An enantioselective synthesis of the topically-active carbonic anhydrase inhibitor MK-0507 : 5,6-dihydro-(S)-4-(ethylamino)-(S)-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride

The key feature in the synthesis of topically-active carbonic hydrase inhibitor MK-0507 (13b) is a Ritter reaction that exhibits an unexpected tendency to proceed with retention of chirality. This phenomenon was further studied on model compounds free from potential diastereomeric effects. A mechanism involving transannular stabilization of the sp 2 -hybridized center by sulfone oxygen is proposed with the net result of double inversion. A second key feature in the preferred sequence to MK-0507 involves the classic problem of how to maximize substitution over elimination.This problem manifests itself in the stereospecific alkylation of 2-mercaptothiophene with derivatized methyl (R)-3-hydroxybutyrate and is compounded by a subsequent Michael reaction leading to a loss of product chirality.Results are presented that eliminate this problem.