Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: from Academy to Industry

Chiral primary amines widely exist in drugs and are exceptionally important subunits or synthons toward 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 the synthesis of them. Although very useful, progress in this field is very slow and important advance has just 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 ; 3) the lack of efficient catalytic systems that enable high enantiocontrol. Generally, the efficiency and enantiocontrol of this reaction is dependent on substrate types, for instance, α-keto esters/amides or aryl alkyl ketones have been well established and even used in industrial production of chiral amine drugs. However, highly enantioselective control on dialkyl ketones, cyclic ketones and α-keto acids remains unsolved. Herein, the historical development of ERA reactions with ammonium salts or ammonia gas are summarized, and the novel synthetic applications toward useful synthons or drugs are presented. In addition, the bottlenecks of this method are also discussed in the review.