有机小分子催化的烯基氟砌块的可控构筑及应用研究

As isostere of amides, vinyl fluorides are versatile building blocks used in drug research and development, however the inconvenient and less selective preparation methods limit their further applications. This project aims to a systematical research of methodologies and applications of regulable vinyl fluorides preparation. The proposal consists of the following three parts: First, we are planning to develop a regulable E1cB reaction involved organocatalytic cascade fluorination system. To do high regio- and stereoselective fluorination of alkenes, conjugated alkenes, and allenes, the mechanism research will be conducted to understand the organocatalysts’ structure and reactivity relationship. Second, these reactions will be applied to the synthesis of applicable bioactive chemicals, such as (Z)-β-fluoro-coniferin under mild conditions. Last but not least, a novel type of HIV-1 protease inhibitors containing vinyl fluoride fragments are proposed. It will not only improve the pharmacodynamics but also reduce the risks of crossing drug resistance. Based on the development of effective methodologies for the preparation of vinyl fluorides, this project will also apply the methods into total synthesis and drug design. It will significantly promote applications of vinyl fluorides in innovative drug development.

烯基氟砌块作为酰胺的电子等排体在药物研发中有着重要作用，然而其繁琐、低选择性的合成方法却限制了它的广泛应用。为此，本项目拟开展烯基氟砌块的可控构筑研究，主要内容包括：（1）构建“有机小分子催化的氟化反应”与“单分子共轭碱消除反应（E1cB）”串联的可调控氟化体系。通过对反应机理的研究，揭示有机小分子催化剂结构与性能之间的一般规律，实现对烯烃、共轭二烯、联烯等底物的区域选择性和立体选择性氟化。（2）将该方法学应用到具有生物活性的烯基氟化物的合成中，在温和的反应条件下实现以氟代松柏甙为代表的目标分子的快速制备。（3）设计以烯基氟砌块为母核的新型HIV-1蛋白酶抑制剂，在改善药代动力学性质的同时，减少交叉耐药性的产生。本项目基于可控构筑烯基氟砌块的方法学，开展了其在全合成和药物分子设计中的应用研究，对拓展烯基氟在新药创制中的应用有重要意义。

本项目开展了烯基氟砌块的可控构筑研究，并将相关技术扩展到杂环骨架构建中。主要包括：（1）构建“有机小分子催化的氟化反应”与“单分子共轭碱消除反应（E1cB）”串联的可调控氟化体系。通过对反应机理的研究，揭示有机小分子催化剂结构与性能之间的一般规律，实现对烯烃的区域选择性和立体选择性氟化。（2）利用高碘试剂氧化、碳氢键官能团化等手段实现了吲哚等杂环骨架的构筑及其区域选择性修饰；（3）将新的方法学应用到生物活性骨架的合成中，降低了前列腺素类药物米索前列醇的生产成本，同时还在利用氟化策略改善其药代性质。本项目基于可控构筑烯基氟砌块的方法学，开展了其在生物活性骨架和药物分子中的应用研究，在相关药物研制过程中有重要意义。