Enzymatic synthesis of (R)-modafinil by chloroperoxidase-catalyzed enantioselective sulfoxidation of 2-(diphenylmethylthio) acetamide

• One-step enzymatic synthesis of (R)-enantiomer of modafinil was achieved by CPO.
• Small quantity of introduced additives played multiple functions.
• The synthetic route is environment-friendly, straightforward and energy efficient.

A one-step asymmetric bio-synthesis of (R)-enantiomer of the racemic drug modafinil was achieved by chloroperoxidase (CPO)-catalyzed enantioselective sulfoxidation of 2-(diphenylmethylthio) acetamide. Ionic liquids, quaternary ammonium salts or polyhydroxy compounds were introduced into the reaction media to improve productivity. The (R)-modafinil yield of 40.8% and high enantiomeric excesses of 97.3% was obtained at pH 5.5 and room temperature in the presence of [EMIM][Br] (VILs/Vbuffer = 10%), and a low enzymatic concentration (0.013 mmol L−1) was required. UV–vis and circular dichroism spectral indicated that the α-helix of CPO was strengthened and the heme became more exposed for easier access of substrate to the active site in CPO in the presence of the above additives, and moreover, enzymatic kinetic data showed that the affinity and the specificity of CPO to substrate was improved.

A one-step synthesis of (R)-modafinil was achieved by chloroperoxidase-catalyzed enantioselective sulfoxidation of 2-(diphenylmethylthio) acetamide with the highest yield (40.8%) and enantiomeric excesses (ee) (97.3%) in the presence of additives.Figure optionsDownload as PowerPoint slide