肝素三糖和四糖衍生物的高立体选择性合成  

Highly stereoselective synthesis of heparin tri-and tetra-saccharide derivatives

作　　者：代元伟 刘威 徐鹏[1] 俞飚[1] Yuanwei Dai;Wei Liu;Peng Xu;Biao Yu(State Key Laboratory of Bioorganic and Natural Products Chemistry,Shanghai Institute of Organic Chemistry,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200032,China;Chongqing Key Laboratory of Natural Product Synthesis and Drug Research,School of Pharmaceutical Sciences,Chongqing University,Chongqing 401331,China;School of Physical Science and Technology,Shanghaitech University,Shanghai 201210,China)

机构地区：[1]中国科学院上海有机化学研究所,生命有机化学国家重点实验室,上海200032 [2]重庆大学药学院,天然产物全合成与创新药物研究重庆市重点实验室,重庆401331 [3]上海科技大学物质科学与技术学院,上海201210

出　　处：《中国科学：化学》2023年第3期529-536,共8页SCIENTIA SINICA Chimica

基　　金：国家自然科学(编号:22177125);国家重点研发计划(编号:2018YFA0507602);中科院青年创新促进会(编号:2020258)资助项目。

摘　　要：肝素是一种高度硫酸化的天然黏多糖类物质,可以介导各种生理和病理过程,临床上主要用于预防和治疗静脉血栓症.本文报道了一条利用正交保护基策略,高立体选择性合成肝素寡糖的路线,获得7个氨基葡萄糖基6-O-硫酸化修饰程度不同的肝素三糖和四糖衍生物(28~34).该路线采用叔丁基二苯基硅基(TBDPS)作为叠氮葡萄糖砌块伯羟基的保护基,利用N-苯基三氟乙酰亚胺酯给体,实现了关键的GlcN-(1→4)-GlcA糖苷键的高α选择性的构建;利用[1+2]和[2+2]糖苷化策略,合成了4个全保护的肝素三糖和四糖前体;采用优化的保护基脱除和硫酸化操作,高效便捷地获得目标肝素三糖和四糖.这一系列肝素寡糖衍生物在还原端带有氨基为端基的连接臂,为制备肝素类寡糖芯片,系统性研究肝素寡糖与蛋白,如乙酰肝素酶的相互作用打下了基础.Heparin,a naturally highly sulfated glycosaminoglycan,mediates various physiologic and pathophysiologic processes,and is mainly used for the prevention and treatment of venous thrombosis in clinic.Here we report an efficient synthesis of heparin oligosaccharides with different degrees of 6-O-sulfonation modification,employing orthogonal protective group strategy.tert-Butyldiphenylsilyl(TBDPS)group is used as the protective group of 6-OH of the 2-azide-glucose donors,and highlyα-selective construction of the key GlcN-(1→4)-GlcUA glycosidic bond was achieved with the corresponding N-phenyl trifluoroacetimidate donors.Thus,tri-and tetra-saccharides are synthesized by the convergent[1+2]and[2+2]glycosylation.The fully elaborated oligosaccharides have then been successfully transformed into the target heparin oligosaccharides 28–34 via an optimal sequence of manipulation of the protecting groups.The post-assembly manipulations include desilylation with HF·Py(for removal of TBDPS group),delevulinoylation with hydrazine hydrate(for removal of levulinoyl group),saponification under Zemplén conditions(for removal of methyl ester and benzoyl group),O-sulfonation with sulfur trioxide pyridine complex(for hydroxyl groups),reduction and N-sulfonation(for azido group),and atmospheric pressure hydrogenation(for removal of benzyl and Cbz groups).The availability of these heparin oligosaccharide derivatives which bear amino linker shall facilitate the preparation of glycan chips for studies on the interaction between heparin oligosaccharides with proteins,such as the heparanase.

关 键 词：肝素寡糖 叔丁基二苯基硅基 N-苯基三氟乙酰亚胺酯给体 α选择性糖苷化 

分 类 号：TQ464[化学工程—制药化工]