Acyl Glycosides through Stereospecific Glycosyl Cross-Coupling: Rapid Access to C(sp³)-Linked Glycomimetics

Abstract

Replacement of a glycosidic bond with hydrolytically stable C-C surrogates is an efficient strategy to access glycomimetics with improved physicochemical and pharmacological properties. We describe here a stereoretentive cross-coupling reaction of glycosyl stannanes with C(sp²)- and C(sp³)-thio(seleno)esters suitable for the preparation <i>C</i>-acyl glycosides as synthetic building blocks to obtain C(sp³)-linked and fluorinated glycomimetics. First, we identified a set of standardized conditions employing a Pd(0) precatalyst, CuCl additive, and phosphite ligand that provided access to <i>C</i>-acyl glycosides without deterioration of anomeric integrity and decarbonylation of the acyl donors (>40 examples). Second, we demonstrated that C(sp³)-glycomimetics could be introduced into the anomeric position via a direct conversion of C1 ketones. Specifically, the conversion of the carbonyl group into a CF₂ mimetic is an appealing method to access valuable fluorinated analogues. We also illustrate that the introduction of other carbonyl-based groups into the C1 position of mono- and oligosaccharides can be accomplished using the corresponding acyl donors. This protocol is amenable to late-stage glycodiversification and programmed mutation of the C-O bond into hydrolytically stable C-C bonds. Taken together, stereoretentive anomeric acylation represents a convenient method to prepare a diverse set of glycan mimetics with minimal synthetic manipulations and with absolute control of anomeric configuration.