Synthetic Studies Toward Anticoagulant Drug Fondaparinux Sodium

This thesis is focused on the synthetic studies toward heparin-based anticoagulant drug Fondaparinux sodium.Heparin-type compounds have been used as natural anticoagulant polysaccharide clinically for more seven decades featuring with remarkable anticoagulant activity both in vitro and in vivo,they are mainly applied in the therapy of cardiovascular diseases and antithrombus,they’re also the most widely used anticoagulant drug around the world.Unfractionated heparin（UFH）and low-molecular-weight heparin（LMWH）are traditional heparin drugs which are mainly extracted from animals,they could cause safety issues during usage due to the source diversity,multiple molecular weight and various structures,especially the risk of contamination by microorganism and pathogenic bacteria.Furthermore,traditional heparin therapy could lead to thrombocytopenia and bleeding side effects clinically as a result of their multiple effect targets.Hence people developed synthetic heparin drugs in order to establish safer,more effective heparin-type medicine with fewer side effects,the most famous one of the synthetic heparin drugs is Fondaparinux sodium,in fact,it’s the first and exclusive synthetic heparin anticoagulant oligosaccharide drug（appeared on the market in 2001,the trade name is ARIXTRA）.Fondaparinux sodium has a number of advantages over traditional heparin-type drugs,such as:1)completely chemically synthetic drug with quality criterion more easily to handle,homogenous constituents with lower risk of contamination;2)high selectivity of effect target,it’s the exclusive Xa coagulation factor suppressant,it wouldn’t result in side effects such as thrombocytopenia and bleeding basically;3)longer half-life period（more than 17 hours）and better human bioavailability.Generally speaking,as the first-class heparin drug,Fondaparinux sodium has attracted considerable attention from pharmaceutical chemists and synthetic chemists for a long time due to its excellent antithrombotic efficacy and promising market prospect.Fondaparinux sodium is a challenging target for synthetic chemists due to its structure complexity and numerous synthetic steps,there’re a number of synthetic reports of Fondaparinux sodium at home and abroad for the past three decades.Fully protected pentasaccharide is the crucial precursor and molecular skeleton of Fondaparinux sodium,the chemical modification from fully protected pentasaccharide to target drug has been reported by many literatures and patents with almost same operation procedures and mature methodology,it’s truthfully a formal synthetic route.So that the emphasis of all synthetic work is how to combine five building blocks together efficiently to generate fully protected pentasaccharide with right structure configuration,ensuring each unit links with the certain glycosidic bond,it’s also the research priority of this thesis.This thesis’s work is mainly consituted of two parts:1)modular synthesis of five monosaccharide building blocks including A、B、C、D and E;2)exploration of glycosylations,combination of five building blocks with certain glycosidic linkages to form fully protected pentasaccharide.Generally we employed a[3+2]convergent synthetic strategy to prepare the fully protected pentasaccharide,that is to say,we combine disaccharide AB with trisaccharide CDE together via glycosylation reaction at late stage.In detail,we reported the synthetic research of disaccharide acceptor AB and trisaccharide donor CDE respectively,difficulities in the work come from efficient construction ofβ-glycosidic bond between building block C with D which cost us considerable endeavor,we have employed numerous methods aimed at this goal:1)the glycosylation between building block D（uronic acid type）with building block C;2)the glycosylation between thioglycoside donor and its derivative Schmidt donor with building block C;3)hydrogen-bond inducing approaches including diarylthiourea cocatalyst and 2-picoloyl（Pico）directing group;4)glycosylations based on Neibouring Group Participation（NGP）.Eventually,we have synthesizedβ-linked disaccharide CD efficiently by means of NGP,and we conducted further functional group modification from disaccharide CD,then glycosylation coupling with building block E to generate trisaccharide CDE,final glycosylation with disaccharide AB to deliver fully protected pentasaccharide successfully.Furthermore,we got the commercially available intermediate which has also been reported in literature through saponification of fully protected pentasaccharide,hence,we completed the formal synthesis of Fondaparinux sodium.In a word,our synthesis work utilizes commercially available D-diacetone glucose and D-glucosamine hydrochloride as starting material,the overall steps of our synthetic route including monosaccharide and oligosaccharide are 50,longest linear route is 19-step（counting with building block D）with 1.3%overall yield.Moreover,we implemented the second-generation synthetic research based on the former one aimd at improving some defects in our synthetic scheme,generally we followed the former[3+2]convergent strategy,specifically speaking:1)we utilized1,6-anhydro structure as common intermediate to prepare building block C and E divergently and efficiently,in this way,we optimized the synthesis of building block E dramatically;2)we altered the assembly order of trisaccharide CDE,that is,we introduced the uronic acid at early stage,used highly-functioned building block D coupled with E to deliver disaccharide DE firstly,then we explored the glycosylation between disaccharide DE with building block C（1,6-anhydro type）.Within the process,we employed the Dehydrative glycosylations developed by David Y.Gin to synthesize disaccharide DE more concisely.In the glycosylation exploration aimed at constructingβ-glycosidic bond between building block C and D,we tried numerous donors and corresponding activating conditions,finally we found only in the reaction which trichloroacetimidate is used as donor and catalyzed by tris（pentafluorophenyl）borane,the target trisaccharide CDE could be obtained as major product（more than trisaccharide isomer）,through further chemical modification,we synthesized the common intermediate shared by the first-generation total synthesis.In general,within the 2^nd generation synthesis,we have reduced total operation steps by 6 compared with the former one,in this way we apparently optimized the synthetic scheme of Fondaparinux sodium and elevated its application value further more.