Development of an Enzymatic Process for the Synthesis of (S)-2-Chloro-1-(2,4-dichlorophenyl) Ethanol

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( S )-2-Chloro-1-(2,4-dichlorophenyl) ethanol ( 3 ) is a chiral intermediate in the synthesis of luliconazole ( ( R )- E -1 ). Here, we report a novel biopreparation of 3 by bioreduction of 2-chloro-1-(2,4-dichlorophenyl) ethanone ( 2 ) using recombinant Escherichia coli expressing LK08, a ketoreductase mutant from Lactobacillus kefiri, as a biocatalyst. The reaction conditions for the biotransformation including pH, temperature, and concentration of isopropanol and NADP +, as well as the amount of recombinant E. coli cells, were optimized to improve the process productivity. When the enzymatic process was carried out on a 300 g scale under the optimized conditions, the ketone 2 was fully converted to chiral alcohol 3 with a product ee value of >99%. Furthermore, 3 was isolated and used to chemically synthesize luliconazole with 38% yield and 99% ee. This study presents an efficient and cost-effective chemoenzymatic process for the production of ( R )- E -1 .

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