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.

Application of Imine Reductase in Bioactive Chiral Amine Synthesis

“…These biotransformations yield crucial motifs present in active pharmaceutical ingredients (Clopidrogel, Efinaconazole, Donepezil) and other bioactive molecules (Scheme 25b). 95 In 2023, Husain's group reported a general-purpose biocatalytic method that uses the IRED to synthesize a variety of substituted tetrahydrobenzoazole diazepines. The IREDs, mainly derived from Streptomyces GF3587, Katambe, and Cysticillus ferobacillus, have high catalytic activity against heptamembered cyclic imines with high enantiomeric excess (up to >99%) and isolation yield (up to 96%).…”

“…The mutant Redam-361-L80S exhibited robust catalytic activity against challenging cyclic amines, such as piperidine and morpholine derivatives. These biotransformations yield crucial motifs present in active pharmaceutical ingredients (Clopidrogel, Efinaconazole, Donepezil) and other bioactive molecules (Scheme b) …”