Post on 31-Jan-2016
description
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)