Applying Lipase Catalysis to Access the Enantiomers of Dorzolamide Intermediates

The kinetic resolution of three dorzolamide intermediates has been studied in the presence of Burkholderia cepacia lipase in organic solvents. All the stereoisomers of 6‐methyl‐5,6‐dihydro‐4 H ‐thieno[2,3‐ b ]thiopyran‐4‐ol were prepared starting from the racemic cis ‐dihydrothiopyranol intermediate giving first the 4 R ,6 S and 4 S ,6 R enantiomers. Subsequent epimerization and purification of the trans enantiomers by enzymatic acylation or alcoholysis then gave the cis enantiomers. The cis ‐4‐hydroxy‐6‐methyl‐5,6‐dihydro‐4 H ‐thieno[2,3‐ b ]thiopyran 7,7‐dioxide enantiomers were also prepared by enzymatic kinetic resolution. The kinetic resolution of ethyl 3‐(2‐thienylthio)butanoate with lipases gave moderate enantioselectivities but the method was not used on a preparative scale with this substrate. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)