Abstract
(R)-2-Chloro-1-(2,4-dichlorophenyl) ethanol is a chiral intermediate of the antifungal agent Miconazole. A bacterial strain, ZJPH1806, capable of the biocatalysis of 2-chloro-1-(2,4-dichlorophenyl) ethanone, to (R)-2-chloro-1-(2,4-dichlorophenyl) ethanol with highly stereoselectivity was isolated from a soil sample. It was identified as the Acinetobacter sp., according to its morphological observation, physiological-biochemical identification, and 16S rDNA sequence analysis. After optimizing the key reaction conditions, it was demonstrated that the bioreduction of 2-chloro-1-(2,4-dichlorophenyl) ethanone was effectively transformed at relatively high conversion temperatures, along with glycerol as cosubstrate in coenzyme regeneration. The asymmetric reduction of the substrate had reached 83.2% yield with an enantiomeric excess (ee) of greater than 99.9% at 2 g/L of 2-chloro-1-(2,4-dichlorophenyl) ethanone; the reaction was conducted at 40 °C for 26 h using resting cells of the Acinetobacter sp. ZJPH1806 as the biocatalyst. The yield had increased by nearly 2.9-fold (from 28.6% to 83.2%). In the present study, a simple and novel whole-cell-mediated biocatalytic route was applied for the highly enantioselective synthesis of (R)-2-chloro-1-(2,4-dichlorophenyl) ethanol, which allowed the production of a valuable chiral intermediate method to be transformed into a versatile tool for drug synthesis.
Highlights
Azoles have been widely performed in the treatment of immunocompromised patients suffering from undergoing invasive surgery or AIDS, graft reception, or anti-cancer therapy [1]
A simple and novel whole-cell-mediated biocatalytic route was applied for the highly enantioselective synthesis of (R)-2-chloro-1-(2,4-dichlorophenyl) ethanol, which allowed the production of a valuable chiral intermediate method to be transformed into a versatile tool for drug synthesis
Miconazole is a broad-spectrum antifungal agent and its mechanism of action is to inhibit ergosterol biosynthesis and cause toxic methylated sterol levels, thereby inhibiting the growth of fungi [3]. (R)-miconazole (Figure 1) appeared to account for a greater degree of the biological activity than did racemic miconazole [2]. (R)-2-Chloro-1-(2,4-dichlorophenyl) ethanol is applied in the synthesis of many antifungal intermediates, such as miconazole, econazole, and sertaconazol
Summary
Azoles have been widely performed in the treatment of immunocompromised patients suffering from undergoing invasive surgery or AIDS, graft reception, or anti-cancer therapy [1]. Pharmacological studies have found that some of the antifungal activity of R-enantiomer is superior to that of the corresponding S-isomer and its racemate, such as sertaconazole, which can significantly improve drug efficacy [2]. (R)-miconazole (Figure 1) appeared to account for a greater degree of the biological activity than did racemic miconazole [2]. (R)-2-Chloro-1-(2,4-dichlorophenyl) ethanol is applied in the synthesis of many antifungal intermediates, such as miconazole, econazole, and sertaconazol. It is necessary to focus on the synthesis of (R)-2-chloro-1-(2,4-dichlorophenyl) ethanol in the preparation of (R)-miconazole. To replace the above racemates, single enantiomers can be produced by chemical methods. To replace the above single enantiomers can bewere produced by chemical the hydrogenation of ketones.
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