2Ort

66%

N

MeO2C

OH

97%

(+)-vinblastine (1)

3 64

65 66

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NHMeO2C

HN

OHEt

ViNH

NaHCO3

rt

N

MeO2C

OH

(+)-vinblastine (1)

solventVi OTs N

NH

OH

Et

H

EtOOCVi

110