Synthesis of the Heparin-Based Anticoagulant Drug Fondaparinux

• Published in: Angewandte Chemie 2014-09, Vol.126 (37), p.10034-10037
• Main Authors: Chang, Cheng-Hsiu, Lico, Larry S., Huang, Teng-Yi, Lin, Shu-Yi, Chang, Chi-Liang, Arco, Susan D., Hung, Shang-Cheng
• Format: Article
• Language: eng ; ger
• Subjects: Accessibility; Anticoagulants; Antikoagulantien; Chemistry; Drugs; Eintopfreaktionen; Heparin; Heparins; Kohlenhydrate; Pharmaceuticals; Synthesis; Totalsynthese
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201404154

Fondaparinux, a synthetic pentasaccharide based on the heparin antithrombin‐binding domain, is an approved clinical anticoagulant. Although it is a better and safer alternative to pharmaceutical heparins in many cases, its high cost, which results from the difficult and tedious synthesis, is a deterrent for its widespread use. The chemical synthesis of fondaparinux was achieved in an efficient and concise manner from commercially available D‐glucosamine, diacetone α‐D‐glucose, and penta‐O‐acetyl‐D‐glucose. The method involves suitably functionalized building blocks that are readily accessible and employs shared intermediates and a series of one‐pot reactions that considerably reduce the synthetic effort and improve the yield. Kurz und gut: Das synthetische Antikoagulans Fondaparinux, ein Pentasaccharid auf Basis der Antithrombin bindenden Domäne von Heparin, wurde über die bisher kürzeste Route hergestellt. Entscheidende Merkmale der Synthese sind die Anwendung von Eintopfstrategien, der Gebrauch gemeinsamer Zwischenstufen und die effiziente Herstellung von Monosaccharid‐Bausteinen aus kommerziellen Quellen.