Synthesis and conformation evaluation of α-N-linked glycopeptides

The synthesis of neo-glycoconjugates has been gaining much attention in recent years, due to the relevance of natural glycopeptides and glycoproteins in human health and disease. Our group has been actively investigating the synthesis of α-N-linked glycosyl amides and glycopeptides. These compounds are practically unknown in nature and may lead to molecules tolerated by biological systems and yet less susceptible to chemical or enzyme-mediated hydrolysis. The synthesis of these unnatural compounds is not trivial because only few methods are available for α-N glycosylation. Recently, a route to obtain α-N-linked glucosyl asparagine was introduced by DeShong and co-workers.3 Starting from this strategy we were able to optimize and scale up the stereoselective synthesis of α-N-glycosylated building blocks of glucosyl and galactosyl asparagine with suitable protecting groups for solid phase peptide synthesis. The resulting α-N-linked glycosylaminoacids were initially employed in solution to determine activation conditions for both C-terminus and N-terminus elongation. After identification of appropriate condensing agents and deprotection conditions, solid phase synthesis (Fmoc protocol) was explored for the synthesis of more complex α-N-linked glycopeptides. The preparation of short model α-N-linked glycopeptides has allowed to initiate the study of conformation and properties of these neo-glycoconjugates.