新型手性双金属络合物催化的不对称Kinugasa反应研究

Many chiral β-lactams have excellent antibacterial activity or other biological activity. They are also used as key intermediates in organic synthesis. The synthesis of chiral β-lactams by the asymmetric Kinugasa reaction between terminal alkynes and nitrones is attractive for the readily available reagents, mild conditions and the variety of functional groups in recent years. Although high enantioselectivity has been achieved with certain type of substrates, the development of a highly efficient and enantioselective catalytic Kinugasa reaction is still a challenging task especially for many chiral drugs and lead compounds containing the structure of β-lactams. Series of polyfunctional ligands containing N and O would be designed and synthesized to complex with various metal reagents so as to construct novel bimetallic catalysts. Thus the bimetallic catalysts will be applied in the asymmetric Kinugasa reaction. The Kinugasa reaction will be studied to achieve high yields and enantioselectivities by investigating different alkynes, nitrones, catalysts and other reaction conditions. The interaction laws of the catalytic reaction, the binding sites of the catalysts as well as the role of the two metals in bimetallic catalysts will be explored through a variety of experimental methods and theoretical knowledge. And then the catalytic mechanism and the transition state will be studied which will indicate the chiral recognition and the control of the stereoselectivity. At the same time a novel catalytic system based on bimetallic catalysts will be developed.

许多手性β-内酰胺化合物具有优良抗菌活性或其他生物活性，同时作为关键中间体也广泛应用于有机合成中。末端炔烃与硝酮的不对称Kinugasa反应合成β-内酰胺因反应物简单易得、反应条件温和且反应不受多种官能团影响等优点而在近些年备受关注。虽然已有了几个高对映选择性反应，但是在收率和选择性上仍有改善的空间；在底物的广谱性上，针对很多含β-内酰胺或衍生结构的手性药物、先导化合物的合成存在不足。申请者拟设计合成多个含N、O的多齿配体，并与金属试剂络合，构建新型双金属催化剂，用于不对称Kinugasa反应。拟研究不同的炔烃、硝酮、催化剂及其他反应条件对不对称Kinugasa反应的影响。通过各种实验手段和理论知识，探究催化反应中的各种相互作用，进而研究反应的催化循环机理和过渡态，寻找手性识别和控制产物立体选择性的规律，从而实现高产率、高对映选择性地合成β-内酰胺类化合物，同时发展新型手性双金属催化体系。

双金属催化体系具有两个催化中心，可相互协调而发生高效催化作用，可同时与反应底物产生多个作用位点，可进一步活化和固定反应底物，比单核催化剂能更好地控制反应的立体选择性和获得更高的反应活性，在不对称催化领域受到广泛关注。本课题致力于新型双金属催化体系的构建及其在不对称反应中的应用，取得了一些有特色的研究成果：发展了一类新型的氨基酚磺酰胺多齿配体，并成功构建了双镍、双钴、锌/锶双金属催化体系，应用于不对称反应并取得了不错的结果，催化剂结构经控制实验、ESI-MS、ESI-HRMS、NMR等多种手段验证，并通过DFT理论计算优化结构，对反应的过渡态进行了分析，对催化剂与底物相互作用与对映选择性的关系做出了推测，为下一步设计更加高效的新型催化体系提供了坚实的基础。开发了一类新型的衍生自TsDPEN的手性N,N,N-亚胺配体并将其成功用于铜催化的不对称Kinugasa反应中，反应操作简单，对空气和潮气耐受，底物普适性好，为具有β-内酰胺结构或衍生结构的天然产物、手性药物及药物中间体提供一条简单、易行、有价值的合成方法。通过对催化剂结构及立体选择性控制模型研究，提出了一种新的不对称催化机制。项目执行期间，共发表学术论文11篇，1篇论文被Synfacts评论，获得专利授权1项。