Synthesis of Heterocycle-Linked C-Glycosyl alpha-Amino Acids and C-Glycopeptides

Non-natural C-glycosyl alpha-amino acids are building-blocks for the co-translational modification of natural glycopeptides. These are key components of the complex machinery that operates in vital processes of all living organisms, ranging from eubacteria to eukaryotes. While a wide range of C-glycosyl amino acids have been synthesized, we have designed and prepared a small collection of a new class of these amino acids whose structure features a heterocycle ring holding the carbohydrate and the amino acid fragments. Isoxazole, triazole, tetrazole, and pyridine moieties were used as suitable linkers in this project owing to their easy construction via Huisgen cycloaddition and Hantzsch multicomponent reaction. Details on the synthesis of each family of these glycolconjugates are given below, some emphasis being given to the efficiency and generality of each method employed. The potential of these glycosyl amino acids in non-natural glycopeptide synthesis is exemplified by the coupling of a pyridine-linked derivative with two natural amino acids to give a non-natural glycotripeptide.