Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

Abstract

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.

Biological synthesis of ursodeoxycholic acid

“…Cofactor regeneration refers to the regeneration of the cofactor from the oxidation state to the reduction state or vice versa, which allows the cofactor to be maintained at a certain catalyst amount level. A number of methods have been proposed to address this cofactor regeneration issue, including chemical, photochemical, enzymatic, and electrochemical regeneration systems (Zhang, 2001;Hummel and Gröger, 2014). Enzymatic UDCA synthesis must also take advantage of a suitable cofactor regeneration system for industrial UDCA production.…”

Ruthenium‐Catalyzed Direct Reductive Amination of Carbonyl Compounds for the Synthesis of Amines: An Overview

“…[24,25] The asymmetric reductive amination (ARA) of carbonyl compounds, catalyzed by transition metals, is a useful and efficient strategy for chiral CÀ N bond formation. [26][27][28][29] Ruthenium is a valuable metal for catalytic reactions as it is the cheapest noble metal with high activity in chemical transformations. [30][31][32] Due to their stability, selectivity, adaptability, minimal toxicity, and high efficiency, ruthenium catalysts are used in reductive amination.…”

Ruthenium-Catalyzed Direct Asymmetric Reductive Amination for the Synthesis of a Chiral Primary Amine Intermediate En Route to a PDE2A Inhibitor, TAK-915

“…Transition metal-catalyzed direct asymmetric reductive amination (DARA) of carbonyl compounds with transition metal hydrides represents the most straightforward route to enantiomerically enriched primary amines, in comparison with the conventional multistep procedures exemplified by the formation of a protected imine, followed by asymmetric hydrogenation and deprotection of the obtained chiral secondary amine. The DARA approach for obtaining unprotected chiral amines (i.e., chiral primary amines) has been limited, in comparison to the well-known methodologies toward chiral secondary amines . A more direct approach to unprotected chiral amines would involve DARA of the corresponding ketones using a suitable NH 3 source.…”