Efficient Access to β-Branched Noncanonical Amino Acids via Transaminase-Catalyzed Dynamic Kinetic Resolutions Driven by a Lysine Amine Donor

08 April 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 multi-enzyme 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, with this discovery in hand, we furnished a broad scope of β-branched arylalanines, including some bearing hitherto intractable cyclopropyl and isopropyl substituents, with high yields and excellent selectivities.

Keywords

Biocatalysis
Transaminases
Smart donor
Dynamic kinetic resolution
Noncanonical amino acids

Supplementary materials

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Supplementary Materials
Description
Experimental procedures, characterization of new compounds, X-ray crystal structure data, NMR spectra, and UPLC/HPLC chromatograms.
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