(–)-Kaitocephalin (100612–TKGP) Y. Ohfune, T.

Shinada1), 2)

Cl
HO
H CO2H
N NH2
Cl
H N
O H CO2H
CO2H HO

Activity Ionotropic glutamate receptor antagonist（イオンチャネル型グルタミン酸受容体アンタゴニスト）

(A) Cu-catalyzed insertion reaction, (B) asymmetric transferring Strecker

Key Reactions synthesis, (C) regioselective azidation, (D) acetonide migration, (E) allylation
of N-acyliminium ion, (F) deprotection using Hard / Soft concept

O 1) ?, Et2O 1) TFA, CH2Cl2 O

BocHN O HN
O
MeO2C Cl 2) Boc-L-Val 2) ?, i-PrOH O
cat Cu(acac)2 O MeO2C
MeO2C CN
B-59 toluene, rt (B)
B-83 (A)

O3 ? NH2
O
N + HN O OH
HO2C
AcOEt, –78 ºC O OH 100 ºC CO2H
MeO2C MeO2C
CN CN
2:3

1) TBSCl, Et3N
Dowex 50Wx4 cat NaCN CO2Me DMAP, CH2Cl2 CO2Me
? O O OTBS
N OH N
MeOH MeOH H 2) ?, Et3N Boc
?, THF

1) TBAF, AcOH CO2Me

THF CO2Me ? CO2Me OsO4, DMAP OH
O O N O N
2) ? N CHO toluene, 80 ºC
Boc Boc CO2Me THF, –78 ºC Boc CO2Me
PhI(OAc)2 HO
CH2Cl2 dr = >10 : 1

CO2Me
CO2Me 1) TFA, CH2Cl2 CO2Me CSA
? O 0 ºC N3 ?
N
Boc O O N
CH2Cl2 O 2) ?, PPTS H CO2Me toluene
DMF HO
S
(C)
 CO2Me CO2Me CO2Me
1) H2, Pd/C
N3 NHCbz CO2Me
AcOEt 1) TFA, CH2Cl2
O N O N O N
CO2Me 2) CbzOSu, DMAP CO2Me 2) ?, ? Boc NHCbz
O O O
CH2Cl2 THF
(D)

MgBr

1) ? CO2Me CuBr·Me2S CO2Me 1) ?, ?

THF, –78 ºC CO2Me BF3·OEt2 CO2Me t-BuOH, H2O
AcO N N
H Boc
2) Ac2O, DMAP Boc NHCbz THF NHCbz 2) TBSOTf, lutidine
CH2Cl2 O –78 ºC to rt O CH2Cl2, –78 ºC
(E)
1 dr = 1 : 2

1) TBAF, AcOH
THF
CO2Me 1) DEAD, Ph3P CO2Me 2) cat ?
?, CH2Cl2 H cat KBr, ?
HO CO2Me Ar N CO2Me
2) ?, THF-H2O acetone, aq NaHCO3
H N O H N
TBSO Boc NHCbz 3) ArCO H, BOPCl Boc NHCbz
O 2 TBSO O 3) TMSCHN2, AcOEt
i-Pr2NEt, CH2Cl2 MeOH
Cl C-16
dr = 1.5 : 1 B-101
ArCO2H = BnO CO2H

Cl

Cl
HO
H CO2Me H CO2H
Ar N CO2Me AlCl3 N 9 NH2
Cl + (9R)-isomer of
H N H N Kaitocephalin
O Boc NHCbz Me2S, rt O H CO2H
CO2Me O CO2H HO
(F)
(Š)-Kaitocephalin

###
CO2Me TMS CO2Me
CO2Me CO2Me
? same as above
AcO N N (7S,9S)- and (7S,9R)-
Boc H Boc isomers of Kaitocephalin
NHCbz CH2Cl2 NHCbz
O O

1 C-51
dr = >99 : 1

References:
1) M. Kawasaki, T. Shinada, M. Hamada, Y. Ohfune, Org. Lett., 7, 4165 (2005)
2) 大船泰史, ファルマシア, 42, 817 (2006)