任磊2011.06.25

NH

X

R R2n

n=1,2X=NR, O

NH

X

R2nO

HN

O

X=O, physovenineX=NMe, physositigmine

NH

OHC

Me

H

N

CO2Me

OH

(+)- Aspidophyline A (1)

N

N

N

NO

O

aspidophylline A

N

N

PMBS

OH

BOC

(-)Minfiensine

N

N

R

R3

R4

R2

NH

NH2NTs

R

HOGrag

NMe

R

RO2C NH

OEt

O

OReisman

NH

O

RR1

N

O

R

R1I

NH

OR1

NH

O

BrR1

CO2MeCO2Me

Stoltz

NR1

R2HN

R O

D. W. C. MacMillan

NR1

R2HN

OEt

O

N2

Qin YongNR1

R2HNCO2Me

NBSor PhthSePh

Danishefsky

n

NO

R1

NO

R1

R2 R2

HNNH

O O

N N

15mol%

Mo(C7H8)(CO)3 10mol%

LiHMDS/LiOtBu RT

Y=92-99%Ee=74-95%

N

N

NO

O OsO4 NMO

NaIO4 NO

O

O MeNH2, Et3N

LAH,THF,reflux

O

H

(-) esermethole

Barry M. Trost J. AM. CHEM. SOC. 2006, 128, 4590-4591

不对称烯丙基化

N

R1

NH

R4

O

O

R2

R

N

R1R2

R

R3O

O

HN

OR3

O

OR4

LA

N

R1R2

R

NOR3

O

O

R4

R-BINOL(0.2eq)

SnCl4 (1.2eq)23OC DCM

Sarah E. Reisman J. AM. CHEM. SOC. 2010, 132, 14418–14420

不对称环加成

Sarah E. Reisman J. AM. CHEM. SOC. 2010, 132, 14418–14420

Samuel J. Danishefsky J. Am. Chem. SOC.1994,116, 11143-11144 J. Am. Chem. Soc. 1999, 121, 11953-11963 Movassaghi, M. Science 2009, 324,238–241.

溴和锡的反应

N

R

E+=SePh or BrNHR

N

R

NHRE

N

R

E

NR

N

R

E+=SePh or BrNHR

N

R

E

NR

N

N

R1

NR1

OEt

O

N2NH

O

O

Cu(OTf)2

O

CO2Et

O

NR1

NHR2

R3

OR

O

N2

M+ NR1

NHR2

R3

CO2R

NR1

NHR2

R3CO2R

NR1

NR2

R3

CO2R

Yong, Qin Org. Lett. 2006, 8, 6011–6014. J. Am. Chem. Soc. 2010, 132, 14052–14054.

偶氮的反应（分子间）

N

NHTs

O

R3

N2

R2

R1 Cu+

N

O

NTsR2

R1

N

O

NTsR2

R1

R3R3

N

O

R2

R1

R3

NTs

R1=H,MeOR2=Me, BOCR3=H,CO2Me

42-82%

Qin, Y. Angew. Chem., Int. Ed.2008, 47, 3618–3621. J. Am.Chem. Soc. 2007, 129, 13794–13795

偶氮的反应（分子内）

NH

O

R1X

CO2RCO2R

O

N NO

PhPh

20mol%

Cu

(SbF6)2

2+

NH

O

R1RO2C

CO2R

Ee=74-91%

NH

O

PhMeO2C

CO2Me

1.LiCl,H2O DMSO 1500C

2.tBuOK, MeI THF

Y=59%NH

O

Ph

CO2Me

AlMe3 , MeNH2.HCl

toluene, 500C

Y=61%NH

O

Ph

CONHMe

LiAH4

THF 00C

Y=99% NH

NMe

Ph

H

O

Brian M. Stoltz Angew. Chem. Int. Ed. 2009, 48, 8037 –8041

不对称烷基化

X

X

NHR

MeO2C

Pd(OAC)2

1700C

microwave

N

O

Ph2P

N

NHR

CO2Me

TFAN

CO2MeNBOCH3

85%99%ee

Overman, L. E. J. Am. Chem. Soc. 2005,127, 10186–10187. Angew. Chem., Int. Ed.2007, 46, 5488–5508.

不对称 Heck 反应

Levy, a. Synlett 1992, 7,601–602.

[4+2]环加成反应

N

NHTs

Bn

R1

N

CO2Me

Bn

R1

MeO2C

N

CO2Me

Bn

R1

MeO2C

NTs

45%

170OC

CO2MeMeO2C

NTs

Keiji Maruoka J. Am.Chem. Soc. 2009, 131, 16620–16621.

NR

O

R1

R2NO2

Cat(1mol%)

NR

O

R1R2

NO2

NR

NH(R3)

R1

R2

Ph Ph

OH

Ph Ph

OH

N O

Cat

Y=34-99%Dr=1/1-12/1Ee=20-95%

1,4-加成

NR

O R2NO2

Cat(2.5mol%)

NR

O

R2

NO2

NR

NH(R3)

R2

Cat

Y=87-99%Dr=5/1-30/1Ee=87-96%

N

N

O

O

O

O

Mn Mn

Masakatsu Shibasaki J. Am.Chem. Soc. 2007, 129, 13794–13795.

