Abstract:

Heparin(HP) is composed of sulfated disaccharide-repeating units of either L-iduronic acid(IdoA) or D-glucuronic acid(GlcA) linked glucosamine(GlcN) residue. It is well established that heparin plays crucial roles in various physiological processes, such as blood anticoagulation, viral infection, inflammatory response, cell adhesion, cell growth regulation, and tumor metastasis. Since the discovery of the specific AT Ⅲ-binding pentasaccharide domain of heparin, the strategies toward total synthesis of pentasaccharide analogues emerged rapidly. Fondaparinux sodium, as a chemically synthesized ultralow molecular weight(ULMW) heparin pentasaccharide, has been clinically used as an antithrombotic drug for the specific AT Ⅲ-binding property. The chemical synthesis of fondaparinux needed more than 50 steps with an overall yield of ca. 0.1%. And the β-stereospecific synthesis of glucuronic acid has always been a big challenge in the synthetic process of fondaparinux sodium because of the absence of neighbouring group participation effect. Herein, seven glycosyl donors based on glucose and glucuronic acid, in which the 2-OH was protected by 2-cyanobenzyl(BCN) group, were prepared. A series of glycosyl acceptors was utilized to examine the effect of β-stereoselectivity mediated by BCN group in dichloromethane(DCM) and toluene(Tol). The NMR results of these correspon-ding products have indicated that the BCN group participation and solvent effect can efficiently improve the ratio of α/βanomer. The ratio of the glycosylation products was more than 1∶10, and the most was 1∶50. This research has built a set of solid theoretical basis for the synthesis of fondaparinux sodium.

Key words: Glucuronic acid, 2-Cyanobenzyl group, β-Stereoselectivity;, Fondaparinux sodium, Glycosylation