Catalytic Processes for Stereoselective Radical Cyclization Reactions

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， 对于制备环状分子，自由基环化是最有效的方法之一， 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。 在金属自由基催化（MRC）概念的指导下，本研究探索了一种 控制C-和N-中心自由基的立体选择性的根本性新方法 反应.钴（II）卟啉[Co（Por）]作为稳定的15 e金属自由基，可以使 重氮化合物和有机叠氮化物，以分别干净地产生C-和N-中心基团， N2作为唯一的副产物以受控和催化的方式。最初形成的C-和N-中心 分别称为a-Co（III）-烷基和a-Co（III）-氨基的自由基保留， 与[Co（Por）]共价键合。它们可以发生常见的自由基反应，如自由基加成反应 对烯烃和氢原子的提取，但与反应性和立体选择性的有效控制 通过卟啉配体环境。除了[Co（Por）]的自由基性质之外， Co-C和Co-N键的能量对于Co（II）基的成功转换起着关键作用。 催化过程，导致有效的自由基环化反应。在D2的支持下， 具有可调电子、空间和手性环境的对称手性卟啉配体，基于Co（II） 金属自由基催化（Co（II）-MRC）将被应用于各种自由基环化反应的发展 立体选择性构建碳环和N-杂环化合物的方法， 不同的环大小和不同程度的分子复杂性。 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。

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 concept of metalloradical catalysis (MRC), this proposed research explores a fundamentally new 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 porphyrin 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.