(R)-2-Chloro-1-(m-chlorophenyl)ethanol (−)-1 is a precursor of (R)-3-chlorostyrene oxide which is the key chiral intermediate for the preparation of several β3-adrenergic receptor agonists that show antiobesity, antidiabetic and antidepression activities. To date, several chemical and biological methods for the preparation of (−)-1 in enantiomerically pure or enriched form have been reported. Chemical reduction suffers from the problem of using expensive chiral catalysts and lower enantioselectivity. Asymmetric reduction of 2-chloro-1-(m-chloro-phenyl)ethanone using an oxazaborolidine-based catalyst gave (−)-1 in 87% yield and 86%.

The microbical synthesis of (−)-1 was achieved by reduction of the corresponding ketone using an acetone powder of Geotrichum candidum in 94% yield and 98% ee, or using the cell-free extract of Rhodotorula glutinis var. dairenensis IFO 415 in 75% yield and more than 99%  or using whole cells of Saccharomyces cerevisiae CGMCC 2.396 in 90% yield and more than 99%. The enantiopure (−)-1 could be obtained from the bioreduction of the corresponding α-chloroketone, while the low productivity of the bioreduction is still a challenge.

The kinetic resolution of (±)-1 is still an attractive method for the preparation of (−)-1 in case of the (+)-1 could be racemized efficiently. A practical synthesis of (R)-3-chlorostyrene oxide starting from 3-chloroethylbenzene was proposed in which (R)-2-bromo-(m-chlorophenyl)ethanol was obtained in more than 99% ee by the treatment of the corresponding racemate with lipase QL in the presence of propionic anhydride, the propionate was racemized in 92% yield by acid-catalyzed racemization.

(R)-2-Chloro-1-(m-chlorophenyl)ethanol, a precursor of (R)-3-chlorostyrene oxide which is the key chiral intermediate for the preparation of several β3-adrenergic receptor agonists was prepared in 40% yield and 99% ee by the Lipozyme TL IM-catalyzed second resolution of the corresponding racemate in the presence of vinyl acetate.

Researchers from Chongqing University of Posts and Telecommunications and Chengdu Institute of Biology, Chinese Academy of Sciences carried out this research.