Heparan sulfates are heavily 0-/A/-sulfated linear polysaccharides ubiquitously expressed on cell surface and in the extracellular matrix. As result of its extreme number of positional isomers, the study of HS has been seriously hindered by a lack of efficient methodologies to prepare diverse libraries of HS oligosaccharides. Enzyme-mediated synthesis of HS is very promising, but limited to enzyme specificities, only highly sulfated heparin-like structures with repetitive sequences can be obtained. Recently we discovered that a 6-O-methyl group on a GlcNS residue not only prevented sulfation of the protected hydroxyl group by 6-OST, but also blocked epimerization/2-O-sulfation of the reducing-side GIcA by C5-epi and 2-OST, providing unique opportunities to control enzymatic epimerization and sulfation of HS backbones [1]. However, the unremovable methyl ether permanently shut down the disaccharide unit, -GlcNS6Me-GlcA-, to modification by 6-OST, C5-Epi and 2-OST, seriously limiting the synthetic flexibility. And the unnatural methyl ether group is likely to interfere binding between the HS analogs and HS-binding proteins.
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