The Remarkable Stability of Unprotected Sugars

Glycopeptides are classified based on the attachment mode of an oligosaccharide to the amino acid side chain of the peptide domain. In N-linked glycopeptides 4, the asparagine carboxamide is glycosylated with a conserved (high mannose) pentasaccharide core structure. Within the cellular context, this linkage is generated via glycosylation of the asparagine amide side-chain, while a common chemical synthesis approach involves peptide-bond formation between a glycosylamine 2 and the side-chain carboxylate of a uniquely disposed aspartate 3. In many cases, the requisite glycosylamine 2 is generated via standard Kochetkov-Lansbury amination (NH₄HCO₃/H₂O, 25° C) from the globally deprotected parent saccharide 1, featuring a free anomeric hydroxyl-group.

Preparation of Precursor 1

Preparation of precursor 1 can be achieved via a number of routes, and one involving the glycal assembly technology is shown below: commercially available tribenzylglucal 5 is converted into the prototypical 2-N-acetylglucose 8 via thioglycosides 6 and 7. Out of concern for the integrity of the terminal hemi-ketal linkage during the harsh Birch-type reaction conditions, direct deprotection of 9 had been avoided, until now. We have successfully deprotected partially benzylated mono- and disaccharides with free anomeric hydroxyl-groups under dissolving metal conditions.

Publication

U. Iserloh, V. Dudkin, Z.-G. Wang and S. J. Danishefsky, Reducing Oligosaccharides via Glycal Assembly: On the Remarkable Stability of Anomeric Hydroxyl Groups to Global Deprotection with Sodium in Liquid Ammonia, Tetrahedron Lett. 2002, 43, 7027-7030. Download PDF.