Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases

A straightforward chemoenzymatic synthesis of luliconazole has been developed. The key step involved the preparation of the enantiomerically pure β‐halohydrin (1 S )‐2‐chloro‐1‐(2,4‐dichlorophenyl)‐1‐ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435®. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the ( S )‐β‐halohydrin was obtained with high selectivity ( ee > 99 %, E > 200) after just 15 min, at 45 °C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the ( S )‐β‐halohydrin was subjected to a mesylation reaction; the mesylated derivative reacted with 1‐cyanomethylimidazole in the presence of CS 2 to give luliconazole in 43 % yield with >99 % ee .