NEOGLYCOPROTEIN SYNTHESIS USING THE COPPER-CATALYZED AZIDE–ALKYNE CLICK REACTION AND NATIVE CHEMICAL LIGATION - Click Chemistry in Glycoscience: New Developments and Strategies - page 247

linear synthesis convergent synthesis

SPPS

Key
starting sugar

amino acid

SPPS glycosylated amino acid

building block

functionalized
sugar component

peptide

SCHEME 10.1 Linear and convergent synthetic strategies employed in the synthesis of

glycopeptides.

protecting groups such as acetates can be an issue as some deprotection methods can
affect the epimerization of the -position of certain amino acids in the protein [4].

In addition, the acid sensitivity of the carbohydrate linkage means it is only compat-
ible with the milder fluorenylmethyloxycarbonyl chloride (Fmoc)-SPPS chemistry
[1, 4], precluding the use of Boc-chemistry SPPS for thioester synthesis and subse-
quent NCL. Site-selective glycosylation post peptide synthesis, on the other hand,
requires extensive protection of the peptide as the delicate glycosylation reaction
requires strictly anhydrous conditions incompatible with free amino acid side chains
[7], and often suffers from low yield [14]. Synthesis of glycoproteins therefore
remains a significant challenge, performed in only a few highly specialized laborato-
ries in the world [2].
An alternate approach involves the synthesis of glycopeptide and glycoprotein
mimetics that involve unnatural glycan-peptide linkages. These “neoglycopeptides”
and “neoglycoproteins” are of great interest as they can simplify a complex, multi-step
synthesis. Naturally, the mimetics should retain as much as possible the geometry and
electronics of the glycosidic bond, and therefore hopefully maintain native biological
activity. An unnatural but isosteric linkage may in fact lead to analogs that are more
stable to chemical and metabolic (enzymatic) degradation, leading to longer half-lives
and more potent biological activity [2].

10.2 STRATEGIES FOR THE SYNTHESIS OF NEOGLYCOPEPTIDES
AS GLYCOPEPTIDE MIMETICS

With the above ideas in mind, we began our investigations in this area, combining
the two core strengths of our two groups (Brimble and Kent): synthetic organic