Biocatalytic Synthesis of Aryl and Heteroaryl γ-Hydroxy-α-amino Acids via an Aldolase–Transaminase One-Pot Reaction

Nonnatural amino acids hold the promise of enhancing enzyme activity and bolstering the efficacy of drugs. Enzymatic synthesis emerges as a valuable adjunct to traditional synthetic methodologies, providing an alternative pathway for the generation of nonnatural amino acids. This study introduces a one-pot enzymatic strategy for the synthesis of aryl and heteroaryl γ-hydroxy-α-amino acids. The process involved the utilization of a newly identified aldolase from Streptomyces to catalyze the formation of C–C bond from the cost-effective fluorinated pyridine aldehyde substrate, and an α-transaminase sourced from Saccharomyces cerevisiae to transfer an amino group. After optimization, a 94% conversion efficiency was achieved, along with a product diastereoselectivity ratio of up to 13:87. Furthermore, the one-pot reaction system demonstrated efficacy across a broad spectrum of substrates, including fluorinated pyridines, quinolines, azabiphenyls, thiazoles, and phenyl derivatives. This study significantly broadened the scope of nonnatural amino acids containing heteroaromatic rings and diversified the array of enzymes accessible for the production of functionally diverse bioactive fluorinated compounds.