Stereoselective Solvolysis in the Synthesis of Dorzolamide Intermediates

The key intermediate in the synthesis of dorzolamide,(4S,6S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol-7,7-dioxide,can beobtained in the diastereoisomerically pure form in two straightforwardsteps starting from diastereoisomeric mixtures of cis/trans-(6S)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl acetate,regardless of their ratio. The reaction of crucial importance in thisscheme is a remarkably stereoselective solvolysis of the acetate esterin an acetone/phosphate buffer mixture as the solvent system. Investigationof this so far unrecognized stereoselective reaction reveals thatit proceeds via an S(N)1-like pathway as indicated by thecorrelation of the solvolysis rate constants with the Y (OTs) values of different solvent mixtures and by trappingof the reaction intermediate with sodium azide. The structure of (4S,6S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol-7,7-dioxide was confirmedby single-crystal X-ray analysis.