Solid Phase Synthesis of NLinked Glycopeptides

N-linked and O-linked glycoproteins are the two major subgroups of glycoproteins, with the former being the most abundant in nature [44]. The biosynthesis of these glycoproteins results from cotranslational glycosylation usually occurring in the en-doplasmic reticulum. The sugars of N-linked glycoproteins are usually attached by an oligosaccharyltransferase to an asparagine having the glycosylation sequence Asn-X-Ser/Thr. Advances in glycopeptide synthesis have been achieved by several groups [45-47].

The synthesis of N-linked glycopeptides [48] on the solid support using a terminal glycal of a synthetic oligosaccharide domain aimed at a highly convergent synthetic strategy [49]. Polymer-supported trisaccharide 32 was reacted with anthra-cenesulfonamide and I(yym-coll)2ClO4 to form intermediate 33 (Scheme 7). Reaction of the iodosulfonamide 33 with tetra-ra-butylammonium azide, followed by acetyla-tion, provided the anomeric azide 34. The anthracenesulfonamide linkage can be cleaved under mild conditions such as 1,3-propanedithiol and Hiinig's base, which concomitantly effected the reduction of the azide. The resulting amine was coupled with pentapeptide 35 in the presence of IIDQ to afford the protected glycopeptide 36.

Orthogonal protecting groups on the C- and N-termini of the peptide provided the opportunity to extend the peptide chain while the ensemble was bound to the solid support. Alternatively, after removal from the support, the liberated peptide terminus may provide a functionality for linking to a carrier molecule to generate other glycoconjugates. The C-terminus of 36 was deprotected to give the acid 37, which was coupled to tripeptide 38 with a free N-terminus to give glycopeptide 39. Retrieval from the solid support afforded trisaccharide-octapeptide 40 in 18% overall yield from 19 [50].

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