Cobalt's dual role in promoting C3-glycosylation of indoles: unraveling mechanistic insights

Abstract

In this study, we present a cobalt-catalyzed C3-glycosylation of indoles using unfunctionalized glycals, yielding 3-indolyl-C-deoxyglycosides. These compounds hold promise as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for treating type 2 diabetes. Control experiments unveiled that cobalt assumes a dual role, facilitating catalytic C-glycosylation while unexpectedly driving the anomerization of α-anomers through endocyclic cleavage of the C1-O5 bond, resulting in the formation of β-C-deoxyglycosides. Furthermore, density functional theory (DFT) calculations shed light on the reaction mechanism, emphasizing the significant role of the pyridine group of indole in stabilizing transition states and intermediates.