Enantioselective Synthesis of Thiomorpholines through Biocatalytic Reduction of 3,6-Dihydro-2H-1,4-thiazines Using Imine Reductases

In this work, an enantioselective biocatalytic synthesis of chiral thiomorpholines using imine reductases (IREDs) is described. As substrates, four prochiral and one chiral 3,6-dihydro-2H-1,4-thiazines were synthesized in a modified Asinger reaction and subsequently reduced using imine reductases as a biocatalyst, NADPH as a cofactor, and a glucose dehydrogenase (GDH)-glucose cofactor regeneration system. As a result, chiral thiomorpholines with a stereogenic center created in 3-position were obtained under mild process conditions with high conversions and excellent enantioselectivities of up to 99%. Furthermore, as a proof of concept, a sequential one-pot process combining both individual reaction steps was achieved.

Automated summary

This work describes an enantioselective biocatalytic synthesis of chiral thiomorpholines using imine reductases as catalysts. Prochiral and chiral 3,6-dihydro-2H-1,4-thiazines were synthesized and subsequently reduced using imine reductases, resulting in chiral thiomorpholines with high enantioselectivities. Additionally, a sequential one-pot process combining both reaction steps was achieved as a proof of concept.