五价磷催化的Mitsunobu反应研究

Mitsunobu反应具有反应条件温和、官能团兼容性好且立体专一性强等特点，在药物分子和天然产物的合成中广泛应用，但反应过程需使用当量的三价膦和偶氮化合物原子经济性差，同时反应结束后生成的副产物增加了分离的难度。本项目拟发展催化的Mitsunobu 反应, 以提高该反应的原子经济性，实现其绿色化学。本研究从反应的机理出发，旨在设计和合成五元环状的五价磷化合物作为催化剂来催化Mitsunobu反应。根据和磷中心相接的杂原子的不同我们拟选用四种不同的催化剂，并通过实验和计算化学辅助相结合的方法寻找到适合的催化剂并将此催化剂应用到C–O、C–N、C–S等化学键的构建以及一些药物分子或药物中间体的合成。通过合成反应中间体以及对反应过程中核磁磷谱追踪来验证此反应的机理。因此，本项目具有重要的理论价值和实际应用意义。

Mitsunobu reaction has been widely used in the synthesis of drug molecules and natural products featuring its mild reaction conditions, broad functional group compatibility and good stereospecificity. However, this reaction requires equivalent trivalent phosphine and equivalent diazo compound，which is not atomic economy. At the same time, the byproducts are difficult to separate. This project mainly develops catalytic Mitsunobu reaction which is satisfied with atomic economy and green chemistry. Herein, we design five-membered ring phosphorus(V) compounds as catalysts to catalyze Mitsunobu reaction. Starting from the reaction mechanism, this study aims to find the suitable catalyst to catalyze Mitsunobu reaction. According to the hetero atoms link to the P center, we will choose four different kinds of catalysts. We will combine experimental and computational chemistry (DFT) for this study and apply this method for the construction of chemical bonds such as C-O, C-N, C-S bonds as well as the synthesis of some drug molecules or drug intermediates. The mechanism will be verified by synthesizing reaction intermediates and tracing phosphorus NMR during the reaction. Therefore, this project has important theoretical value and practical significance.