Improved Methodology for the Preparation of Chiral Amines

eductive amination of the prochiral ketone resulting in 80% ee with 60% yield. They also
tested reduction of isolated imine resulting in the same enantioselectivity and with
unacceptable chemical purity. Higher ees are usually required for pharmaceutical
development levels. Later they tested the chiral auxiliary approach for the synthesis of chiral
amine moiety. They tested different derivatives of MBA and phenylglycinaol. They reported
86% yield with 90% de which was improved by crystallization. The instability of substituents
under hydrogenolysis standard conditions was another challenge. BCl 3 and BBr 3 gave the
cleanest N-debenzylation without affecting the chloro substituent and tetrahydrocarbazole
moiety.
Cl
HCO 2 NH 4 ,MeOH,60 o C Cl
N
H
O
N NH 2
H
80% ee, yield 60%
NH 3
(7N in MeOH)
TsOH
SO 2
N
Ru
N
H 2
Cl
Cl
N
H
NH
[RuCl 2 (benzene)] 2 Cl
HCO 2 NH 4 ,MeOH,65 o C
N
H
81% ee
NH 2
PPh 2
Cl
N
H
O
p-TsOH, or conc.HCl
toluene, reflux
H 2 N
X
Cl
PPh 2
N
H
N
Y
X
1. NaBH 4
EtOH, -30 o CtoRT
2. HCl
Cl
N
H
(R)
HN
Y
X
Cl
Y
Cl
N
H
HN
OMe
1. BCl 3 ,DCM,0 o C
2.
Scheme 4.17. Synthesis of Tetrahydrocarbazoles:
N
COOH,i-PrOH
80-92%
Cl
N
H
N
ee 99.2%
NH 2
COOH
T3P (50% in EtOAc)
i-Pr 2 NEt, DCM, 0 o C
60-87%
Pr
T3P= O
O
P P
O Pr
O O P
Pr
O
Cl
N
H
HN
O
Tetrahydrocarbazoles
ee >99.5%
N
96