Detecting glycosyl-oxonium and glycosyl-nitrilium ions using exchange NMR to investigate solvent effects in glycosylation reactions

The stereoselective synthesis of glycosidic bonds can be promoted by the addition of stereodirecting solvents. In particular, nitrile and ether based solvents are known to promote the selective production of β- or α-glycosides, respectively. Even though the application of co-solvents in glycosylation protocols is well-established, the understanding of their impact on the glycosylation mechanism as well as the reaction intermediates formed upon their addition, remains incomplete. As the exact mechanism of solvent stereo direction remains debated, this limits the ability to develop stereoselective glycosylation methods. Herein, we report the application of relaxation and exchange NMR techniques to establish that acetonitrile and tetrahydrofuran form covalent glycosyl-nitrilium and glycosyl-oxonium ions, respectively. In contrast, other ethereal solvents such as diethyl ether and 1,4-dioxane were not able to do so. This work highlights the potential of exchange NMR to study reaction mechanisms, provides evidence for the formation of glycosyl-solvent adducts despite their very low populations, and improves our ability to develop better stereoselective glycosylation protocols.