(+)-Vinblastine (111022-TKGP) T. Fukuyama, S.

Yokoshima1), 2)

OH
N

H N
H
N
H
MeO2C OH
MeO N OAc
H
Me CO2Me

Activity Antitumor（抗腫瘍活性）
(A) radical-mediated indole synthesis, (B) Mitsunobu reaction of DNs amide,
Key Reactions (C) [4+2] cycloaddition, (D) macrocyclization of Ns amide,
(E) stereoselective coupling

? Et
PhMgBr OH NaOAc ?
CHO
THF Ph n-BuOCH=CH2 OHC
AcOH
reflux Ph

Et Et Et
Ac2O ?
NC pyridine NC THF-H2O NC
OH Ph OAc Ph 50 °C OH Ph

Et
Et ?, ? Et
O3 ?;

MeOH-CH2Cl2 NC OH toluene NC H2O, ?; O

78 °C; Me2S O 0 to 80 °C O DNsCl, CH2Cl2 HN
DNs
1

###
?
MsCl Na2CO3 HO
Et3N THF-H2O; ?, CSA

HO N CH2Cl2 MsO N NaBH4 CH2Cl2

MeOH MsO NCS

THPO
THPO ? 1) ? OTHP
NaH ?
S CO2Bn
THF CO2Bn 2) Boc2O MsO N
0 °C MsO N Boc
MsO NCS H Et3N, DMAP CO2Me
CO2Me
(A)
 1) H2, Pd/C OTHP OH
EtOH CSA

2) ?, ? MsO N MeOH MsO N

Boc Boc
AcONa, AcOH CO2Me CO2Me

DNs OH
N O 1) TFA, ? N ?
1
?, ? CH2Cl2, rt ?

benzene Et 2) ? MeCN
MsO N MeOH-MeCN MsO N
(B) Boc H
CO2Me CO2Me
(C) C-71

N N N
1) ?
MeOH (PhSeO)2O

2) MeI benzene;
MsO N t-BuOK MeO N MeO N OH
H H H2O H
CO2Me CO2Me CO2Me

mCPBA
N N
aq NaHCO3
MeOH-CH2Cl2; NaOAc
OH OH
? MeO N OH Ac2O MeO N OAc
NaBH3CN, HCl; H H
Na2CO3, NaHSO3 Me CO2Me Me CO2Me
(–)-Vindoline (2)

###

1) ?
1) ? ?
? 135 °C O ?, Et3N;
Et
Et CHO OH Et
2) LiAlH4 2) KOH OH Bn
EtOH-H2O LiN

O O

(i-PrO)TiCl3
O ?; O Bn
Bn NC
Et ? NC 1) ? OTBDPS
N N
Et
CH2Cl2 Et O 2) TBDPSCl
O 0 °C O imidazole
O

HO OTBDPS
1) ? N OTBDPS aq ? ?
Et
2) ? CH2Cl2 N Et AcOH
B-89, 90
NaOAc O
 OTES
OTBDPS OTBDPS 1) ? OTMS
? ?
Et
O MeO2C
Et AcOH Et 2) TESCl
O O imidazole;
HO OH
TMSCl OTBDPS

LDA; THPO
OTHP THPO
OTES
OTES Bu3SnH
? OTMS
NCS H OTMS
N Et
THF Et THF
–78 to 0 °C N
S H
(A) MeO2C OTBDPS
MeO2C
OTBDPS

HO HO
OH
1) Boc2O, Et3N 1) ? O
DMAP, CH2Cl2 OH TsCl, Et3N
Et Et
2) ? N 2) ? N
80 °C Boc DMF, 80 °C Boc
MeO2C OTBDPS MeO2C OTBDPS

H
N Ns
Ns
NsNH2 O N
?, ? ? OH
Et
Et
toluene N DMF, 90 °C N
Boc Boc
MeO2C (D) MeO2C
OTBDPS OTBDPS

Ns
N
1) ?, CH2Cl2 Ns OTFA
2) TsCl N 1) t-BuOCl
? Et
OTFA CH2Cl2 N
H N
3) TFAA, pyridine Et OTs H
N 2) vindoline (2) MeO2C
CH2Cl2 H TFA
MeO2C OH
OTs CH2Cl2
MeO N OAc
H
(E) Me CO2Me

H OH
N
OH N
Et
1) ?, MeOH N NaHCO3
H N H N
H H
2) ? MeO2C OTs N
i-PrOH H
DBU, acetone OH H2O OH
MeO2C
MeO N OAc MeO N OAc
H H
Me CO2Me Me CO2Me
(+)-Vinblastine
References:
1) S. Yokoshima, T. Ueda, S. Kobayashi, A. Sato, T. Kuboyama, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc., 124,
2137 (2002)
2) S. Kobayashi, T. Ueda, T. Fukuyama, Synlett, 883 (2000)