Synthesis of α‐N‐Linked Glycopeptides

Abstract

AbstractA practical synthesis of Nα‐fluorenylmethoxycarbonyl‐Nγ‐(2,3,4,6‐tetra‐O‐acetyl‐α‐D‐glycopyranosyl)‐L‐asparagine in the gluco and galacto series has been achieved by using the methodology developed by DeShong and co‐workers. The resulting α‐N‐linked glycosyl amino acids were used in a linear approach to the synthesis of glycopeptides featuring the unnatural α‐N‐glycosyl linkage. Activation conditions for both C‐ and N‐terminus elongation in solution have been defined. The main side‐reaction encountered was the formation of cyclization by‐products (aspartimide) from the activated amino acid during C‐terminus elongation. Appropriate condensing agents were identified, which allowed a high yield of dipeptide formation and no epimierization of the glycosyl amino acids. Conditions for sugar deacetylation have also been optimized. Solid‐phase synthesis (Fmoc protocol) conditions were explored and PyBROP was found to be the reagent of choice for the activaton of glycosyl amino acids. The synthesis of more complex α‐N‐linked glycopeptides has thus become feasible, which will allow the properties of these neo‐glycoconjugates to be studied.