Direct Asymmetric Synthesis of Chiral β‐Hydroxy‐α‐Amino Amides via PLP ‐Inspired Biomimetic Aldol Reaction

Chiral β‐hydroxy‐α‐amino amides represent important structural motifs ubiquitous in pharmaceuticals and bioactive molecules. Current synthetic approaches typically rely on multistep conversion from the corresponding β‐hydroxy‐α‐amino acids, resulting in poor step‐economy and potential α‐racemization during amidation. However, direct asymmetric synthesis of these compounds via aldol reactions remains highly challenging because of the low reactivity of glycinamides and the instability of the corresponding aldol products. Herein, we report a chiral pyridoxal‐catalyzed biomimetic aldol reaction of glycinamides with aldehydes, producing a broad range of structurally diverse chiral β‐hydroxy‐α‐amino amides in up to 98% yield, >20:1 dr, and 99% ee. Notably, this biomimetic strategy accommodates structurally complex dipeptides and polypeptides, allowing direct modification of peptide chains and providing efficient access to these significant peptide‐based chiral β‐hydroxy‐α‐amino amides. The key intermediate of the drug eliglustat was also readily synthesized via this strategy. Mechanistic studies suggest a cooperative carbonyl catalysis pathway analogous to threonine aldolase, accounting for the high reactivity and stereocontrol.