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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. Specifically, the conversion of the carbonyl group into a CF2 mimetic is an appealing method to access valuable fluorinated analogues. Second, we demonstrated that C(sp³)-glycomimetics could be introduced into the anomeric position via a direct conversion of C1 ketones. 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). 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. Replacement of a glycosidic bond with hydrolytically stable C-C surrogates is an efficient strategy to access glycomimetics with improved physicochemical and pharmacological properties.

The improved affinity, selectivity, and low cytotoxicity suggest that the quinoline-galactoside derivatives provide an attractive starting point for development of galectin-8N inhibitors. The compounds were demonstrated to be non-toxic in an MTT assay with several breast cancer cell lines and one normal cell line. Molecular dynamics simulations proposed an interaction mode in which Arg59 had moved 2.5Å and in which a inhibitor carboxylate and quinoline nitrogen formed structure-stabilizing water-mediated hydrogen bonds. Evaluation of the quinoline, indolizine and coumarin-derivatised galactosides as inhibitors of galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9N, and 9C revealed quinoline derivatives that selectively bound galectin-8N with up to near 60-fold affinity improvements relative to methyl -D-galactopyranoside. In this report, we have developed straightforward methods to incorporate quinoline, indolizine, and coumarin structures into galactoside derivatives under robust reaction conditions. Quinolines, indolizines, and coumarins are well known structural elements in many biologically active molecules.