An electrochemically promoted modular synthesis of diverse glycomimetics via acyloxyphosphonium ions

Abstract

The installation of sugar residues can significantly enhance the hydrophilicity, pharmacological activity, and bioavailability of natural products and bioactive compounds. In this study, we developed an electrochemical strategy for the efficient conjugation of sugar units to target molecules, enabling the synthesis of glycomimetics (C-acyl and C-heteroaryl glycosides). This approach leverages the anodic oxidation of iodide anions to mediate the oxidation of triphenylphosphine (Ph₃P), generating electrophilic acyloxyphosphonium ions in situ. This mechanism facilitates direct coupling between nucleophilic molecules (N-, S-, O-, C-) and glycosyl carboxylic acids without the need for additional oxidants, metal catalysts, or condensing agents. Under optimized conditions, the reaction demonstrates broad applicability across various glycosyl carboxylic acids and structurally complex target molecules, exhibiting excellent functional group compatibility with yields of up to 99%. Furthermore, this methodology has been successfully applied to incorporate sugar motifs into diverse bioactive scaffolds, including drug molecules and natural products, as well as to construct sugar-containing linkers for bioconjugation, polysaccharide amide fragments, and pharmacologically relevant glycosyl oxazoles. These results highlight the method's considerable potential in the development of bioactive molecules.