C -Glycosylation as the Organizing Principle for Heterocycle Construction and Tailoring in C -Nucleosides Biosynthesis

Conspectus C-Nucleosides, characterized by a chemically robust C–C glycosidic bond in place of the canonical C–N linkage, represent a distinct class of nucleoside natural products with diverse biological activities. Their close structural similarity to N-nucleosides enables their incorporation into primary metabolic processes, including de novo nucleoside biosynthesis and RNA polymerization. As a result, both natural and synthetic C-nucleosides exhibit potent antibacterial, antiviral, and anticancer activities, making them attractive targets for drug development in medicinal chemistry and chemical biology. Natural product discovery efforts have uncovered a number of C-nucleosides in which C–C glycosidic bond formation generally involves either decarboxylative electrophilic aromatic substitution or Knoevenagel-Mannich condensation. In both cases, C-glycosylation relies on the biosynthesis of highly nucleophilic heterocycles prior to glycosidic bond formation. These nucleophiles arise from distinct precursors, including d-glutamate-derived heterocyclic carboxylates and l-glutamine-derived scaffolds formed via oxidative cyclization. Following C-glycosylation, d-glutamate-derived intermediates undergo pyrimidine elaboration that parallels aminopyrimidine formation in de novo purine biosynthesis, whereas l-glutamine-derived heterocycles undergo oxidative tailoring reactions that ultimately define their final structure and biological function. Thus, C-glycosylation is indeed the central mechanistic feature of C-nucleoside biosynthesis that places requirements on the initial construction of the nucleophilic heterocycle to facilitate C–C bond formation and in the process defines the properties that govern subsequent tailoring reactions.