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 174 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 a newline newline