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

Shi, Yongjie1; Rong, Nianxin2; Zhang, Xumu1; Yin, Qin2

2023

10.1055/a-2002-5733

SYNTHESIS-STUTTGART   Impact Factor & Quartile

0039-7881

1437-210X

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 alpha-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 alpha-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 Introduction2 Enantioselective Reductive Amination via Hydrogenation2.1 Enantioselective Reductive Amination of beta-Keto Esters/Amides2.2 Enantioselective Reductive Amination of Simple Ketones2.3 Enantioselective Reductive Amination of alpha-Functionalized Ketones2.4 Enantioselective Reductive Amination/Cyclization Cascade Reactions2.5 Others3 Enantioselective Reductive Amination via Transfer Hydrogenation4 Synthetic Applications5 Conclusions and Outlook

enantioselective reductive amination chiral primary amines drug synthesis industrial applications metal catalysis ketones

SCI

English

First ; Corresponding

National Natural Science Foundation of China["22071097","21991113"] ; Shenzhen Science and Technology Innovation Program["JCYJ20190809142013478","JCYJ20220818100804010"] ; Guangdong Basic and Applied Basic Research Foundation[2021B1515020062]

Chemistry

Chemistry, Organic

WOS:000919253100003

GEORG THIEME VERLAG KG

CHEMISTRY

Web of Science

1.Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China
2.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China

Shi, Yongjie,Rong, Nianxin,Zhang, Xumu,et al. Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry[J]. SYNTHESIS-STUTTGART,2023.

Shi, Yongjie,Rong, Nianxin,Zhang, Xumu,&Yin, Qin.(2023).Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry.SYNTHESIS-STUTTGART.

Shi, Yongjie,et al."Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry".SYNTHESIS-STUTTGART (2023).