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Catalytic Processes for Stereoselective Radical Cyclization Reactions

立体选择性自由基环化反应的催化过程

基本信息

批准号：
10587778
负责人：
X. Peter ZHANG
金额：
$ 35.53万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2027-08-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Catalytic Processes for Stereoselective Radical Cyclization Reactions Cyclic structures, including both carbocycles and heterocycles, are common motifs of natural products and synthetic compounds with important biomedical activities. Among different approaches for preparing cyclic molecules, radical cyclization represents one of the most powerful approaches for construction of ring structures. Among a number of inherent synthetic advantages, radical reactions typically proceed at fast reaction rates under mild and neutral conditions in a broad spectrum of solvents and exhibit significantly high functional group tolerance. Furthermore, radical processes have the capability to perform in a cascade fashion, allowing for the rapid construction of complex molecular structures with generation of multiple stereogenic centers. To further enhance the synthetic applications of radical cyclization, new approaches will be needed for achieving high control of their reactivity as well as stereoselectivity, especially enantioselectivity, challenging issues that are intrinsically associated with the “free” nature of radical chemistry. Guided by the mechanistic principles of metalloradical catalysis (MRC), this proposed research explores a fundamentally different approach for controlling stereoselectivity of both C- and N-centered radical reactions. Cobalt(II) porphyrins [Co(Por)], as stable 15e metalloradicals, can enable the activation of diazo compounds and organic azides to cleanly generate C- and N-centered radicals, respectively, with N2 as the only byproduct in a controlled and catalytic manner. The initially-formed C- and N-centered radicals, which are termed as a-Co(III)-alkyl radicals and a-Co(III)-aminyl radicals, respectively, remain covalently bonded with [Co(Por)]. They can undergo common radical reactions, such as radical addition to alkenes and hydrogen-atom abstraction, but with effective control of reactivity and stereoselectivity by the porphyrin ligand environment. In addition to the radical nature of [Co(Por)], the low dissociation energy of Co–C and Co–N bonds plays a key role for the successful turnover of the Co(II)-based catalytic processes, resulting in effective radical cyclization reactions. Through the support of D2-symmetric chiral amidoporphyrin ligands with tunable electronic, steric, and chiral environments, Co(II)-based metalloradical catalysis (Co(II)-MRC) will be applied for the development of various radical cyclization processes for stereoselective construction of both carbocylic and N-heterocyclic compounds with different ring sizes and varied degrees of molecular complexity. We hope these studies will ultimately lead to the development of cost-effective and environmentally benign radical cyclization processes that can be successfully applied for the stereoselective synthesis of biologically important natural products and pharmaceutically interesting small molecules.

项目总结/摘要立体选择性自由基环化反应的催化方法环状结构，包括碳环和杂环，是天然产物的常见基序。产品和具有重要生物医学活性的合成化合物。在不同的方法中，在制备环状分子时，自由基环化是制备环状分子的最有效方法之一。环状结构的构建。在许多固有的合成优势中，自由基反应通常在温和和中性条件下以快速反应速率进行，溶剂，并表现出显著高的官能团耐受性。此外，激进的进程以级联方式执行的能力，允许快速构建复杂的分子具有多个立体中心的结构。为了进一步提高合成应用自由基环化，将需要新的方法来实现其反应性的高度控制，以及作为立体选择性，特别是对映选择性，挑战性的问题，自由基化学的“自由”本质。本文以金属自由基催化机理为指导，探索了一种从根本上不同的方法，用于控制C-和N-中心的立体选择性激进的反应钴（II）卟啉[Co（Por）]作为稳定的15 e金属自由基，可以使活化重氮化合物和有机叠氮化物以干净地产生C-和N-中心基团，分别以受控和催化的方式以N2作为唯一的副产物。最初形成的C- 和N-中心基团，其被称为α-Co（III）-烷基和α-Co（III）-氨基，分别保持与[Co（Por）]共价键合。它们可以发生普通的自由基反应，例如对烯烃自由基加成和夺取氢原子，但有效控制卟啉配体环境的反应性和立体选择性。除了激进的性质， [Co（Por）]，Co-C和Co-N键的低解离能对成功的合成起着关键作用。周转的钴（II）为基础的催化过程，导致有效的自由基环化反应。通过D2-对称手性氨基卟啉配体的支持，具有可调的电子，空间，手性环境中，Co（II）基金属自由基催化（Co（II）-MRC）将用于发展了各种自由基环化方法，用于立体选择性地构建碳环以及具有不同环尺寸和不同分子复杂程度的N-杂环化合物。我们希望这些研究将最终导致成本效益和环境的发展可成功应用于立体选择性合成的良性自由基环化过程生物学上重要的天然产物和药学上有趣的小分子。