Enzymatic Production of Opine‐Type Chiral Amines with Controlled Stereoselectivity

Abstract Chiral secondary amine dicarboxylic acid derivatives are key building blocks of several peptidomimetic angiotensin‐converting enzyme (ACE2) inhibitors. Reductive amination of α‐keto acids with α‐amino esters can yield orthogonally functionalized derivatives facilitating further chemical modifications. Biocatalysis offers a sustainable and selective way to implement this synthetic strategy. Here we report the selection of a ketimine reductase enzyme ( Rn KIRED) for this transformation from a pool of three separate enzyme classes (opine dehydrogenases, imino acid reductases, and imine reductases). We describe the extended substrate scope of this enzyme among α‐keto acids and α‐amino esters and demonstrate the synthetic applicability of our approach in sixteen preparative scale reactions. In addition, we report the unique stereoselective behavior of Rn KIRED that allows controlling the configuration on the newly formed stereocenter. Coupling small amino esters to large keto acids yields ( S ) configuration, while coupling large amino esters with small keto acids results in ( R ) configuration. The molecular background for this unique stereospecificity is also provided.