Chemical Synthesis of Syndecan‐3 Glycopeptides Bearing Two Heparan Sulfate Glycan Chains

Abstract

Despite the ubiquitous presence of proteoglycans in mammalian systems, methodologies to synthesize this class of glycopeptides with homogeneous glycans are not well developed. Herein, we report the first synthesis of a glycosaminoglycan family glycopeptide containing two different heparan sulfate chains, namely the extracellular domain of syndecan‐3. With the large size and tremendous structural complexity of these molecules, multiple unexpected obstacles were encountered during the synthesis, including high sensitivity to base treatment and the instability of glycopeptides with two glycan chains towards catalytic hydrogenation conditions. A successful strategy was established by constructing the partially deprotected single glycan chain containing glycopeptides first, followed by union of the glycan‐bearing fragments and cleavage of the ester‐type protecting groups. This work lays the foundation for preparing other members of this important class of molecules.

Structural Determination and Chemical Synthesis of the N‐Glycan from the Hyperthermophilic Archaeon Thermococcus kodakarensis

“…The synthesis of 1 was achieved by the global deprotection of 23 (Scheme 3). After cleavage of the TMS group using tetrabutylammonium fluoride (TBAF), the azide groups were converted reductively into acetamide groups using a zinc‐copper couple in the presence of acetic acid, [28] followed by amine‐selective acetylation. Finally, the removal of all benzyl groups by hydrogenation afforded 1 , which features a 1D‐ myo ‐inositol‐3‐phosphate.…”

Synthesis of Uronic Acid Containing Oligosaccharides

“…69 In 2014, Huang and co-workers also reported the synthesis of syndecan-3 glycopeptides bearing two heparan sulfate chains using a slightly adapted strategy. 70 Chondroitin sulfate (CS) and dermatan sulfate (DS) are structurally related GAG molecules, and the constituting disaccharides are composed of b(1 !3)-linked GlcA or a(1! 3)-IdoA and GalNAc disaccharide units, which in turn are connected via b(1!…”

“…More recently, Huang and co-workers synthetized a CS 24-mer, representing the longest synthetic CS chain to date to establish its role in the anti-inflammatory activity of bikunin, a CS-proteoglycan (Scheme 8). 80 The protected 24-mer 84 was prepared via a modular glycosylation strategy, using three core GlcA-GalN building blocks (70,71,74). A TBS group was used for the protection of the GlcA 4-OH and Lev and Ac-esters were used to differentiate the GalN-C-4-alcohols that were to be sulfated or not.…”

Chemical Synthesis of Glycosaminoglycans

“…490 The same group reported also the synthesis of Syndecan-3. 491 Zulueta et al developed a glucosamine-derived trichloroacetyl donor 337 for highly stereoselective α-glycosylation reactions with various acceptors. They utilized their methodology for the preparation of heparin analogues ranging from di-to octasaccharides.…”