A Type 1 Aldolase, NahE, Catalyzes a Stereoselective Nitro‐Michael Reaction: Synthesis of β‐Aryl‐γ‐nitrobutyric Acids

Michael addition reactions are highly useful in organic synthesis and are commonly accomplished using organocatalysts. However, the corresponding biocatalytic Michael additions are rare, typically lack synthetically useful substrate scope, and suffer from low stereoselectivity. Herein we report a biocatalytic nitro‐Michael addition, catalyzed by NahE, that proceeds with low catalyst loading at room temperature in moderate to excellent enantioselectivity and high yields. A series of β‐nitrostyrenes reacted with pyruvate in the presence of NahE to give, after oxidative decarboxylation, β‐aryl‐γ‐nitrobutyric acids in up to 99 % yield without need for chromatography, providing a simple preparative‐scale route to chiral GABA analogues. This reaction represents the first example of an aldolase displaying promiscuous Michaelase activity and opens the use of nitroalkenes in place of aldehydes as substrates for aldolases. The stereoselective Michael addition of pyruvate to β‐nitrostyrenes catalyzed by NahE, a type 1 aldolase, is reported. β‐Aryl‐γ‐nitrobutyric acids can be isolated after oxidative decarboxylation in high yields on a preparative scale, providing access to precursors of γ‐aminobutyric acid (GABA) analogues of demonstrated pharmacological activity.