何玉萍20120609
Total synthesis of (+)-vinblastine
MeO
CO2Me
N
NH
OAcMe
OH
NH
N
MeO2C
OH
(+)-vinblastine (1)
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
◆
◆
◆
◆
◆
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 ◆
NMsO
Cl Cl
S
NMsO
S ClCl-OH- NMsO O-
S Cl
NC
S
O
◆
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 ◆
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
◆
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
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
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
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
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
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
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
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
NHMeO2C
HN
OHEt
ViNH
NaHCO3
rt
N
MeO2C
OH
(+)-vinblastine (1)
solventVi OTs N
NH
OH
Et
H
EtOOCVi
110
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