Chlorocarbonylsulfenyl chloride cyclizations towards piperidin-3-yl-oxathiazol-2-ones as potential covalent inhibitors of threonine proteases

Abstract

Using rescaffolding approach, we designed piperidine compounds decorated with an electrophilic oxathiazol-2-one moiety that is known to confer selectivity towards threonine proteases. Our efforts to prepare products according to the published procedures were not successful. Furthermore we identified major side products containing nitrile functional group, resulting from carboxamide dehydration. We systematically optimized reaction conditions towards our desired products to identify heating of carboxamides with chlorocarbonylsulfenyl chloride and sodium carbonate as base in dioxane at 100 °C. Our efforts culminated in the preparation of a small series of piperidin-3-yl-oxathiazol-2-ones that are suitable for further biological evaluation.

Keywords

• cyclization
• amide dehydration
• oxathiazole-2-one
• threonine protease
• covalent inhibitors
• irreversible inhibition