Biocatalytic Asymmetric Reduction of γ‐Keto Esters to Access Optically Active γ‐Aryl‐γ‐butyrolactones

Abstract

AbstractAn efficient stereoselective syntheses of a series of functionalized optically active γ‐aryl‐γ‐butyrolactones is achieved by enzymatic asymmetric reduction of the corresponding sterically demanding γ‐keto esters employing wild‐type and recombinant alcohol dehydrogenases. The best stereoselectivities for the reduction via hydrogen transfer was obtained with two short chain dehydrogenases (SDRs) of complementary stereospecificity from Aromatoleum aromaticum, namely the Prelog‐specific NADH‐dependent (S)‐1‐phenylethanol dehydrogenase [(S)‐PED] and the anti‐Prelog‐specific (R)‐1‐(4‐hydroxyphenyl)‐ethanol dehydrogenase [(R)‐HPED], respectively. Biotransformations catalyzed by both enzymes, followed by TFA‐catalyzed cyclization of the resulting γ‐hydroxy esters, furnished the respective (S)‐ and (R)‐configured products with exquisite optical purity (up to >99% ee). The synthetic value was demonstrated on preparative scale for the asymmetric bioreduction of the model compound, methyl 4‐oxo‐4‐phenylbutanoate, affording optically pure (S)‐γ‐phenyl‐γ‐butyrolactone (>99% ee) in 67–74% isolated yield at 89–95% conversion depending on the applied scale.magnified image