New synthetic methods for the preparation of carbohydrate-based vaccines

描述（由申请人提供）：糖生物学和糖医学进展的主要障碍是缺乏纯的和结构明确的碳水化合物和糖缀合物。在许多情况下，定义明确的寡糖只能通过化学合成获得。不幸的是，没有通用的方法可用于制备具有生物学重要性的复合碳水化合物，并且主要的绊脚石之一是缺乏用于立体选择性形成1，2-顺式糖苷的可靠方法。我们的初步研究表明，用手性助剂如（S）-（苯硫基甲基）苄基醚取代的糖基供体可用于立体选择性引入1，2-顺式糖苷如α-葡糖苷和α-半乳糖苷。邻基参与的手性助剂导致一个准稳定的异头锍离子，这是由于空间和电子因素形成的反式十氢萘环系统。通过羟基置换<$-锍离子导致立体选择性引入α-糖苷。本申请的目的是进一步开发合成方法，并将其应用于制备具有开发为疫苗潜力的寡糖。将确定助剂与常用糖基化方案和保护基团操作的相容性。辅助为基础的方法将扩展到各种各样的1，2-顺式糖苷的引入。新一代的手性助剂将被开发，具有更好的性质，如更好的酸稳定性，在敏感保护基团存在下的选择性可去除性，以及与高活性糖基供体相容。最后，新的方法将被应用于合成的寡糖来自弗朗西斯菌tularensis和炭疽杆菌，这是A类生物恐怖主义剂。将进行免疫学实验以确定合成化合物是否可用作候选疫苗。公共卫生相关性：糖生物学和糖医学发展的一个主要障碍是缺乏纯的和结构明确的碳水化合物。建议开发新的合成方法来制备定义明确的复杂碳水化合物。新方法将用于制备来源于病原体的寡糖，这些病原体被归类为A类生物恐怖主义制剂。将进行免疫学实验以确定合成化合物是否可用作候选疫苗。

DESCRIPTION (provided by applicant): A major obstacle to advances in glycobiology and glyco-medicine is the lack of pure and structurally well-defined carbohydrates and glycoconjugates. In many cases, well-defined oligosaccharides can only be obtained by chemical synthesis. Unfortunately, no general method is available for the preparation of complex carbohydrates of biological importance and one of the main stumbling blocks is the lack of a reliable methodology for the stereoselective formation of 1,2-cis-glycosides. Our preliminary studies have shown that a glycosyl donor substituted with a chiral auxiliary, such as a (S)-(phenylthiomethyl)benzyl ether, can be employed for the stereoselective introduction of 1,2-cis glycosides such as a-glucosides and a-galactosides. Neighboring group participation by the chiral auxiliary leads to a quasi-stable anomeric sulfonium ion, which due to steric and electronic factors is formed as a trans-decalin ring system. Displacement of the ¿-sulfonium ion by a hydroxyl leads to the stereoselective introduction of a-glycosides. The aim of this application is to further develop the synthetic methodology and apply it to the preparation of oligosaccharides that have the potential to be developed as vaccines. The compatibility of the auxiliaries with commonly used glycosylation protocols and protecting group manipulations will be established. The auxiliary based methodology will be extended to the introduction of a wide variety of 1,2-cis-glycosides. A new generation of chiral auxiliary will be developed with improved properties such better acid stability, selective removable in the presence of sensitive protecting groups, and compatible with highly reactive glycosyl donors. Finally, the new methodology will be applied to the synthesis of oligosaccharides derived from Francisella tularensis and Bacillus anthracis, which are category-A bio-terrorism agents. Immunological experiments will be performed to establish whether the synthetic compounds can be employed as vaccine candidates. PUBLIC HEALTH RELEVANCE: A major obstacle to advances in glycobiology and glyco-medicine is the lack of pure and structurally well-defined carbohydrates. It is proposed to develop new synthetic methodologies for the preparation for well-defined complex carbohydrates. The new methodology will be applied to the preparation of oligosaccharides derived from pathogens, which are classified as category-A bio- terrorism agents. Immunological experiments will be performed to establish whether the synthetic compounds can be employed as vaccine candidates.