Highly stereoselective synthesis of heparin tri- and tetra-saccharide derivatives

Abstract

<p indent="0mm">Heparin, a naturally highly sulfated glycosaminoglycan, mediates various physiologic and pathophysiologic processes, and is mainly used for the prevention and treatment of venous thrombosis in clinic. Here we report an efficient synthesis of heparin oligosaccharides with different degrees of 6-<italic>O</italic>-sulfonation modification, employing orthogonal protective group strategy. <italic>tert</italic>-Butyldiphenylsilyl (TBDPS) group is used as the protective group of 6-OH of the 2-azide-glucose donors, and highly α-selective construction of the key GlcN-(1→4)-GlcUA glycosidic bond was achieved with the corresponding <italic>N</italic>-phenyl trifluoroacetimidate donors. Thus, tri- and tetra-saccharides are synthesized by the convergent [1 + 2] and [2 + 2] glycosylation. The fully elaborated oligosaccharides have then been successfully transformed into the target heparin oligosaccharides <bold>28</bold>–<bold>34</bold> <italic>via</italic> an optimal sequence of manipulation of the protecting groups. The post-assembly manipulations include desilylation with HF·Py (for removal of TBDPS group), delevulinoylation with hydrazine hydrate (for removal of levulinoyl group), saponification under Zemplén conditions (for removal of methyl ester and benzoyl group), <italic>O</italic>-sulfonation with sulfur trioxide pyridine complex (for hydroxyl groups), reduction and <italic>N</italic>-sulfonation (for azido group), and atmospheric pressure hydrogenation (for removal of benzyl and Cbz groups). The availability of these heparin oligosaccharide derivatives which bear amino linker shall facilitate the preparation of glycan chips for studies on the interaction between heparin oligosaccharides with proteins, such as the heparanase.