Synthesis of Chiral Amines via a Bi‐Enzymatic Cascade Using an Ene‐Reductase and Amine Dehydrogenase

Access to chiral amines with more than one stereocentre remains challenging, although an increasing number of methods are emerging. Here we developed a proof‐of‐concept bi‐enzymatic cascade, consisting of an ene reductase and amine dehydrogenase (AmDH), to afford chiral diastereomerically enriched amines in one pot. The asymmetric reduction of unsaturated ketones and aldehydes by ene reductases from the Old Yellow Enzyme family (OYE) was adapted to reaction conditions for the reductive amination by amine dehydrogenases. By studying the substrate profiles of both reported biocatalysts, thirteen unsaturated carbonyl substrates were assayed against the best duo OYE/AmDH. Low (5 %) to high (97 %) conversion rates were obtained with enantiomeric and diastereomeric excess of up to 99 %. We expect our established bi‐enzymatic cascade to allow access to chiral amines with both high enantiomeric and diastereomeric excess from varying alkene substrates depending on the combination of enzymes. Dynamic duo: The combination of Old Yellow Enzymes and amine dehydrogenases gives access to chiral amines. By combining these enzymes with a cofactor recycling system into a cascade, inexpensive unsaturated aldehydes and ketones were converted into chiral amines with up to two stereocenters and high enantiopurity.