C-Glycosyl α-Amino Acids as Structural Encoders of Peptide Conformation

C-glycosylation is a well-established strategy for improving the pharmacokinetic properties of peptides; however, the influence of chiral C-glycosyl amino acid incorporation on peptide conformation remains insufficiently explored. Most existing synthetic approaches restrict C-glycosyl amino acid placement to the N-terminus, C-terminus, or specific residues containing pre-installed reactive groups. Here, we present a more versatile strategy based on the design and synthesis of customized C-glycosyl amino acids. Four variants bearing protected galactopyranose, ribofuranose, sorbofuranose, or allofuranose side chains were synthesized and incorporated into peptides using a solid-phase methodology, enabling substitution at diverse sequence positions. Detailed NMR analyses revealed that each C-glycosyl α-amino acid promotes distinct conformational preferences, primarily stabilized by hydrogen-bonding networks between backbone amides and carbohydrate side chains. These findings uncover conformational information encoded within four non-canonical C-glycosyl α-amino acids, offering new molecular tools for catalysis, materials development and drug discovery.