Probing the mechanism of sulfoxide-catalyzed hemiacetal activation in dehydrative glycosylation

The concept of sulfoxide-covalent catalysis has been established in the context of a versatile hemiacetal hydroxyl activation/substitution reaction for the formation of anomeric linkages. Mechanistic studies focused on the hemiacetal activation process show that this transformation proceeds in the presence of a sulfonic anhydride and an acid scavenger through the intermediacy of a glycosyl sulfonate species (10), which serves as a resting state prior to the addition of an external nucleophile and subsequent glycosidic bond formation. Successful determination of the proportion of O-18 incorporation in 10 as a function of its formation, via the technique of dynamic monitoring of C-13-(16)/O-18 isotopic chemical shift perturbations, provides strong evidence that hemiacetal activation proceeds through initial nucleophilic addition of the hemiacetal hydroxyl to the S(IV)-center of putative sulfonium sulfonate 6. Further confirmation was obtained through the independent synthesis, structure verification, and H-1 NMR detection of glycosyl oxosulfonium 11 during the sulfoxide-catalyzed conversion of hemiacetal 3 to glycosyl sulfonate 10.