1,4-加成

Keiji Maruoka Angew. Chem. Int. Ed. 2009, 48,4559 –4561

NR

OCat(1mol%)

NR

O

NR

NH(R3)

R2

PBu

Bu

Cat

Y=93-99%Ee=90-99%

CF3

CF3

CF3

F3C

R2

O

R2

O

R1

R1

R1

1,4-加成

D. W. C. MacMillan Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482–5487. Chem.Sci.2011,2,308-311

N

COBHN

O

prerryl

NH

NO

Ph20mol%

1)

2)NaBH4 ,MeOHBr NNBOC

OH

BrN

NBr

90% ee78% yield

HX

OH

NPMB

OBn

R

CHO

NH

NO

Ph

HX

30mol%

O

NPMB

OBn

R

O

Dr>20/1

不对称串联

N

COBHN

O

PMB

NH

NO

Na-B20mol%

N

NHBOCHX

SMe

TBA/-500C

N+R

RSMe

PMB

X- H+

N

NHBOC

N+R

RSMe

PMB

X-

N

N

PMBS

OH

BOC

87%96%ee

D. W. C. MacMillan J. Am.Chem. Soc. 2010, 131, 10606-10607

不对称串联

NH

NH2 H

ONH

R

H

H+

R

X

n=1,2X=NR1, O

X

OH

n n

RX

H

NH

Xn

NH

R1.[3,3]重排

2.H+

H

NH

Xn

NH2

R

NH3

NH

R Xn

n

Neil K. Garg, Org. Lett. 2009, 11, 3458–3461. Tetrahedron 66 (2010) 4687–4695 J. Am. Chem. Soc. 2011, 133, 5752–5755

Fischer 吲哚的合成

NH

NH2

NH

OOHO

Cat(1.2eq)

benzene, 400C

Y=62%Ee=28%

O

OP

O

OH

CF3

CF3

CF3

CF3

R-

H

Neil K. Garg Tetrahedron 66 (2010) 4687–4695

Fischer 吲哚的合成

NH

NH2 R2

O

R1

NH

R1

R2 NH3

NH

NH2R2

O

R1

NH

N

R2

R1

NH

N

R2

R1

NH

NH

R2

R1H

1.[3,3]重排

2.H+

NHNH+

2

R2

R1

N+

R1

R2

H

互变异构

NH2NH+

2

R2

R1

H HNH2

H+迁移

NH

R1

NH3

HR2

NH

R1

R2 NH3

Cat

Fischer,E.;Jourdan,F. Ber. 1883, 16, 2241–2245;Fischer,E.;Hess,O. Ber. 1884, 17, 559–568.

Kam, T.-S. J. Nat. Prod.2007, 70, 1783–1789.

NH

OHC

Me

H

N

CO2Me

OH

(+)- Aspidophyline A (1)

1) Kopsia singaporensis (also called White Kopsia) is a species of plant in the Apocynaceae famil2） Isolated by Kam and co-workers in 2007.3) Drug resistance in resistant KB cells.

逆合成分析

Neil K. Garg J. Am. Chem. Soc. 2011, 133, 8877–8879

RN

H

MeCO2Me

H

OOH

NHH2N

RN

H

MeCO2Me

H

RORO

RORO

NR I

Me

CO2Me

21

NO

OBn

CO2HCO2H

16

NH

OHC

Me

H

N

CO2Me

O

(+)- Aspidophyline A (1)

NBn

O

BnO

PhMe,reflux

Ref 8

OO O

14

BnOO N

Bn

H

O

O

HO

15

Cu2O,bipyridyl

quinoline,H2O,150 oCmicrowave reactor50-69% yield

NO

OBn

CO2-

CO2-

16

Cu(l)

NBn

OO

17

1.HC(OCH3)3,9-TsOH,MeOH

2.Na,NH3,-78 oCT-BuOH.THF

(87%yiled,2steps)

HNO

MeOMeO

18

1.n-BuLi,TsCl

THF,-50 oC

2.K2CO3,MeOH

(90%yield,2steps)

NHTsMeO

MeO

CO2Me

19

Br

I

Me

CsCO3,CH3CN(70%yield)

MeOMeO

NTs I

Me

CO2Me

21

Pd(PPH3)4

pentamethylpiperidine

CH3CN,70 oC95-99%yield

TsNMeO

MeO

H

MeCO2Me

H

22

i.LiHMDS, DMPU, THF

ii. allyl iodide, -50 oC

(75% yield)

24

1.OsO4,NalO4

NaOAc,THF,H2O

2.NaBH4,MeOH, 0 oC

(83%yield,2steps)

1.H2SO4,THF(aq)

2.Dess-Martin CH2Cl2,NaHCO3

(76%yield,2steps)

30

TsNMeO

MeO

H

MeCO2Me

In.90 oC,EtOHaq,NH4Cl

H

22

FeCl3 6H2O

CH2Cl2(90%yield,2stepsdr=8/1)

TsN

HO

MeCO2Me

H

23

TsN

HO

MeCO2Me

H

TsN

HO

MeCO2Me

H

TsN

MeCO2Me

OHC

HOH

H

TsN

H

MeCO2Me

HO

HO

H

TsN

H

Me

HO

O O

H

31

TsN

H

Me

HO

O O

HN NH2

TFA, DCF,400C

HN

NH

Ts

Me

H

H

HN

O O

NH

Ts

Me

H

O O

N

(not isolated)

NH

Ts

Me

H

N

CO2Me

-O

NH

Ts

Me

H

N

CO2Me

OH

70%yield

(one-pot,from 31)

3132

33

34

1.Mg,NH4Cl,MeOH

2.formic acid DIC

DMAP CH2Cl2

(68%yield, 2 steps)

K2CO3

MeOH600C

HNH Me

H

N

CO2Me

OH

27

NH

OHC

Me

H

N

CO2Me

OH

(+)- Aspidophyline A (1)