催化不对称碳-氢官能团化研究

Enantiopure ɑ-substituted nitrogen- and oxygen-containing heterocycles, like tetrahydroisoquinolines (THIQs), tetrahydroquinolines (THQs), piperidines, isochromans, and tetrahydrofurans (THFs)， are one of the most common structural motifs spread across biologically active natural products and synthetic pharmaceuticals. However, to the best of our knowledge, no asymmetric catalysis has been reported for the synthesis of such molecules through C-H functionalization of oxygen-containing or N-acyl heterocyclic substrates. In the proposal, two strategies are designed to enantioselectively construct a variety of ɑ-substituted oxygen- and nitrogen-containing heterocycles relying on "cation pool" protocol and triphenylcarbenium ion mediated mild C-H functionalization method. By using "chiral nucleophile" strategy, a variety of heterocycles will be coupled with terminal alkynes and β-dicarbonyl compounds, respectively, in the presence of suitable chiral catalyst. By using "chiral counterion" strategy, the heterocyclic substrates will be coupled with a wide range of organoboranes and C-H nucleophiles, respectively, under the catalysis of suitable chiral Lewis acid. Subsequently, the "chiral counterion" strategy will be applied as the key step in the asymmetric total synthesis of natural product (+)-deoxyfrenolicin possessing potent antifungal and antivirus activities. The synthetic efficiency here is expected to be improved compared to the shortest synthetic route to date for the molecules, indicating that the approach developed herein should have potential applications in complex molecule synthesis, and will open a new synthetic strategy for future efforts in the synthesis of molecules containing such structures.

光学纯的ɑ-取代的氮杂环和氧杂环结构广泛存在于活性天然产物和药物分子中，例如四氢（异）喹啉、哌啶、异色满和四氢呋喃。但到目前为止，还没有通过对氧杂环或N-酰基杂环底物的C-H修饰，构建上述结构的不对称催化体系的报道。本课题拟发展一个以"碳正离子池"和三苯甲基碳正离子介导的C-H修饰为基础的不对称催化体系，通过分别运用"手性亲核试剂"和"手性离子对"两种策略，实现上述一系列氧杂环和氮杂环分别与末端炔和β-二羰基化合物（"手性亲核试剂"策略）以及多种有机硼试剂和C-H亲核试剂（"手性离子对"策略）的不对称偶联，对映选择性的合成结构多样的ɑ-取代杂环衍生物。然后应用此方法，对具有重要抗菌和抗病毒活性的天然产物(+)-deoxyfrenolicin进行不对称全合成研究。拟发展一条比已知最短路线更有效的合成策略，验证该方法在复杂分子合成中的应用潜能，为含上述结构的复杂分子的合成提供新的思路。

光学纯的alpha-取代醚和胺广泛存在于活性天然产物和药物分子中。从廉价易得的醚或胺出发，通过对醚或胺邻位sp3碳氢键的选择性官能化，构建上述骨架，较依赖官能团转化的传统合成策略，在步骤经济和原子经济性方面均具有较为明显的优势，符合理想合成的定义。为此，本项目围绕这一主旨，通过发展新反应、新策略和新试剂，从区域、立体和对映选择性三方面，系统的对一系列结构多样的醚和胺邻位sp3碳氢键官能化进行了探讨，取得了较为突出的创新性成果。（1）发展了温和的氧化体系，实现了包括四氢吡啶、四氢异喹啉、二氢喹啉、四氢-β-咔啉和甘氨酸酯等胺类底物以及四氢呋喃、四氢吡喃、乙醚和苯并吡喃等醚类底物的选择性碳氢官能团化。（2）设计、发展了一个“缩醛池”策略。通过应用“缩醛池”策略，实现了对一系列胺和醚邻位sp3 碳氢键的催化不对称氧化官能化，包括四氢异喹啉的催化不对称氧化碳氢炔基化、烷基化、烯基化和芳基化；四氢-β-咔啉和四氢吡啶的有机催化不对称碳氢烯基化和芳基化；二氢喹啉的催化不对称烷基化；甘氨酸酯的催化不对称碳氢炔基化；四氢呋喃、四氢吡喃、乙醚和苯并吡喃等的催化不对称碳氢烷基化。（3）通过应用“缩醛池”策略，实现了结构多样的苯并吡喃和吲哚并吡喃等环醚的氧化去外消旋化。（4）实现了烷氧自由基引导的远端未活化sp3 碳氢键的氟化、氯化、胺化和炔基化。上述方法在具有生物活性的天然产物的不对称全合成或形式合成中均展示出了较传统策略更好的步骤经济性。在该领域以通讯作者身份共发表论文30篇，其中包括Angew. Chem. Int. Ed. 4 篇，Nature Communications 1 篇，Organic Letters 9 篇，Chemical Communications 3 篇，Advanced Synthesis & Catalysis 1 篇，Organic Chemistry Frontiers 1 篇，Chinese Journal of Chemistry 1 篇，Organic & Biomolecular Chemistry 6 篇。这些创新成果为选择性的碳氢官能团化研究提供了新的、独特的见解和发展方向，并为拓展该领域的适用范围及推动其在真实合成和药物化学研究中的应用做出了重要贡献。