基于多组分反应及多重串联策略高效合成稠环吲哚类化合物

The fused indoline natural product have a variety of biological activities and attract the interest of a wide range of synthetic chemists. Therefore, it is essential to develop a simple, rapid and efficient synthesis method. Among them, the combination of multi-component reaction and multiple tandem reactions such as de-aromatization/nucleophilic extraction and alkynyl activation can skillfully form a plurality of chemical bonds in a single pot, and can efficiently synthesize complex heterocyclic compounds while reducing energy loss, in line with the green chemical concept. There are two major challenges in this kind of reaction, namely, the scope of application and chemical selectivity. In recent years, applicant has been engaged in the study of multi-component tandem reactions for the efficient synthesis of skeleton-rich nitrogen-containing heterocyclic compounds by one-pot method. This project aims to apply Ugi multi-component reactions to the synthesis of fused ring indole alkaloids in Pd-mediated multiple tandem catalytic systems to expand the substrate range of this type of reaction and solve the problem of reaction selectivity. By exploring the application of this strategy in the synthesis of complex fused alkaloids, this project will develop novel, efficient, simple, atomic and economical catalytic systems and reaction methodologies that apply to the rapid and large-scale synthesis of structurally active molecules in order to establish a library of compounds for biological activity screening.

稠环吲哚类天然产物具有多种多样的生物活性，吸引了广大合成化学家的兴趣，因此发展一种简洁、快速、高效的合成方法至关重要，其中将多组分反应与金属催化的去芳构化/亲核攫取以及炔基活化等多重串联反应结合可以巧妙地使多个化学键一锅连续形成，能够高效合成复杂杂环化合物，同时降低能量的损耗，符合新时代绿色化学理念。该类反应存在两大挑战，即反应的适用范围和化学选择性。近年来，申请人一直从事多组分串联反应的研究，一锅法高效合成骨架多样性的含氮杂环化合物。本项目旨在将 Ugi 多组分反应运用于 Pd 介导的多重串联催化体系中合成稠环吲哚生物碱，拓展该类反应的底物范围，解决反应选择性的难题。通过探索该策略在复杂稠合吲哚生物碱合成中的应用，发展新颖、高效、简捷、原子经济性的催化体系和反应方法学，并应用于结构多样性的活性分子的快速、大量合成，以期能建立供生物活性筛选的化合物库。

稠环吲哚类天然产物以及含氮杂环小分子化合物具有多种多样的生物活性，其简单、高效、绿色的合成方法研究具有重要的意义。本项目完成了多重Heck型去芳构化构建稠合的七元含氮杂环螺环吲哚化合物，将不同类型的Ugi加合产物用于Pd介导的多重串联反应合成稠环吲哚，成功拓展该类反应的底物范围，提高了底物的多样性。通过调控Ugi反应，将不同的活性基团组装到Ugi加合产物中，然后筛选Pd前体种类、磷配体的电子云密度、溶剂、添加剂等，从而改变多重串联反应的反应历程，提高了Pd介导的多重串联策略构建稠合吲哚环的选择性难题。此外，基于前期的研究工作，完成了多组分串联环化反应高效构建C(sp3)-N键、铜催化的脱羧还原偶联合成吲哚二芳基甲烷衍生物以及氧化/去芳构化合成多环螺吲哚醌、无金属催化的还原偶联合成具有抗癌活性的吡啶化二芳甲烷衍生物，实现了含氮杂环小分子化合物的简单高效合成，快速构建小分子化合物库。将合成的化合物进行生物活性测试，拓展了该类化合物的应用前景。