Expanding Synthetic Applications of Δ1-Piperidine-2-carboxylate/Δ1-pyrroline-2-carboxylate Reductase from Pseudomonas syringae (DpkAPsyrin). Biocatalytic Asymmetric Synthesis of (S,E)-2-hydroxy-4-arylbut-3-enoic Acid Derivatives

Abstract

Chiral 2-hydroxy-4-arylbut-3-enoic acid derivatives are important precursors for the synthesis of angiotensin converting enzyme (ACE) inhibitors, such as enalapril, lisinopril, cilapril or benazepril. In this work, we take advantage of the unexplored promiscuous ketoreductase activity of Δ1-piperidine-2-carboxylate/Δ1-pyrroline-2-carboxylate reductase from Pseudomonas syringae pv. tomato DSM 50315 (DpkAPsyrin) for the synthesis of (S,E)-2-hydroxy-4-arylbut-3-enoic acids. The strategy was designed as an enzymatic cascade comprising an aldol condensation between pyruvate with aryl aldehydes, catalyzed by the trans-o-hydroxybenzylidene pyruvate hydratase-aldolase from Pseudomonas putida (HBPAPputida), for the construction of carbon scaffold, and an ensuing asymmetric reduction of the carbonyl group catalyzed by DpkAPsyrin. The enzymatic cascade provided quantitative conversions, with global isolated yields between 57–85%. A total of nine structurally diverse (S,E)-2-hydroxy-4-arylbut-3-enoic acids were prepared in ee between 87–99%.