基于螺三元环氧化吲哚的不对称合成及其应用研究

The three membered ring spiro-oxindoles including spiro-epoxyoxindoles, aziridine spiro-oxindoles, spirocyclopropyl oxindoles can be used for the synthesis of bioactive natural products and pharmaceuticals. However, due to its low reactivity and difficulty to be controlled by the chiral catalyst, the asymmetric synthesis from these three membered spiro-oxindoles is a long-standing challenge. Therefore, the asymmetric activation of the three membered ring spiro-oxindoles has become the key problems to be solved urgently in the asymmetric synthesis . Recently, We have developed the asymmetric synthesis of spiro-epoxyoxindoles with indoles and 1- naphthols for the construction of series of chiral oxindole derivatives, two of which have a strong inhibition of autophagy related proteins. On the basis of these work, we'll develop the asymmetric reactions of the three membered oxindoles to obtain the chiral oxindole derivatives by using organocatalysis or organic-metal synergetic catalysis. These new oxindoles will be used for the discovery of the hit or lead compounds.

螺三元环氧化吲哚包括螺环氧化吲哚环氧乙烷、螺环氧化吲哚氮杂环丙烷、螺环丙烷氧化吲哚，可用于活性天然产物和药物分子的合成。但因其反应活性低、选择性难以控制，其不对称合成研究富有挑战，参与的不对称合成鲜见报道。因此螺三元环氧化吲哚的选择性活化成为其不对称合成中亟待解决的关键问题。我们近期报道了螺环氧化吲哚环氧乙烷与吲哚和1-萘酚的不对称反应，构建了系列手性氧化吲哚衍生物，发现了两个分子对自噬相关蛋白具有强烈抑制作用。在此工作基础上，本课题拟利用有机或有机-金属协同催化策略，发展螺三元环氧化吲哚参与的不对称合成新方法，构建手性氧化吲哚衍生物，筛选具有药用前景的苗头化合物或先导化合物。

螺三元环氧化吲哚可用于活性天然产物和药物分子的合成，其反应活性低，有多个反应位点且选择性难以控制，其参与的不对称合成研究富有挑战。本课题执行期间，课题组发现通过简单改变条件可以调控螺环氧化吲哚氮杂环丙烷与1-萘酚的反应历程，实现1-萘酚不对称傅克反应和去芳香化串联环化；发展了不对称有机催化合成高光学纯含氮杂环衍生物的体系，如氨基茚酮、异喹啉酮、N,O杂环；发展了仿生ADPr-N3立体选择性合成和多取代三氮唑合成新方法，设计合成了三氮唑新配体，实现了ADP核糖化模拟多肽构建和铜催化细胞偶联标记，并用于蛋白质ADP核糖化修饰和抗肿瘤活性研究。