CHEMICAL SYNTHESIS AND STRUCTURE OF BACTERIAL POLYSACCHARIDES

这项工作一直致力于发展固相法 用于合成与奈瑟氏球菌荚膜相关的寡糖 A群脑膜炎 长期目标是为研究提供工具 糖-蛋白质缀合物抗原性的几个结构方面。 为此，设计了一种方案，该方案允许合成 在还原末端带有连接臂的确定长度的寡糖 终止于可用于偶联的硫醇。 的合成 固相载体和所需的反应性单体已经 完成 在过去的一年中， 已完成，并研究了几个突出问题。 到 使合成效率最大化希望的是，唯一的固相- 结合的亲核位点是在二硫键连接的间隔基末端的那些， 然而，在大量的实验中，已经发现， 这些位点被氧化剂裂解。 一小部分遗址 不能被还原剂裂解。因此，分析方法 被开发来研究这些问题。固相化学 也被重新审视。 四个密切相关的分离 反应性单体的非对映异构体已经完成，并且它们已经 通过1H NOE NMR表征。 这些研究证实了 化学位移相似性的基础上，并确认 苄基在保护这类亚磷酸酯方面的优越性 化合物。 从磷酸酯中除去苄基保护基 糖的4位是很难的。 模型化合物具有 合成并用于测试几种已发表的脱保护 战略布局 迄今为止，催化氢化、转移氢化、 电化学氧化，间接电化学还原，游离 电子还原和与三甲基碘硅烷裂解已被发现 无法使用。 取代二硫键所需的化学反应 正在考虑连接器。

This work has been directed towards the development of a solid phase method for the synthesis of an oligosaccharide related to the capsule of Neisseria meningitidis group A. The long-term aim is to provide a tool for the study several structural aspects of saccharide-protein conjugate antigenicity. Toward this end, a scheme has been devised which allows the synthesis of defined length oligosaccharides bearing, at the reducing end, a linker arm terminating in a thiol that could be used for coupling. The synthesis of the solid phase support and the required reactive monomers has been completed. In the past year synthesis of a protected hexasaccharide has been completed, and several outstanding problems have been studied. To maximize efficiency of synthesis it is desirable that the only solid phase- bound nucleophilic sites be those at the end of a disulfide linked spacer, however in a large number of experiments it has been found that 30-50% of the sites are cleaved by oxidizing reagents. A fraction of the sites cannot be cleaved by reducing reagents. Analytical methods have therefore been developed to study these problems. The chemistry of the solid phase has also been reexamined. Separation of the four closely related diastereomers of the reactive monomer has been completed and they have been characterized by 1H NOE NMR. These studies confirm the assignments made earlier on the basis of chemical shift similarities and confirm the superiority of the benzyl group for protecting the phosphite in this class of compounds. Removal of the benzyl protecting group from the phosphate and the 4-position of the sugar has been difficult. Model compounds have been synthesized and used to test several published deprotection strategies. To date, catalytic hydrogenation, transfer hydrogenation, electrochemical oxidation, indirect electrochemical reduction, free electron reduction, and cleavage with trimethylsilyl iodide have been found to be unusable. The chemistry required to replace the disulfide bond in the linker is being considered.