ENANTIOSELECTIVE SYNTHESIS OF (S)-(-)-1-(4-FLUOROPHENYL)ETHANOL

Abstract

S)-(–)-1-(4-Fluorophenyl)ethanolis an intermediate in the synthesis of an antagonist of the CCR5 chemokine receptor that can be protective against HIV infection. Along with o-fluoro-substituted analogs, (S)-(–)-1-(4-fluorophenyl)ethanol can be used to study the role of substituents in the chiral recognition of molecular complexes, and (R)-(+)-1-(4-fluorophenyl)ethanol is a com-ponent of an antimalarial drug and a γ-secretase modulator necessary for the treatment of Alzhei-mer's disease.We proposed an approach to the synthesis of (S)-(-)-1-(4-fluorophenyl)ethanol based on the enantioselective reduction of prochiral 1-(4-fluorophenyl)ethanone catalyzed by Daucus carota cells. We found the conditions that make it possible to obtain (S)-(–)-1-(4-fluorophenyl)eth-anol by bioreduction of 1-(4-fluorophenyl)ethanone in the presence of a D. carota biocatalyst for 48 h with 55% yield (98% ee).We also studied the possibility of optimizing the transformation of 1-(4-fluorophenyl)ethanone in a reaction medium containing various exogenous reducing agents(ethanol, isopropanol, or glucose), which are known to significantly affect the product yield and the enantioselectivity of the process. Biotransformation of 1-(4-fluorophenyl)ethanone in the pres-ence of ethanol (1-5%) gives (S)-(-)-1-(4-fluorophenyl)ethanol with 7-85% yields and optical purity 10-98% ee.Enantioselective reduction of the initial ketone in the presence of isopropanol (1-5%) does not lead to a significant increase in the yield and optical purity of S-alcohol (7-57% (18-98% ee).In the case of biotransformation of 1-(4-fluorophenyl)ethanone in the presence of an equimo-lar amount of glucosefor 48 hthe yield of (S)-(-)-1-(4-fluorophenyl)ethanol is 66% (98% ee).Fur-ther transformation of the initial ketone (144 h) both in the absence of an exogenous reducing agent and in the presence of an equimolar amount of glucose leads to an increase in the yield of alcohol to 73% and 76%, respectively, however, the optical purity of the alcohol decreases to 62% ee and 80% ee, which suggests the stereoinversion.