Improved Methodology for the Preparation of Chiral Amines

library of organocatalysts which were used efficiently for different organic transformations.
Several research groups focused their efforts on the synthesis of novel organocatalysts for
asymmetric imine reduction and reductive amination. Among these transformations are imine
reduction and reductive amination. At this time, development in the application of
organocatalysis for reductive amination is still in its infantile stage compared to other
transformations. [56]
X +2 [H]
H
X
∗
chiral
catalyst R 1
X=CR 2 ,O,NR
R 1 R 2
R 2
Scheme 3.17. Asymmetric Reduction of prochiral Compounds.
Inspired by nature and how living organisms reduce imino group through the employment of
organic dihydropyridine cofactors such as nicotinamide adenine dinucleotide (NADH) in
combination with enzyme catalysts (figure 3.2). [57]
H
H
O
NH 2
.
- O
O
O
P
O
O
P
O -
O
N
H H
O
H H
OH OH
O H HAdenine
O
H H
OH OH
reduced nicotinamide
adenine dinucleotide
(NADH)
Figure 3.2. Reduced Nicotinamide Adenine Dinucleotide
Scientists started to think of NADH analogues and they found that the best analogues would
be Hantzsch esters. These hydrogen sources in the presence of achiral Lewis or Brønsted acid
catalysts proved to be efficient in imine reduction. [58] List investigated the catalytic cycle of
reductive amination utilizing Hantzsch esters. He proposed that reductive amination of
ketones is initiated by protonation of the in situ generated ketimine from a chiral Brønsted
acid catalyst (Scheme 3.18). The resulting iminium ion pair, which may be stabilized by
68