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 C-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 C-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.