Organocatalyzed Reductive Amination and its Application in the
Construction of Biologically Significant Molecules
Pavel Kočovský
Department of Organic Chemistry, Charles University
12843 Prague 2, Czech Republic
pavel.kocovsky@natur.cuni.cz
A new class of amino acid-derived N-methyl formamides, such as the Sigamide (now commercially
available), have been developed as Lewis-basic organocatalysts for asymmetric reduction of imines
with Cl3SiH (≤97% ee at ≥1 mol% loading). Their application will be highlighted by the
enantioselective synthesis of N-acetyl colchinol (a potent anti-cancer agent with a mode of action
similar to that of taxol) and SCH 48461 (a drug that reduces the intake of cholesterol from food). The
reaction also works as a direct, one-pot reductive amination, starting with the corresponding ketone,
and without the need for isolation of the imine. With aldehydes, the reaction does not require a
sophisticated chiral entity and works perfectly well with both primary and secondary amines and DMF
as the Lewis basic catalyst. Tolerance of a wide range of functional groups and heteroaromatic
moieties can be demonstrated by the reductive amination of keto aldehydes, where the aldehyde
group reacts with excellent chemoselectivity. Being not experimentally demanding, the method is
particularly suitable for parallel chemistry, generating libraries of secondary and tertiary amines.
R1 R2
N
R3
R1
R2
HN
R3
*
Toluene, r.t. (< 97% ee)
Cl3SiH
Sigamide
(> 1 mol%)
NMe
H
O
O
HN
*
Sigamide
N
O
MeO
MeO
SCH 48461
* *
N-Acetyl Colchinol
H
N
HO
MeO OMe
OMe
*
O
N
H
Bu
O
87%
O
O
n-BuNH2, 4A MS
Toluene, rt 4 h
then
Cl3SiH, DMF (10 mol%)
Toluene, rt 8 h
o