Thiamine diphosphate (ThDP)-dependent enzymes are well known biocatalysts for the asym- metric synthesis of a-hydroxy ketones with preferential (R)-selectivity. Pharmaceutically relevant phenyl- acetyl 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 de- scribe the synthesis of (S)-phenylacetyl carbinol products with extended reaction scope employing the readily available wild-type ThDP-dependent enzyme acetoin :dichlorophenolindophenol oxidore- ductase (Ao:DCPIP OR) from Bacillus lichenifor- mis. 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 enan- tioselectivities (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 medi- ated by Ao:DCPIP OR via carboligation of benzal- dehyde with 3,4-hexanedione is also reported.

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

GIOVANNINI, Pier Paolo
Primo
;
Lerin, Lindomar Alberto;BERNACCHIA, Giovanni;DE BASTIANI, Morena;CATANI, Martina;DI CARMINE, Graziano
Penultimo
;
MASSI, Alessandro
Ultimo
2016

Abstract

Thiamine diphosphate (ThDP)-dependent enzymes are well known biocatalysts for the asym- metric synthesis of a-hydroxy ketones with preferential (R)-selectivity. Pharmaceutically relevant phenyl- acetyl 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 de- scribe the synthesis of (S)-phenylacetyl carbinol products with extended reaction scope employing the readily available wild-type ThDP-dependent enzyme acetoin :dichlorophenolindophenol oxidore- ductase (Ao:DCPIP OR) from Bacillus lichenifor- mis. 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 enan- tioselectivities (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 medi- ated by Ao:DCPIP OR via carboligation of benzal- dehyde with 3,4-hexanedione is also reported.
2016
Giovannini, Pier Paolo; Lerin, Lindomar Alberto; Müller, Michael; Bernacchia, Giovanni; DE BASTIANI, Morena; Catani, Martina; DI CARMINE, Graziano; Massi, Alessandro
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