Stereoselective Synthesis of Structurally Diverse (S)‐Lactams via an Engineered Amine Dehydrogenase

Abstract Optically pure lactams have a wide diversity of applications, one of which is serving as important intermediates in the synthesis of agricultural bioactive compounds or pharmaceuticals. Efficient stereoselective synthesis of chiral lactams with low‐cost amine donors under mild conditions is desired for manufacturing of these important chemicals. Herein, a two‐step chemo‐enzymatic strategy has been designed to produce ( S )‐lactams by engineering a natural amine dehydrogenase from Thermoanaerobacter thermohydrosulfuricus ( Tther AmDH). Tther AmDH was subjected to eight cycles of directed evolution to enhance its reductive amination activity toward keto acid substrates. The variants showed improved specific activity toward 6 tested substrates and gave high stereoselectivities of up to 99% in the asymmetric synthesis of γ‐ and δ‐ lactams. In particular, Tther AmDH V8 showed a 237‐fold higher specific activity toward the model substrate levulinic acid and gave ( S )‐5‐methyl‐2‐pyrrolidone in 99% ee with a space‐time yield of 75.3 g L −1 d −1 . These results indicate that the engineered amine dehydrogenase Tther AmDH can serve as an efficient biocatalyst for the manufacture of highly valued chiral lactams. magnified image