Stereoselective C1-Arylation of Native Sugars via Ligand-Promoted Nickel Catalysis

Aryl C-glycosides represent a valuable class of carbohydrates with broad biological activity in drug discovery, yet their rapid and stereoselective synthesis from unprotected native saccharides remains a significant challenge. Here we report a nickel-catalyzed, ligand-promoted stereoselective C1-arylation of unprotected saccharides with aryl bromides, enabled by glycosyl sulfonylhydrazide donors that are accessible in one step from native sugars. Notably, a series of N,N'-disulfonylpyridinedicarboxamidine tridentate ligands was developed and found to be critical for achieving both high reactivity and anomeric selectivity. The present method accommodates a broad range of aryl and heteroaryl bromides and is applicable to diverse mono- and oligosaccharides. To showcase the synthetic utility of this approach, we constructed a Taxol-sugar conjugate library. In vitro anticancer activity studies revealed that most conjugates retained significant antiproliferative activity against the tested cancer cell lines, while compound 6n was identified as selectively targeting glucose-dependent cancer cells with markedly improved water solubility compared with Taxol, emerging as a promising lead compound for cancer therapy.