手性磷酸共价有机框架材料的构建及其不对称催化氧化性能研究

Chiral drugs have been at the cutting-edge of pharmaceutical industry, and their global sales have reached hundreds of billions of dollars, about 60% of which are single optically active compounds. Utilizing asymmetric catalysis to precisely prepare optically pure compounds with specific single chiral site has become a key technology in their production. The proposed work aims at the vital issues of low efficiency, high cost of catalyst in the asymmetric catalytic oxidation of chiral sulfoxide drugs and the separation and left-over of the catalyst under the conditions of homogeneous reaction. In view of the catalytic sites associated with chiral phosphoric acids as well as confined space of COFs, an organic chiral phosphoric acid catalyst monomer with asymmetric catalytic oxidation of thioethers is introduced directly into a covalent porous frameworks (COFs) by means of "bottom up" strategy to form a chiral COFs phosphoric acid catalyst. Given the core issues of the efficiency and selectivity of asymmetric catalytic oxidation of thioethers, the proposal focuses on the construction and development of a new type of chiral COFs phosphoric acid catalytic system through detailed investigation of their key regulatory factors and mechanism in asymmetric oxidation of thioethers. The successful implementation of this project is expected to provide scientific basis and practical applications for the efficient and clean preparation of chiral sulfoxide drugs.

手性制药是医药行业的前沿领域，目前约60%的上市药物为单一光学活性体，手性药物的销量已经达到数千亿美元。不对称催化精准制备具有特定单一手性的光学纯化合物已成为其生产的关键技术。本项目针对手性亚砜类药物不对称催化氧化过程中催化剂效率低、成本高，以及均相反应条件下催化剂分离困难和残留等关键问题，利用手性磷酸的催化功能位点和COFs材料受限空间的立体效应，通过“bottom up”的合成方法，将具备硫醚不对称催化氧化功能的有机手性磷酸单体作为构建砌块直接引入到COFs材料中，形成高催化位点密度的共价多孔框架催化材料，围绕硫醚不对称催化氧化的效率和选择性等核心问题，建立和发展新型手性COFs磷酸催化体系，从反应动力学和反应机理出发研究手性COFs磷酸催化硫醚不对称氧化的关键调控因素。研究结果有望为手性亚砜类药物高效清洁制备提供科学基础和应用参考。

手性亚砜类药物是一类重要的生物活性结构，是药物生产与设计中重要的母核结构。因此实现该类化合物的高效构建能极大的促进化学工业与制药工业的发展，促进新药的发现与合成。硫醚不对称氧化是众多合成手性亚砜途径中最高效的方法之一。本项目针对有机小分子催化剂在不对称氧化过程中效率低、成本高，以及均相反应条件下分离困难和残留等关键问题。通过“bottom up”的合成方法，将手性磷酸等功能化位点引入到有机框架材料骨架中，利用框架材料的孤立效应和受限空间的限域效应，形成具有高催化位点密度的共价有机框架材料。围绕硫醚氧化的效率和选择性等核心问题，建立和发展了基于框架材料的新型选择性氧化体系。并且从反应动力学和反应机理出发研究该类催化剂催化硫醚不对称氧化的关键调控因素。项目取得成果为快速开发高效催化氧化催化体系和手性亚砜类药物的高效制备提供科学基础和应用参考。在本项目资助下，发表了12篇SCI学术论文；申请和授权发明专利6件；指导和协助指导博士生7名，培养硕士生5名；参加国内外学术会议30人次；项目负责人入选2019年度“长江学者奖励计划”特聘教授。