光催化碳碳键断裂反应在天然产物nepalactone A, deoxycollybolidol和Jiadifenolide全合成中的应用

Total synthesis of natural products have been driving the development of modern synthetic methodologies. Of the current catalytic systems, photoredox catalysis has emerged recently as a powerful tool for the efficient construction of molecular complexity in natural product synthesis. [3.2.1]-octane bridged lactone skeleton widely exists in bioactive natural products like deoxycollybolidol, Nepalactone A and Jiadifenolide etc. The unique skeleton has been demonstrated to be crucial to their interesting bioactivities. However, no systematic study has been reported for the concise construction of this important molecular skeleton. Intrigued by the unique photoredox properties of cerium complex, we plan to develop a new paradigm for establishing the bridged lactone core utilizing a photocatalytic C-C bond cleavage reaction. We anticipated that the coordination complex of Ce(IV) species and cycloalkanols generated in situ could be readily photoexcited through the ligand to metal charge transfer process, and subsequently undergo Ce(IV)−OR homolysis to generate the transient alkoxy radical. The highly reactive alkoxy radical could then promote the challenging β-scission cleavage to afford a carbon-centered radical, which could be efficiently trapped by Michael acceptors and further cyclized to form the expected [3.2.1]-octane bridged lactone. This process provides a general catalytic platform for a one-step synthesis of the bridged lactone through direct homolytic activation of simple cycloalkanols under mild conditions, and finally offers a very promising key reaction in the concise total syntheses of the above three natural products.

天然产物的全合成不断推动着合成反应方法学的发展。在当前发展的一系列催化体系中，可见光催化近年来逐渐成为高效的合成复杂分子的一种强大手段。[3.2.1]-辛烷桥环是天然产物中一种较为常见的骨架结构，如nepalactone A、 deoxycollybolidol和Jiadifenolide等。该桥环骨架与它们潜在的重要生理活性有着十分紧密的联系，但是迄今尚未有构建该类骨架的系统方法学报道。我们计划利用铈复合物独特的光学性质，在可见光催化条件下，现场生成的四价铈和环醇的配合物通过光激发的配体到金属跃迁过程，生成高活性的烷氧自由基，随后发生环醇β位碳碳键裂解，生成的碳自由基被Michael受体捕获，并进一步环化生成桥环内酯。利用该铈催化的碳碳键断裂反应，通过后续转化设计，我们从简单的环醇出发，就可以一步合成桥环骨架结构，应用于以上三个天然产物的全合成中。

本项目利用铈催化的环醇碳碳键断裂反应作为关键反应对三个天然产物的合成进行了探索。在可见光光照条件下，我们利用铈催化剂和有机光催化剂的协同作用，发展了由简单的环丁醇底物和Michael受体发生环醇扩环反应来一步构筑[3.2.1]-桥环内酯骨架的合成方法，并完成了天然产物nepalactone A和Jiadifenolide的三环骨架合成。通过本项目研究，我们发现在反应体系中引入含蒽骨架有机光催化剂（如9,10-二苯基蒽等）能大幅提高铈催化反应效率，使该体系能够被应用于一些活性较低的缺电子双键底物中，拓展了该反应潜在的合成应用价值。此外，我们还尝试利用铈催化剂固有的Lewis酸性，在反应体系中引入含氮配体等添加剂来改善反应的非对映选择性，遗憾的是，在上述三个天然产物的合成探索过程中，我们尚未找到对该反应体系的立体选择性控制比较理想的解决方案，这为后续铈催化体系与其他过渡金属催化模式相结合提供了前期的研究基础。