Synthesis of Heparan Sulfate Backbone Oligosaccharides by Directly Installing <i>cis</i> ‐Linkages on Solid‐Phase

Comprehensive Summary 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.