(S)‐Selectivity in Phenylacetyl Carbinol Synthesis Using the Wild‐Type Enzyme Acetoin:Dichlorophenolindophenol Oxidoreductase from Bacillus licheniformis

Abstract

AbstractThiamine diphosphate (ThDP)‐dependent enzymes are well known biocatalysts for the asymmetric synthesis of α‐hydroxy ketones with preferential (R)‐selectivity. Pharmaceutically relevant phenylacetyl carbinol (PAC) has been prepared with absolute (S)‐configuration only on a few occasions using enzyme variants suitably designed through rational site‐directed mutagenesis approaches. Herein, we describe the synthesis of (S)‐phenylacetyl carbinol products with extended reaction scope employing the readily available wild‐type ThDP‐dependent enzyme acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) from Bacillus licheniformis. On a semipreparative scale, cross‐benzoin‐like condensations of methylacetoin (donor) and differently substituted benzaldehydes proceed with almost complete chemoselectivity yielding the target (S)‐1‐hydroxy‐1‐phenylpropan‐2‐one derivatives with high conversion efficiencies (up to 95%) and good enantioselectivities (up to 99%). Ao:DCPIP OR accepts hydroxy‐ and nitrobenzaldehydes and also sterically demanding substrates such as 1‐naphthaldehyde and 4‐(tert‐butyl)benzaldehyde, which are typically poor acceptors in enzymatic transformations. The explorative synthesis of (S)‐phenylpropionyl carbinol mediated by Ao:DCPIP OR via carboligation of benzaldehyde with 3,4‐hexanedione is also reported.magnified image