Cupin‐Type Dimethylsulfoniopropionate Lyase from Pelagibacter ubique (DddKPu) Catalyzes Aza‐Michael Addition of Primary and Secondary Amines to Acrylic Acid

The formation of carbon─nitrogen (C─N) bonds is a cornerstone of organic synthesis, underpinning the production of amines, imines, and nitriles found in numerous active ingredients. Among the methods for C─N bond formation, the aza‐Michael addition stands out as a powerful and versatile approach. Herein, we present a biocatalytic strategy for the efficient aza‐Michael addition of primary and secondary amines to acrylic acid, i.e., aza‐Michaelase activity, leveraging the promiscuity of dimethylsulfoniopropionate (DMSP) lyase from Pelagibacter ubique HTCC1062 (DddK Pu ). In vivo DddK Pu catalyzes the β‐elimination of DMSP to sodium acrylate and dimethylsulfide (i.e., a retro sulfa‐Michael reaction). Here, we screened DddK Pu against a diverse library of 30 primary and 44 secondary amines. The wild‐type enzyme achieved 90%–100% conversion and 40%–86% isolated yields of N , N ‐disubstituted‐β‐amino acids with secondary amines. For primary amines, the W26G variant proved optimal, furnishing 50%–100% conversion and 43%–81% isolated yields of N ‐substituted‐β‐amino acids. Notably, the enzyme exhibited remarkable chemoselectivity: for pyrrolidin‐2‐ylmethanamine, the reaction occurred exclusively at the secondary amine, while for piperidin‐2‐ylmethanamine, it reacted selectively at the primary amine. These findings highlight DddK Pu as a versatile biocatalyst for the selective synthesis of β‐amino acids, expanding the toolbox for C─N bond formation.