自由基参与的分子内不对称碳氢键胺化反应的研究

RESEARCH ON RADICAL-INVOLVED INTRAMOLECULAR ASYMMETRIC C-H AMINATION

田宇

11749231

硕士

化学

刘心元

2019-05-25

2019-07-10

哈尔滨工业大学

深圳

手性含氮杂环是众多天然产物、药物以及生物活性分子结构的重要组成单元，因而发展高效的不对称催化方法来合成手性含氮杂环化合物受到了化学家们越来越多的关注。相较于传统的合成方法，近年来发展的不对称碳氢键胺化反应因其高反应效率和原子经济性成为了该领域研究的热点。然而，目前成功发展的过渡金属催化的碳氢键活化和金属氮宾插入碳氢键等策略往往需要使用钯、铱、铑等贵金属作为催化剂，反应的底物范围也有一定的局限性，因此亟需发展其它高效的不对称碳氢键胺化反应克服现有合成方法的缺陷。刘心元教授课题组之前成功发展了金属铜/手性磷酸协同催化体系实现了自由基进攻烯烃引发的非活性烯烃不对称双官能团化反应。本文利用铜/手性磷酸协同催化体系实现了分子内的不对称碳氢键胺化反应来高效地构建手性含氮杂环化合物。使用偕二取代的脲类芳基化合物作为底物，通过系统的反应条件（铜盐、手性磷酸、氧化剂、NHPI衍生物、添加剂、溶剂等）筛选，成功地实现了自由基参与的分子内非活性碳氢键不对称胺化反应。实验结果表明合适的氧化剂，添加剂和经修饰后的手性磷酸对反应的效率和对映选择性的提高都起到了十分重要的作用。在对反应的普适性考察中，发现苯环上可以很好的兼容吸电子和给电子基团，以及芳杂环和不饱和的烯烃、炔烃等取代基团，说明该反应具有较好的底物适用范围和官能团耐受性，可以用于合成含不同取代基和官能团的具有潜在生物活性的手性四氢吡咯类化合物（产物对映体过量值可到达94%），并有望成为一个高效和可供选择的合成工具来合成手性含氮杂环化合物。在机理研究实验中，通过对副产物形成的分析，发现这些副产物的生成都由关键的活性苄基自由基中间体转化而来，证明了在反应过程中经历了分子间自由基攫氢的历程。本文的研究首次实现了经由自由基攫氢历程实现的不对称碳氢键胺化反应，拓展了铜/手性磷酸协同催化体系在自由基不对称化学中的应用。

Chiral N-containing heterocycles are important motifs widely displayed in natural products, pharmaceuticals and bioactive molecules, so the development of efficient asymmetric catalysis methods to access those compounds has attracted much attention from synthetic chemists. Compared to the well-documented classical methods, the asymmetric CH amination has high reaction efficiency and high atom economy; and for these reasons, the asymmetric CH amination has become a hot topic in recent years. However, the asymmetric CH amination successfully developed commonly involves transition metal-catalyzed CH bond activation or metallonitrene insertion into CH bond, where noble metals are requisite as catalyst and the substrate scope/accessibility of starting material in these reactions often suffers from some limitations. Therefore, it is highly desirable to develop ample efficient asymmetric CH amination reactions for overcoming the defects existed in current methods. Liu’s group has successfully developed a dual catalytic system of copper/chiral phosphoric acid (Cu/CPA) to realize the asymmetric radical 1,2-difunctionalization of unactivated alkenes. Inspired by these work, we envision that Cu/CPA catalytic system might be applied in radical involved intramolecular asymmetric CH amination to provide an efficient approach to chiral N-containing heterocycles. In this work, radical-involved intramolecular asymmetric amination of unactivated C-H bond was successfully developed after systematic screening of reaction conditions. The experimental results showed that the choice of suitable oxidants, additives and modified CPAs plays an important role in obtaining good reaction efficiency and high enantioselectivity. In addition, a variety of substrates bearing different functional groups were well-tolerated in this reaction, which potentially provides an efficient tool to synthesize chiral pyrrolidine derivatives. In the end, the mechanism studies indicated that the active benzylic radical species resulting from intermolecular HAT process might be the key intermediate in the context of the transformation.

不对称催化 碳氢键胺化 铜和手性磷酸 四氢吡咯 自由基攫氢

asymmetric catalysis CH amination copper/chiral phosphoric acid pyrrolidine derivatives hydrogen atom abstraction

中文

联合培养

南方科技大学

田宇. 自由基参与的分子内不对称碳氢键胺化反应的研究[D]. 深圳. 哈尔滨工业大学,2019.