Expanding the Chemical Space of Sugar Frameworks by Quaternization of the Anomeric Carbon Atom

The anomeric position of carbohydrates is a privileged site for structural diversification in the development of glycomimetics. Quaternization of the anomeric carbon represents a promising strategy to enable dual and orthogonal functionalization at C-1, while preserving critical binding features. Herein, the synthesis of novel bifunctional C-fucoside scaffolds, bearing a quaternary anomeric center, is reported. The strategy employs radical bromination of β-cyano and β-carbomethoxy fucosides to access key anomeric α (axial) bromide intermediates, which enable downstream derivatization via azide substitution or CC bond formation through radical allylation. The latter reaction occurs with high α (axial) selectivity from the β-carbomethoxy-α-fucosyl bromide, while mixtures are obtained from the corresponding β-cyano derivative. Azide substitution occurs with full inversion of configuration starting from both bromides. While attempts at amide coupling are hampered by anomeric epimerization, copper-catalyzed azide–alkyne cycloaddition proceeds efficiently, yielding α-C,β-N-fucosides with high yields and selectivity. The developed methodology expands the chemical space at the anomeric position and supports future applications in ligand design, multivalent systems, and carbohydrate-based therapeutics.