Transaminase-Catalyzed Synthesis of β‑Branched Noncanonical Amino Acids Driven by a Lysine Amine Donor

• Published in: Journal of the American Chemical Society 2024-06, Vol.146 (23), p.16306-16313
• Main Authors: Dunham, Noah P., Winston, Matthew S., Ray, Ritwika, Eberle, Claire M., Newman, Justin A., Gao, Qi, Cao, Yang, Barrientos, Rodell C., Ji, Yining, Reibarkh, Mikhail Y., Silverman, Steven M.
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Amino Acids - chemical synthesis; Amino Acids - chemistry; Biocatalysis; byproducts; imines; lysine; Lysine - chemistry; Molecular Structure; transaminases; Transaminases - chemistry; Transaminases - metabolism; transamination
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c05175

Transaminases are choice biocatalysts for the synthesis of chiral primary amines, including amino acids bearing contiguous stereocenters. In this study, we employ lysine as a “smart” amine donor in transaminase-catalyzed dynamic kinetic resolution reactions to access β-branched noncanonical arylalanines. Our mechanistic investigation demonstrates that, upon transamination, the lysine-derived ketone byproduct readily cyclizes to a six-membered imine, driving the equilibrium in the desired direction and thus alleviating the need to load superstoichiometric quantities of the amine donor or deploy a multienzyme cascade. Lysine also shows good overall compatibility with a panel of wild-type transaminases, a promising hint of its application as a smart donor more broadly. Indeed, by this approach, we furnished a broad scope of β-branched arylalanines, including some bearing hitherto intractable cyclopropyl and isopropyl substituents, with high yields and excellent selectivities.