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

Abstract:

Thiamine 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. (Figure presented.).