Engineered Biocatalysts for Enantioselective Reductive Aminations of Cyclic Secondary Amines

Abstract Reductive aminases (RedAms) have recently emerged as promising biocatalysts for the synthesis of chiral secondary amines by coupling primary amines with aldehydes/ketones. However, access to tertiary amines remains more problematic, particularly when coupling ketones with secondary amines. Here we show that the scope of these enzymes can be extended to allow selective reductive aminations of cyclic secondary amines, such as piperidines and morpholines, with both aldehydes and ketones. These biotransformations provide access to important motifs found in active pharmaceutical ingredients and other bioactive molecules. RedAm‐361, discovered from a metagenomic library, was engineered via directed evolution to allow efficient coupling of cyclic amines with carbonyl partners, including dynamic kinetic resolutions of α‐functionalized aldehydes and enantioselective amination of ketones. These RedAms now serve as valuable scaffolds for the engineering of industrial biocatalysts to produce key pharmaceutical intermediates.