Synthesis of C‐Glycosyl Amino Acid Building Blocks Suitable for the Solid‐Phase Synthesis of Multivalent Glycopeptide Mimics

Five C‐glycosyl functionalized lysine building blocks, featuring C‐glycosidic derivatives of α‐rhamnose, α‐mannose, α‐galactose, β‐galactose, and β‐N‐acetyl glucosamine have been designed and synthesized. These derivatives, equipped with acid‐labile protecting groups, are eminently suitable for solid‐phase synthesis of multivalent glycopeptides. The lysine building blocks were prepared from C‐allyl glycosides that underwent a Grubbs cross‐metathesis with an acrylate, followed by a reduction of the C=C double bond in the resulting α,β‐unsaturated esters, and liberation of the carboxylate to allow condensation with a lysine side chain. The thus obtained C‐glycosides, five in total, were applied in the solid‐phase peptide synthesis (SPPS) of three glycopeptides, showing the potential of the described building blocks in the assembly of well‐defined mimics of homo‐ and heteromultivalent glycopeptides and glycoclusters. Reported is the synthesis of five C‐glycosyl amino acids, which are stable against the acidic conditions used in solid phase peptide synthesis. Key steps include the introduction of a C‐allyl on the carbohydrate, a Grubbs cross‐metathesis, reduction of the obtained alkene, and condensation with a protected lysine.