In an effort to develop a practical method for the synthesis of optically pure 2,2,2-trifluoro-1-phenylethanol,we found that the carbonyl reductase(SSCR)from Sporobolomyces salmoni-color showed excellent activity and enantioselectivity toward the halogenated acetophenones.Especially,SSCR exhibited more than 1000 times higher activity toward α,α,α-trifluoroacetophenone than unsubstituted acetophenone a strikingly different observation from the previously well-studied alcohol dehydrogenase(LBADH)from Lactobacillus brevis.Enzyme-substrate docking and site-directed mutagenesis studies revealed the molecular basis for the high enzyme activity and enantioselectivity of SSCR toward the α-halogenated acetophenones.The hydrogen bond of the Asn207 side chain with the substrate halogen atom and the XH/π interaction of the substrate phenyl group with the side chains of Ser222/Thr223 resulted in the formation of the highly reactive conformation of α-halogenated acetophenones in the active site of the enzyme.(S)-2,2,2-Trifluoro-1-phenylethanol was prepared in excellent isolated yield and enantiomeric excess from the reduction of α,α,α-trifluoroacetophenone with mutant T209A.These results suggest that tuning the interactions between the halogen atoms/phenyl group of the substrate and the amino acid residues of the enzyme would lead to valuable mutants for the practical synthesis of β-haloalcohols.