Expanded Substrate Pattern of the Ene‐Reductase‐Catalyzed Reduction of Activated C═N Bonds to Yield Prim ‐Amines

The biocatalytic reduction of oximes may offer a potential alternative route to primary amines. However, previous studies on biocatalytic oxime reduction using α ‐oximo‐ β ‐keto ester substrates led to an amine intermediate which spontaneously dimerized to the corresponding pyrazine. In this study, to access the primary amine, the reduction of α‐oximo malonic esters catalyzed by ene‐reductases (EREDs) was explored as a promiscuous activity. Thus, a panel of 14 oximes activated by two adjacent ester moieties was evaluated, employing both wild‐type and engineered EREDs. The reduction of these substrates indeed led to the corresponding stable primary amine functionality. Moreover, the unprecedented ERED‐catalyzed reduction of the nitro functionality of dimethyl nitromalonate and a hydrazone functionality to the corresponding amines was demonstrated. The nitro reduction is proposed to proceed via the oxime and subsequently imine intermediates in analogy to the reduction of the oxime moiety. These results highlight the synthetic potential of EREDs in the reduction of diverse nitrogenous functionalities toward valuable amine compounds.