Biocatalytic Synthesis of Homochiral 2-Hydroxy-4-butyrolactone Derivatives by Tandem Aldol Addition and Carbonyl Reduction.

Abstract

Chiral 2-hydroxy acids and 2-hydroxy-4-butyrolactone derivatives are structural motifs often found in fine and commodity chemicals. Here, we report a tandem biocatalytic stereodivergent route for the preparation of these compounds using three stereoselective aldolases and two stereocomplementary ketoreductases using simple and achiral starting materials. The strategy comprises (i) aldol addition reaction of 2-oxoacids to aldehydes using two aldolases from E. coli, 3-methyl-2-oxobutanoate hydroxymethyltransferase (KPHMT Ecoli ), 2-keto-3-deoxy-l-rhamnonate aldolase (YfaU Ecoli ), and trans-o-hydroxybenzylidene pyruvate hydratase-aldolase from Pseudomonas putida (HBPA Pputida ) and (ii) subsequent 2-oxogroup reduction of the aldol adduct by ketopantoate reductase from E. coli (KPR Ecoli ) and a Δ1-piperidine-2-carboxylate/Δ1-pyrroline-2-carboxylate reductase from Pseudomonas syringae pv. tomato DSM 50315 (DpkA Psyrin ) with uncovered promiscuous ketoreductase activity. A total of 29 structurally diverse compounds were prepared: both enantiomers of 2-hydroxy-4-butyrolactone (>99% ee), 21 2-hydroxy-3-substituted-4-butyrolactones with the (2R,3S), (2S,3S), (2R,3R), or (2S,3R) configuration (from 60:40 to 98:2 dr), and 6 2-hydroxy-4-substituted-4-butyrolactones with the (2S,4R) configuration (from 87:13 to 98:2 dr). Conversions of aldol adducts varied from 32 to 98%, while quantitative conversions were achieved by both ketoreductases, with global isolated yields between 20 and 45% for most of the examples. One-pot one-step cascade reactions were successfully conducted achieving isolated yields from 30 to 57%.