Synthesis of Heparan Sulfate Backbone Oligosaccharides by Directly Installing cis-Linkages on Solid-Phase
Shuangli Wang , Zimiao Qin , Tan Liu , Xin Gu , Xiaobin Wu , Yutong Fu , Chuanying Zhang , Meng Wang , Linghan Bu , Yimei Guo , Yishu Yan , Pan Zhu , Yuntao Zhu
Chinese Journal of Chemistry ›› 2026, Vol. 44 ›› Issue (9) : 1320 -1328.
Glycans are essential biomolecules across species, and a thorough understanding of their structure-function relationships heavily depends on high-quality samples obtained through chemical or enzymatic synthesis. Solid-phase glycan synthesis (SPGS) is a powerful technique for preparing well-defined glycans. However, assembling structures with multiple cis-glycosidic bonds, particularly cis-glycosamines, remains a significant challenge for SPGS. In this study, we targeted heparan sulfate (HS) backbone oligosaccharides, which contain two types of 1,4-cis linkages between glucosamine (GlcN) and D-glucuronic acid (GlcA) or L-iduronic acid (IdoA). We evaluated ten 2-azido-2-deoxy-thioglucopyranosides with diverse C3-OH/C6-OH functionalities as potential building blocks for glucosamine residues. Considering reactivity and stereoselectivity, a candidate with a bulky tert-butyldiphenylsilyl group at C6-OH demonstrated superior performance compared to 3,6-diesterified species in our study. This silyl building block also proved to be well-compatible with SPGS, facilitating the successful preparation of four disaccharides and four tetrasaccharides containing GlcN-GlcA or GlcN-IdoA on solid-phase. Finally, for the first time, we successfully synthesized a Fondaparinux-type pentasaccharide backbone containing GlcN, GlcA, and IdoA residues simultaneously by directly installing all types of cis-linkages on solid-phase without using disaccharide building blocks or special reagents.
Solid-phase synthesis / Carbohydrates / Heparan sulfate / Glycan / Fondaparinux / cis-Linkages / Oligosaccharide / Glucosamine
2026 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
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