Three-Component C-Glycosylation of Amino Acids and Peptides Enabled by Photoinduced Palladium Catalysis

Abstract

Glycosylation represents a powerful strategy for modulating the properties and functions of peptides and proteins, with significant implications for biochemical and medicinal research. Particularly, C-glycosyl peptides and proteins-structural mimics of native O/N-glycosides-exhibit superior metabolic stability, rendering them attractive candidates for therapeutic development. Despite impressive advances in glycosyl radical-based synthesis of C-Glycopeptides, current approaches largely depend on harnessing nucleophilic reactivity of glycosyl radicals and pre functionalizing amino acid substrates to introduce electrophilic sites. To explore more reactivity patterns of glycosyl radicals and eliminate additional prefunctionalization steps, we herein disclose a photoinduced palladium-catalyzed, three-component glycosylation strategy for the direct assembly of saccharides with non-preactivated amino acids and peptides using 1,3-dienes as versatile coupling linkers. Notably, this approach transforms nucleophilic glycosyl radicals into electrophilic π-allylpalladium species, representing a novel reactivity pattern in glycosyl radical chemistry. Featuring mild conditions and good functional group tolerance, this method provides a versatile and general platform for constructing structurally diverse C-glycoamino acids, peptides, and drug conjugates in good yields with high stereoselectivity.