title: Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium.
abstract: The practical formal synthesis of the anticoagulant drug fondaparinux sodium 1 was accomplished using an optimized modular synthetic strategy. The important pentasaccharide 2, a precursor for the synthesis of fondaparinux sodium, was synthesized on a 10 g scale in 14 collective steps with 3.5% overall yield from well-functionalized monosaccharide building blocks. The strategy involved a convergent [3 + 2] coupling approach, with excellent stereoselectivity in every step of glycosylation from the monosaccharide building blocks. Efficient routes to the syntheses of these fully functionalized building blocks were developed, minimizing oligosaccharide stage functional-group modifications. The syntheses of all building blocks avoided rigorous reaction conditions and the use of expensive reagents. In addition, common intermediates and a series of one-pot reactions were employed to enhance synthetic efficiency, improving the yield considerably. In the monosaccharide-to-oligosaccharide assembly reactions, cheaper activators (e.g., NIS/TfOH, TESOTf, and TfOH) were used to facilitate highly efficient glycosylations. Furthermore, crystallization of several monosaccharide and oligosaccharide intermediates significantly simplified purification procedures, which would be greatly beneficial to the scalable synthesis of fondaparinux sodium.
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Dai
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Chunwei
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Shuqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Innovative Drug Research Centre, Chongqing University , Chongqing, 401331, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Tang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Song
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Qin
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry; D003460:Crystallization; D000077425:Fondaparinux; D006031:Glycosylation; D015394:Molecular Structure; D011134:Polysaccharides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000925:Anticoagulants; D011134:Polysaccharides; D000077425:Fondaparinux