基于导向策略的钯催化立体选择性构建C-芳基糖苷的研究

C-glycosides derivatives are important molecular scaffolds that widely occur in various biologically active natural products and drug molecules. At present, the development of highly efficient and stereospecific method for the synthesis of saturated C-aryl glycosides is an outstanding challenge that must be addressed. Recently, directing strategy has been employed to promote the regio- and stereoselectivities in chemical reactions, and it has been used for the construction of O- and N-glycosides. However, saturated C-aryl glycosides had not been achieved by using this strategy. Due to the anomeric organometallics can easily undergo a β-elimination process. The aim of this project is to stabilize the saturated anomeric organometallics by coordinated with the directing group. As a consequence, the anomeric organometallics could then coupling with aryl metal species to the stereoselective synthesis of C-aryl glycosides. The following topics will be investigated: diastereoselective palladium-catalyzed synthesis of saturated a- and β-C-aryl glycosides based on directing strategy. Besides, natural products Aspalathin, Chafurosides A and B will be constructed by using this methodology. Finally, the mechanism of this C-glycosylation reaction will be investigated. We expect that this project to providing an efficient method in stereospecific synthesis of C-glycosides and a new way for total synthesis of C-glycoside natural products.

C-芳基糖苷是许多具有生物活性天然产物和药物分子的重要骨架结构。目前，发展高效的催化手段立体选择性合成饱和C-芳基糖苷是一个关键而又亟待解决的问题。导向策略已被发展用于调控有机反应的区域和立体选择性，利用该策略可实现O-和N-糖苷的立体选择性合成，但其在饱和C-芳基糖苷合成中的应用还未被实现。针对饱和异头位有机金属物种容易发生β消除的特点，本课题拟利用导向基团的诱导作用稳定异头位金属物种从而抑制β消除，使其与芳基金属试剂发生偶联反应，实现饱和C-芳基糖苷的立体选择性构建。研究内容包括：在钯催化下，通过导向基的调控立体选择性合成a和β型饱和C-芳基糖苷，并将该方法学应用于天然产物Aspalathin, Chafurosides A和B的全合成中。此外，我们还将对反应机理进行深入研究。本项目的完成将为C-糖苷的立体选择性合成提供新思路，为复杂含糖天然产物的全合成提供新途径。

C-糖苷骨架结构在许多具有生物活性天然产物和药物分子中广泛存在。因此，发展高效合成C-糖苷骨架的方法受到巨大的关注。在项目资助期间，我们利用过渡金属催化碳碳键的构建发展了一些C-糖苷的合成新方法，主要包括：钯催化2-碘代糖烯和对甲苯磺酰腙的偶联反应合成2-碳支链糖。2-碳支链糖缀合物和丙烯酸甲酯可以较好地发生Diels−Alder反应，以中等偏上的产率得到含有碳苷结构的氧杂十氢化萘骨架；钯催化的C-糖苷化和亲核环化反应合成3-吲哚基-C-糖苷，产物进一步衍生化可以立体选择性专一地得到2-脱氧-C-吲哚糖苷；邻二苯基膦苯甲酸酯(o-DPPB)导向作用下立体选择性合成C-糖苷。与此同时，通过分子内碳钯化和环异构化串联反应，我们发展了一种合成含吲哚嗪和吲哚嗪酮类双杂环骨架的方法。通过本项目的实施，共发表SCI论文5篇，申请发明专利2篇。相关研究结果对糖苷以及杂环化合物的合成具有重要参考价值。