‘Green’ synthesis of important pharmaceutical building blocks: enzymatic access to enantiomerically pure α-chloroalcohols

Thirty one recombinant ketoreductase enzymes were screened for the reduction of six α-chloroketones, the precursors of pharmaceutically valuable α-chloroalcohols. Several highly active and enantioselective ketoreductases were found and their applications to the synthesis of both enantiomers of these α-chloroalcohols were demonstrated on a preparative scale. This offers a convenient, ‘green’ access to this type of important pharmaceutical building blocks.

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2-Chloro-1-phenylethanolC8H9ClOEe >99%[α]D22=+53.8 (c 1.0, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: S

2-Chloro-1-(3-chlorophenyl)ethanolC8H8Cl2OEe >99%[α]D22=+43.5 (c 1.0, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: S

2-Chloro-1-(4-chlorophenyl)ethanolC8H8Cl2OEe >99%[α]D22=-46.0 (c 1.0, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: R

2-Chloro-1-(3,4-dichlorophenyl)ethanolC8H7Cl3OEe >99%[α]D22=-35.1 (c 1.0, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: R

2-Chloro-1-(4-nitrophenyl)ethanolC8H8ClNO3Ee >99%[α]D22=+40.5 (c 1.0, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: S

2-Chloro-1-(4-methanesulfonamidophenyl)ethanolC8H12ClNO3SEe >99%[α]D22=+32.0 (c 1.0, CHCl3)Source of chirality: enzymatic reductionAbsolute configuration: S