手性冠醚是手性识别、手性分子组装研究的重要超分子主体分子。由于手性冠醚分子结构的单一或手性冠醚合成步骤的冗长，严重限制了其在超分子化学研究中的应用。本博士论文致力于建立和发展具有不同类型的手性冠醚分子的催化不对称合成方法，利用简单易得，甚至商业可得的非手性冠醚为原料，通过导向基团和非共价作用策略，实现高效及高对映选择性地直接针对冠醚骨架上惰性C-H键的活化及去对称化，合成多类结构新颖的手性冠醚大环化合物，同时探索其在手性分子识别领域中的应用，拓展和丰富手性冠醚的超分子化学体系。具体工作如下：（1）从廉价易得的氮杂冠醚出发，利用手性磷酸催化的不对称串联[1,n]-氢迁移/环化反应，实现了氮原子α-位C(sp3)-H键活化，以41-95%的产率，83-96%的ee值合成得到了一系列不同环系大小、官能团多样的含四氢喹啉结构的手性氮杂冠醚类化合物。同时，以该类含四氢喹啉结构的手性氮杂冠醚作为手性核磁位移试剂，实现了对含生色基团的手性铵盐和不含生色基团的手性氨基酸类衍生物的对映体拆分，且成功将其应用于药物分子衍生物溶液的ee值测定中。我们还探究了该类主体分子与非手性铵盐在识别、组装与手性传递方面的应用前景。（2）从全氧杂冠醚出发，利用光催化的包含自由基攫氢过程的远程C-H键活化策略，实现了氧原子α-位C(sp3)-H键活化，并通过在体系中加入手性铵盐，借助超分子催化策略初步实现了对产物的手性诱导。目前能以75%的产率，15%的ee值得到含有二氢异苯并呋喃结构的手性全氧杂冠醚。（3）利用手性放大-连接子切断策略，通过两次催化不对称Ugi反应，实现了高对映选择性异吲哚啉酮的合成，并成功构筑了骨架中含氮、氧的类冠醚类手性大环。综上，本论文创新性地从非手性单元出发，借助催化不对称反应，成功合成了一系列结构丰富的手性冠醚类化合物，并尝试探究了其在手性识别领域的应用，为手性超分子大环主体化合物的构筑提供了新的思路。
Chiral crown ethers are important supramolecular hosts for the study of chiral recognition and chiral molecular assembly. Due to the lengthy synthetic steps and lack of structural diversities, chiral crown ethers’ application in the field of supramolecular chemistry have been severely restrained. This doctoral dissertation is devoted to the establishment and development of catalytic asymmetric synthetic methods of different types of chiral crown ether compounds. Starting from easily accessible, even commercially available achiral crown ethers, by connecting directing groups to the crown ethers or supramolecular catalysis strategy, we realized the inert C(sp3)-H bond activation and desymmetrization reaction on the crown ethers’ skeleton and constructed a variety of structurally diversified chiral crown ether compounds. Their application in the field of chiral recognition was investigated, which no doubt expanded and enriched the supramolecular system of chiral crown ethers. The specific work is as follows:(1) Starting from easily accessible azacrown ethers, we constructed chiral azacrown ether hosts through asymmetric tandem [1,n]-hydride transfer/cyclization reaction, which realized the activation and functionalization of α-C(sp3)-H of nitrogen atom with chiral phosphoric acids. A series of chiral azacrown ethers containing the structure of tetrahydroquinoline with different ring sizes and diverse functional groups were synthesized in 41-95% yields and 83-96% ee values. We used these chiral azacrown ether hosts containing tetrahydroquinoline structure as nuclear magnetic shift reagents and resolved racemic chromophore-containing ammonium salts and chromophore-free amino acid derivatives successfully. And these supramolecular hosts could be applied in determining ee value of drug molecule derivatives. The performance of chiral crown ether hosts accompanied with achiral ammonium salts were also explored in the field of recognition, assembly and chirality transfer. (2) Starting from crown ethers without other heteroatoms except oxygen, we realized the α-C(sp3)-H activation of oxygen atom by light-induced remote C-H bond functionalization reaction involving 1,5-hydrogen atom transfer process. With supramolecular catalytic strategy, the stereoselective control of the reaction was achieved by adding chiral ammonium salts to the system. The chiral crown ethers containing the structure of 1,3-dihydroisobenzofuran could be obtained with ee value up to 15%. (3) With chiral amplification-linker cleavage strategy, we achieved the synthesis of highly enantiopure isoindolinones through double catalytic asymmetric Ugi reaction and successfully constructed the crown ether-like chiral supramolecular macrocycle bearing nitrogen and oxygen atoms. In summary, with catalytic asymmetric reactions, we innovatively synthesized varieties of chiral crown ether compounds starting from achiral units, which provided a new methodology to build chiral supramolecular macrocyclic hosts. What’s more, the application of these chiral crown ethers in the field of chiral recognition had been explored.
