Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one: a precursor of thiolactomycin and determination of its absolute configuration

A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol to provide (R)-2 in a 94% ee and its enantiomer (S)-9 in a 98% ee. The absolute configuration at the C-5 position has been determined by Mosher’s method.

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(5R)-Hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-(5H)-thiophen-2-oneC9H14O4SEe = 94% [by chiral HPLC][α]D25=-17.7 (c 1.02, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (5R)

(5S)-Methylacetate-3,5-dimethyl-4-(methoxymethoxy)-(5H)-thiophen-2-oneC11H16O5SEe = 98% [by chiral HPLC][α]D25=-27.9 (c 1.03, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (5S)