Abstract
Chiral primary amines widely exist in drugs and are exceptionally important subunits
or synthons in the syntheses of chiral secondary and tertiary amines of medicinal
interest. Metal-catalyzed enantioselective reductive amination (ERA) of ketones with
ammonium salts or ammonia provides a direct method for their synthesis. Although very
useful, progress in this field has been very slow and important advances have only
been achieved in the last few years. Several major challenges exist in this reaction,
including (1) the reversible formation of unstable NH-imine intermediates; (2) the
strong coordination property of N-containing reagents toward metal species; and (3)
the lack of efficient catalytic systems that enable high enantiocontrol. Generally,
the efficiency and enantiocontrol of this reaction is dependent on the substrate type,
for instance, the use of α-keto esters/amides or aryl alkyl ketones is well established
and they have even been used in the industrial production of chiral amine drugs. However,
highly enantioselective control in dialkyl ketones, cyclic ketones, and α-keto acids
remains unsolved. Herein, the historical development of ERA reactions with ammonium
salts or ammonia gas is summarized, and novel synthetic applications toward useful
synthons or drugs are presented. In addition, the factors restricting the growth of
this method are also discussed.
1 Introduction
2 Enantioselective Reductive Amination via Hydrogenation
2.1 Enantioselective Reductive Amination of β-Keto Esters/Amides
2.2 Enantioselective Reductive Amination of Simple Ketones
2.3 Enantioselective Reductive Amination of α-Functionalized Ketones
2.4 Enantioselective Reductive Amination/Cyclization Cascade Reactions
2.5 Others
3 Enantioselective Reductive Amination via Transfer Hydrogenation
4 Synthetic Applications
5 Conclusions and Outlook
Key words
enantioselective reductive amination - chiral primary amines - drug synthesis - industrial
applications - metal catalysis - ketones
