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 be
obtained in the diastereoisomerically pure form in two straightforward
steps 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 this
scheme is a remarkably stereoselective solvolysis of the acetate ester
in an acetone/phosphate buffer mixture as the solvent system. Investigation
of this so far unrecognized stereoselective reaction reveals that
it proceeds via an SN1-like pathway as indicated by the
correlation of the solvolysis rate constants with the YOTs values of different solvent mixtures and by trapping
of 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 confirmed
by single-crystal X-ray analysis.