DNA-金属配合物杂合催化剂的设计、合成及其不对称催化反应研究

Development of novel highly efficient approach for enantioselective catalysis is one of the frontier field in organic chemistry. DNA are chemically stable, readily available, conformations variable and water compatible, thus making them promising candidates as a source of chirality to set up DNA-based hybrid catalysts, which have been proven to be useful in the construction of chiral C-C, C-O, and C-F bonds. However, the stereo-induction mechanism is not fully understood and remains a challenge, which can be attributed to the prevalent adoption of unspecific non-covalent strategy for the assembly of DNA-based hybrid catalysts, so scarce guidance could be supplied for their rational design. On the basis of previous research on DNA modification, this project aims to covalently modify B-DNA at the major and minor groove, followed by finely tuning the coordination environment of attached bipyridine-copper (II) complex, thus a series of DNA-based catalyst will be assembled, with the enantioselectivity being investigated via asymmetric Michael addition reaction. Through systematic structure-function studies, the efficient catalyst will be obtained and applied to construct chiral C-N, C-S bonds. To elucidate the stereo-induction mechanism, thorough mechanism study will be carried out extensively via UV-Vis spectroscopy, Circular Dichroism, and Single crystal diffraction (X-ray), to generate the reasonable mechanism which can be served as the guidance for the rational design of DNA-based hybrid catalysts, and to prompt the development and application of DNA-based hybrid catalysts, thus becoming a practical complementary approach for acquiring optically active compounds.

发展高效高选择性不对称催化新方法是有机化学的前沿领域之一。利用DNA的手性环境可制备DNA-金属配合物杂合催化剂，能在水中反应的特性使其在手性C-C，C-O和C-F键的构筑方面已展现出很好的应用前景。目前研究不足之处在于主要利用非共价键结合的方式构建杂合催化剂，没有特异性，难以提出合理的立体诱导催化机制，严重制约了合理设计高效的杂合催化剂。基于文献调研和研究积累，本项目旨在通过共价修饰B-DNA的大小沟区，并系统性地优化定域其中的联吡啶铜（II）配合物的配位环境，构建一系列杂合催化剂，依据不对称Michael加成反应研究其立体选择性。期望通过系统的构效关系研究寻找有效的杂合催化剂，将其应用于手性C-N和C-S键的构建。利用光谱、单晶衍射等方法进行催化机制研究，以期为设计高效的杂合催化剂提供理论依据和指导，切实推进基于DNA的杂合催化剂的设计和应用，丰富获得手性化合物的手段。

本项目致力于DNA-过渡金属杂合催化剂的构建其在纯水相中不对称催化Michael加成、aza-Michael加成和催化Sonogashira偶联等反应的调控途径与规律。主要研究成果包括：① 构建了九聚双链DNA-联吡啶铜杂合催化剂，可以99% ee值不对称催化Michael加成，是目前不对称催化该反应所需最短的DNA。机理研究表明DNA保持二级结构完整是取得良好立体选择性的先决条件。② 构建了DNA-联吡啶铜杂合催化剂可诱导苯并三氮唑与N-杂查尔酮发生不对称aza-Michael加成，系DNA-过渡金属杂合催化剂首次实现该转化。③构建了一类DNA-硫代嘌呤铜/镍杂合催化剂，可以86%的ee值得到Michael加成产物，使可供和DNA杂合构建催化剂的金属配合物过少的局面有望得到改观。④构建了DNA-钯杂合催化剂，可在纯水介质中高效催化酰氯与炔烃发生Sonogashia偶联合成炔酮。荧光竞争、偏光显微、溶解度、光电子能谱等机理研究表明DNA与钯催化剂通过嵌插作用结合，且其碱基疏水层为反应提供反应空间，得以实现乳液催化，是反应加速的重要原因。作为首例DNA-过渡金属杂合催化体系在C-C键偶联反应的应用，为拓展DNA催化功能进行了有益的探索。⑤以鸟苷为原料合成了8-碘代鸟苷单体可供通过共价方式引入催化中心。由于碳-碘键不稳定，不利于积累原料进行后续研究。稳定性较小的溴核苷单体因活性不足难以和催化中心所在片段连接，仍需继续努力克服。⑥发展了纯水相聚醚胺催化Aldol反应制备3-羟基-2-吲哚2酮类化合物的新策略，可作为DNA不对称催化反应的备选反应。⑦设计合成了二茂钛双官能团催化剂，可高效催化Mannich反应生成喹诺酮衍生物。二茂钛类配合物因和DNA具有良好的结合能力，可作为构建DNA-过渡金属杂合催化剂的备选配合物。项目执行期间，发表SCI学术论文4篇，发表会议论文2篇，申请发明专利2件，已授权1件，另有2篇文章处在整理投稿阶段，国内会议做墙报展示2次，培养硕士研究生2名。