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Current synthetic approaches typically rely on multistep conversion from the corresponding \u03b2\u2010hydroxy\u2010\u03b1\u2010amino acids, resulting in poor step\u2010economy and potential \u03b1\u2010racemization 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\u2010catalyzed biomimetic aldol reaction of glycinamides with aldehydes, producing a broad range of structurally diverse chiral \u03b2\u2010hydroxy\u2010\u03b1\u2010amino amides in up to 98% yield, &gt;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\u2010based chiral \u03b2\u2010hydroxy\u2010\u03b1\u2010amino 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.<\/jats:p>","DOI":"10.1002\/anie.7937631","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:08:07Z","timestamp":1790658487000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct Asymmetric Synthesis of Chiral \u03b2\u2010Hydroxy\u2010\u03b1\u2010Amino Amides via\n                    <i>PLP<\/i>\n                    \u2010Inspired Biomimetic Aldol Reaction"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7863-1802","authenticated-orcid":false,"given":"Hanyu","family":"Liang","sequence":"first","affiliation":[{"name":"The Education Ministry Key Lab of Resource Chemistry Shanghai Frontiers Science Center of Biomimetic Catalysis Shanghai Normal University  Shanghai China"},{"name":"State Key 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