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.

Martinelli A., Volpicelli R., Verzini M., Cotarca L., Maini L., Pengo P., et al. (2023). Stereoselective Solvolysis in the Synthesis of Dorzolamide Intermediates. ACS OMEGA, 8(31), 28851-28858 [10.1021/acsomega.3c03959].

Stereoselective Solvolysis in the Synthesis of Dorzolamide Intermediates

Maini L.;
2023

Abstract

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.
2023
Martinelli A., Volpicelli R., Verzini M., Cotarca L., Maini L., Pengo P., et al. (2023). Stereoselective Solvolysis in the Synthesis of Dorzolamide Intermediates. ACS OMEGA, 8(31), 28851-28858 [10.1021/acsomega.3c03959].
Martinelli A.; Volpicelli R.; Verzini M.; Cotarca L.; Maini L.; Pengo P.; Pasquato L.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/949853
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