Exploration of Silver-Assisted Gold Catalysis for the Synthesis of Anticoagulant Heparin Pentasaccharide and a Heptasaccharide of Mycobacterium tuberculosis Cell Surface

Abstract

Heparin is a well-known linear polysulfated polysaccharide with alternating D-glucosamine (GlcN) and either D-glucuronic acid (GlcA) or L-iduronic acid (IdoA) units of the glycosaminoglycan family. Since 1940, it has been used as an antithrombotic agent. In the early 1980s, a unique pentasaccharide domain in heparin chains capable of activating antithrombin III was discovered which is a serine protease inhibitor that blocks factor Xa in the coagulation cascade. Two pharmaceutical companies, Sanofi and Organon synthesized an analog of this pentasaccharide, which was developed into a novel antithrombotic drug, fondaparinux sodium (Arixtra®) in 2002. Subsequently, G. A. van der Marel, C-H Wong, S-C Hung, P. Wang, Y. Qin groups reported different routes for the synthesis of anticoagulant heparin pentasaccharide.

There are some important synthetic challenges such as i) preparation of orthogonally protected IduA building block, ii) stereoselectivity in glycosylations, iii) orthogonal protecting groups on pentasaccharide for effective deprotection and sulfation, and iv) number steps and purification issues. As it has extreme heterogeneity, a rapid and facile synthesis is still in demand to overcome the above challenges.

With the above information in hand, we developed an efficient route with [3+2] and/or [3+1+1] coupling strategy using [Au-phosphite/AgOTf] catalytic system and glycosyl carbonate donor chemistry that was recently discovered in our laboratory. Using this strategy, we successfully achieved overall stereoselectivity and challenging GluA and IduA glycosylation with excellent yields. Additionally, we explored some of the proposals to the synthesis IdoA that enabled us to prepare it efficiently via a new route by employing chelation assisted Grignard reaction. Further, three GlcN building blocks (D, E, F) were prepared in 13 steps using a modified route by utilizing a common intermediate and regiodefined heparin pentasaccharide was prepared. Importantly, this strategy offers a new route to the synthesis of mono 3-O-sulfation at F-ring of fondaparinux pentasaccharide which is hitherto very difficult to synthesize, shows very significant improvement in the anticoagulant activity.

Apart from this, we synthesized the branched heptasaccharide subunit of mycobacterial (MTb) arabinogalactan (AG) by split-react-couple strategy and glycosylated with other subunits to prepare the pentacosafuranoside (25 mer) employing silver-assisted gold catalysis.