C-Glycoside Synthesis and Applications

C-Glycosides are glycan constructs in which the sugar moiety is tethered to a non-sugar component through a carbon–carbon bond at the anomeric centre. This linkage endows the resulting molecules with enhanced chemical and metabolic stability compared with conventional O-glycosides, rendering them valuable for therapeutic, diagnostic and materials applications. Advances in catalytic methodologies, including radical-mediated and transition-metal-catalysed cross-coupling strategies, have enabled more direct, stereoselective and protecting-group-free access to diverse C-glycoside architectures. Such innovations have not only streamlined the assembly of complex oligosaccharides but have also facilitated late-stage functionalisation of bioactive scaffolds, leading to the discovery of novel enzyme inhibitors and drug candidates. The broad scope of these methods underpins ongoing efforts to exploit C-glycosides in drug discovery, chemical biology and materials science.

Research from Nature Portfolio

Recent studies have introduced a photoinduced radical approach that bypasses conventional protecting-group manipulations to achieve site- and stereoselective C-glycosylation directly from native sugars. This light-activated protocol generates transient anomeric radicals that undergo controlled cross-coupling with electrophiles, delivering a wide array of metabolically robust C-glycosides. Notably, the method extends to post-translational glycosylation of proteins under biocompatible conditions. A complementary strategy exploits palladium-catalysed nondirected C1–H activation and C2 functionalisation of glycals to construct C-oligosaccharides in a modular and highly stereoselective fashion. Computational studies support an oxidative addition mechanism and account for the high stereocontrol. In addition, nickel-catalysed reductive hydroglycosylation of alkyne-tagged amino acids and peptides has unlocked access to vinyl C-glycosyl amino acids, enabling further elongation of sugar and peptide chains and broadening the utility of C-glycosides in biomolecular design.

C-Glycoside Synthesis and Applications publication trend

The graph below shows the total number of articles in c-glycoside synthesis and applications across all publications each year (not limited to Nature Index journals).

Technical terms

C-Glycoside: A glycoside in which the sugar unit is linked to an aglycone via a carbon–carbon bond at the anomeric position, imparting enhanced stability.

Glycal: An unsaturated sugar derivative featuring a carbon–carbon double bond at the anomeric (C1–C2) position, frequently used as a precursor in C-glycosylation reactions.

Anomeric radical: A reactive species generated at the anomeric centre of a sugar that can undergo radical-mediated cross-coupling to form C–C bonds.

Stereoselectivity: The preferential formation of a specific stereoisomer when multiple stereochemical outcomes are possible in a reaction.

C–H activation: Direct functionalisation of a carbon–hydrogen bond to forge a new carbon–carbon bond, often mediated by a transition-metal catalyst.

Cross-coupling: A catalytic reaction that constructs carbon–carbon bonds by joining two distinct organic fragments, typically via transition-metal catalysis.

References

1. Direct radical functionalization of native sugars. Nature (2024).
2. Stereoselective assembly of C-oligosaccharides via modular difunctionalization of glycals. Nature Communications (2024).
3. Facile access to C-glycosyl amino acids and peptides via Ni-catalyzed reductive hydroglycosylation of alkynes. Nature Communications (2021).
4. Direct Construction of C‐Alkyl Glycosides from Non‐Activated Olefins via Nickel‐Catalyzed C(sp3)─C(sp3) Coupling Reaction. Advanced Science (2024).
5. C–H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT‑2 Inhibitors. ACS Central Science (2023).
6. Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis—A Comprehensive Review. Molecules (2022).