Direct Asymmetric Reductive Amination of Alkyl (Hetero)Aryl Ketones by an Engineered Amine Dehydrogenase

Abstract

The direct asymmetric reductive amination of heteroaryl ketones has been a long‐standing synthetic challenge. Here we report the engineering of an amine dehydrogenase (AmDH) from Jeotgalicoccus aerolatus for the asymmetric synthesis of chiral α‐(hetero)aryl primary amines in excellent conversions (up to 99 %) and enantioselectivities (up to 99 % ee). The best AmDH variant (Ja‐AmDH‐M33) exhibited high activity and specificity toward alkyl (hetero)aryl ketones, even for those bearing a bulky alkyl chain. An efficient directed evolution approach based on molecular docking was implemented to enlarge the active pocket with a more hydrophobic entrance, which is responsible for the high activity. The Ja‐AmDH‐M33 was also used for preparative‐scale synthesis of pharmaceutically relevant amines and a key intermediate of chiral pincer ligands, which highlighted its practical application in synthetic chemistry.

Immobilized enzymatic alcohol oxidation as a versatile reaction module for multienzyme cascades

“…The acetone was removed by heating at 60 °C, and the pH was adjusted to 9.5. Then 1 mL ADH-A (from Rhodococcus ruber) [38] solution and isopropanol (30% v/v) were added. After the reaction at 30 °C for 24 h, the reaction solution was extracted by ethyl acetatethe reaction solution was extracted by ethyl acetate.…”

“…Wrinkled MSNs were prepared by a modified reverse microemulsion method [38] and then functionalized with an amino (-NH 2 ) group, providing reaction sites for covalent immobilization of enzymes. The morphology and pore structures of the MSNs were characterized by SEM and TEM.…”