Synthesis of Anticoagulant Idraparinux and Development of New Glycosylation Methods

Abstract

Heparin (H) and Heparan sulfates (HS) are the heterogeneous, polyanionic molecules of glycosaminoglycan known to interact with biologically important proteins and play significant role in many physiological processes. The low molecular weight heparins (LMWH) and heparin based-drugs are clinically being used for the treatment of thromboembolic diseases and as an anticoagulant. However obtaining these LMWH and HS from natural sources are very tedious and hence often obtained as heterogeneous mixture and low quantity. Therefore, the chemical synthesis of heparin and heparin-based anticoagulants such as Fondaparinux (Arixtra®), Idraparinux and Idrabiotaparinux are at high demand. Recently, we have developed a novel, modular and highly efficient protocol for clinically approved heparin-based anticoagulant Fondaparinux pentasaccharide based on silver assisted gold-catalyzed glycosidation. In this thesis (Chapter 2), we have developed a highly efficient, short route synthetic protocol for second-generation anticoagulant Idraparinux pentasaccharide. The synthetic methodology was built on the solid foundation of silver assisted gold-catalyzed glycosidation from novel starting materials. The choice of maltose disaccharide as a starting material has significantly reduced the number of synthetic steps as it has an in-built 1,2-cis-glycosidic linkage. All the building blocks synthesis was optimized and synthesized with good to excellent yields in complete stereo-selective fashion. The pentasaccharide was synthesized by highly convergent [3+2] glycosidation strategy thus for the first time we have achieved the total synthesis of Idraparinux under 31 steps. In the chapter 3A, the glycosyl ester having alkyne appendage on leaving group are investigated to decipher the role of gold salts in activation of donors. The results showed that the glycosyl esters can be activated using the sub-stoichiometric amount Brønsted acid TfOH to synthesize disaccharides and glycosides. However, acidic reaction condition compromised the application of this protocol for oligosaccharides synthesis thus signifying the importance of gold catalysis. In the chapter 3B, the glycosyl vinylogous carbonates were investigated as donor under metal-free condition. The donor was found suitable to produce azido-glycoside, alicyclic-glycosides, phenolic-glycoside and disaccharides in good to excellent yield. Further the application donor in oligosaccharide synthesis has been demonstrated by synthesizing the pentaarabinofuaranoside moiety present on the cell surface of Mycobacterium tuberculosis.