Abstract
(R)-1-[4-(Trifluoromethyl)phenyl]ethanol is an important pharmaceutical intermediate of a chemokine CCR5 antagonist. In the present study, a bioprocess for the asymmetric reduction of 4-(trifluoromethyl)acetophenone to (R)-1-[4-(trifluoromethyl)phenyl]ethanol was developed by recombinant Escherichia coli cells with excellent enantioselectivity. In order to overcome the conversion limitation performed in the conventional buffer medium resulting from poor solubility of non-natural substrate, we subsequently established a polar organic solvent-aqueous medium to improve the efficacy. Isopropanol was selected as the most suitable cosolvent candidate, based on the investigation on a substrate solubility test and cell membrane permeability assay in different organic solvent-buffer media. Under the optimum conditions, the preparative-scale asymmetric reduction generated a 99.1% yield with >99.9% product enantiomeric excess (ee) in a 15% (v/v) isopropanol proportion, at 100 mM of 4-(trifluoromethyl)acetophenone within 3 h. Compared to bioconversion in the buffer medium, the developed isopropanol-aqueous system enhanced the substrate concentration by 2-fold with a remarkably improved yield (from 62.5% to 99.1%), and shortened the reaction time by 21 h. Our study gave the first example for a highly enantioselective production of (R)-1-[4-(trifluoromethyl)phenyl]ethanol by a biological method, and the bioreduction of 4-(trifluoromethyl)acetophenone in a polar organic solvent-aqueous system was more efficient than that in the buffer solution only. This process is also scalable and has potential in application.
Highlights
Enantiopure alcohols are valuable and versatile building blocks for the manufacturing of chiral pharmaceuticals [1]. (R)-1-[4-(Trifluoromethyl)phenyl]ethanol is a crucial enantiomerically enriched intermediate for the production of AD101 (SCH-350581), a chemokine CCR5 antagonist widely used in AIDS patients to inhibit the replication of HIV-1 via blockade of its entry into cells [2]
We found a carbonyl reductase derived from the Leifsonia xyli HS0904 isolate exhibiting catalytic activity toward 4-(trifluoromethyl)acetophenone by investigating the substrate specificity of this purified enzyme for several aromatic ketones, alkyl ketones and keto esters [7]
Microorganisms isolated from soil samples or preserved in our laboratory, including bacterial, yeast and filamentous fungus, were tested for their abilities to produce (R)-1-[4(trifluoromethyl)phenyl]ethanol
Summary
Enantiopure alcohols are valuable and versatile building blocks for the manufacturing of chiral pharmaceuticals [1]. (R)-1-[4-(Trifluoromethyl)phenyl]ethanol is a crucial enantiomerically enriched intermediate for the production of AD101 (SCH-350581), a chemokine CCR5 antagonist widely used in AIDS patients to inhibit the replication of HIV-1 via blockade of its entry into cells [2]. A chemical approach for the (R)-1-[4-(trifluoromethyl)phenyl]ethanol synthesis has been reported through the asymmetric reduction with BH3 Me2 S in the presence of a chiral catalyst oxazaborolidine, while the drawbacks of this method are the expensive chiral reagent and environmental pollution [3]. The search for alternative biocatalytic processes for efficient preparation of enantiometrically pure (R)-1-[4-(trifluoromethyl)phenyl]ethanol attracts more attention. An alternative way is the enantioselective reduction of prochiral compounds using enzymes or enzyme-containing cells [4]. The use of microbial whole-cells with metabolic activity as catalysts provides several merits over isolated enzymes, including the cofactor recycling in situ and better protecting target enzymes against inactivation, thereby significantly cutting down the process cost [5,6].
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