含氮杂环化合物的高选择性脱氢官能团化研究

Nitrogen containing heterocyclic structure is a kind of important unit in a lot of drug molecules. So the high selective dehydrogenative functionalization of nitrogen containing heterocyclic compounds is the hot and challenging research topic of organic synthesis. To serve pharmaceutical synthesis and establishment of bioactive molecules libraries, our group is going to investigate the practical method for highly selective transformation of N-containing compound. On the hetero-cycle, based on the distance between the reaction sites and nitrogen atom, we will design the novel catalyst to realize the above kind of transformation. This project will start from the design and synthesis of novel metal catalysts which contain chiral ligand. For the catalyst, the chiral part could control the stereoselectivity based on the steric effect; the hydrogen bond donor part would binding the Nitrogen atom and control the regioselectivity by the group length. During the above study, based on the preliminary results, we will use multi-dimensional parameterization to analyze the mathematical relationship between the steric hindrance parameter of the ligand and stereoselectivity of the reaction. At the same time, we would focus on analyze the mathematical relationship between the electronic effect and group length of catalyst and regioselectivity of the reaction. Based on the function, we could calculate and expect the optimum catalyst, which could be used to synthesize a series of pharmaceutical molecules.

含氮杂环骨架是很多药物分子的重要结构单元。因此实现含氮杂环化合物的高选择性脱氢转化一直是合成研究的热点，但也是难点。申请人计划系统的研究简单含氮杂环化合物的高选择性官能团化方法，为药物分子的合成以及生物活性分子库的建立提供便捷的途径。若要实现含氮杂环化合物上不同位点的选择性转化，就要充分的利用这些反应位点与杂环上氮原子的距离的差别。申请人将设计并合成一系列手性配体络合的金属催化剂。该类催化剂通过位阻作用控制反应的对映选择性；同时通过催化剂中的氢键供体与杂环上氮原子相作用，并通过基团长度控制该反应的区域选择性。在进行以上研究过程中，申请人将通过初步结果收集催化剂与反应结果之间的相关信息，之后利用多维参数化分析研究基团的位阻与反应对映选择性之间的数学方程关系，以及研究基团的电子效应和基团长度与反应区域选择性之间的数学方程关系。并利用方程推导最优的催化剂，最终发展出合成一系列药物分子的高效方法。

发展新合成方法学，为生物活性分子提供高效的合成途径是有机合成研究的重要目标之一。硼化物是重要的合成子以及药物活性分子的片段，发展其高效的制备方法受到越来越多的关注。在本项基金的支持下，申请人系统的研究了烯烃的高选择性硼化反应。以上方法条件温和，官能团兼容性好，能够用于制备含氮杂环的硼化物。实验结果证明，以上方法可以被成功的用于合成药物分子。在以上研究中，申请人利用控制实验和动力学实验等对反应机理进行了详细的研究，为后续更加深入的研究工作奠定了坚实的基础。