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肺炎链球菌9N血清型荚膜多糖三糖中间体的化学合成

Chemical synthesis of trisaccharide intermediates related to Streptococcus pneumoniae serotype 9N capsular polysaccharide

  • 摘要: 肺炎链球菌是诱发肺炎、中耳炎、脑膜炎等多种感染性疾病的关键致病菌,其荚膜多糖作为核心免疫原,是肺炎链球菌疫苗研发的核心靶点。化学合成结构明确、均一的寡糖在多糖免疫活性构效关系解析和新型糖疫苗创制中起着关键作用。本研究实现了9N血清型肺炎链球菌荚膜多糖三糖中间体的高效化学合成。以简单易得的D-甘露糖和D-葡萄糖为起始原料,采用还原端向非还原端合成的策略,通过优化保护基筛选、调控溶剂效应等关键反应条件,成功构建两种1,2-顺式糖苷键,其中1,2-顺式-α-糖苷键的产率可达90%,1,2-顺式-β-糖苷键的产率则提升至原来的3倍,其立体选择性也得到有效改善。此外,在受体糖基位点的邻位羟基引入供电子保护基,解决了氨基糖C4位氧亲核性低的问题,最终分别通过11步和10步的总反应步骤,高效合成两种目标三糖中间体,为肺炎链球菌9N血清型荚膜多糖五糖重复单元及更长链寡糖的制备奠定了坚实基础。

     

    Abstract: Streptococcus pneumoniae (SP) is a key pathogen that induces various infectious diseases such as pneumonia, otitis media, and meningitis. As a core immunogen, its capsular polysaccharide serves as the key target for the research and development of pneumococcal vaccines. The chemical synthesis of structurally well-defined and homogeneous oligosaccharides plays a pivotal role in elucidating the structure-activity relationship underlying the immunological activity of polysaccharides and in the development of novel glycoconjugate vaccines. This study achieved the efficient chemical synthesis of two trisaccharide intermediates of the capsular polysaccharide from Streptococcus pneumoniae serotype 9N. Starting from readily available D-mannose and D-glucose, a reducing-end to non-reducing-end synthetic strategy was adopted. By optimizing key reaction parameters including protecting group screening and solvent effect regulation, two types of 1,2-cis glycosidic linkages were efficiently constructed. Specifically, the yield of the 1,2-cis-α-glycosidic bond reached 90%, whereas that of the 1,2-cis-β-glycosidic bond was tripled, with its stereoselectivity significantly improved. Furthermore, the issue of low nucleophilicity at the C4 position of amino sugars was resolved by the introduction of electron-donating protecting groups at the hydroxy groups adjacent to the receptor glycosylation sites. Eventually, two target trisaccharide intermediates were efficiently synthesized in 11 and 10 total steps, respectively, laying a solid foundation for the preparation of the pentasaccharide repeating unit and longer-chain oligosaccharides of the Streptococcus pneumoniae serotype 9N capsular polysaccharide.

     

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