Catalytic Processes for Stereoselective Radical Cyclization Reactions

 描述（由申请人提供）：立体选择性自由基环化反应的催化过程环状结构，包括碳环和杂环，是具有重要生物医学活性的天然产物和合成化合物的常见基序。在制备环状分子的不同方法中，自由基环化是构建环状结构最有效的方法之一。自由基反应具有许多固有的合成优点，通常在温和和中性条件下在广谱溶剂中以快速反应速率进行，并显示出显著高的官能团耐受性。此外，自由基过程具有以级联方式进行的能力，允许快速构建具有多个立体中心的复杂分子结构。为了进一步提高自由基环化的合成应用， 将需要新的方法来实现对它们的反应性以及立体选择性，特别是对映选择性的高度控制，挑战与自由基化学的“自由”性质内在相关的问题。 在金属自由基催化概念的指导下，这项研究应用了一种全新的方法来控制C-和N-中心自由基反应的立体选择性。钴（II）卟啉[Co（Por）]作为稳定的金属自由基可以使重氮试剂和叠氮化物的活化分别干净地产生C-和N-中心自由基，其中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-中心的自由基，这仍然与[Co（Por）]络合，并被称为钴-卡宾和-氮烯自由基，分别可以进行常见的自由基反应，如自由基加成烯烃，但有效地控制反应性和立体选择性的卟啉配体环境。除了激进的 由于[Co（Por）]的性质，Co-C/Co-N键的低键离解能对Co（II）基催化卡宾和氮烯转移的成功转换起着关键作用，从而导致有效的环化反应。通过卟啉配体的可调电子，空间和手性环境的支持，这种基于Co（II）的金属自由基催化的一般概念将 可应用于开发各种自由基环化方法，用于立体选择性构建具有不同环尺寸和不同分子复杂程度的碳环和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友好的自由基环化过程的发展，可以成功地应用于生物学上重要的天然产物和药学上有趣的小分子的立体选择性合成。

 DESCRIPTION (provided by applicant): 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 most powerful approaches for construction of ring structures. With a number of inherent synthetic advantages, radical reactions typically precede at fast reaction rates under mild and neutral conditions in a broad spectrum of solvents and show 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 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, this proposed research applies a fundamentally new approach for controlling stereoselectivity of both C- and N-centered radical reactions. Cobalt(II) porphyrins [Co(Por)] as stable metalloradicals can enable the activation of diazo reagents and 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 remain complexed with [Co(Por)] and are termed as cobalt-carbene and -nitrene radicals, respectively, can undergo common radical reactions such as radical addition to alkenes, but with effective control of reactivity and stereoselectivity by the porphyrin ligand environment. In addition to the radical nature of [Co(Por)], the low bond dissociation energy of Co-C/Co-N bonds plays a key role for the successful turnover of the Co(II)-based catalytic carbene and nitrene transfers, resulting in effective cyclization reactions. Through the support of porphyrin ligands with tunable electronic, steric, and chiral environments, this general concept of Co(II)-based metalloradical catalysis will be applied for the development of various radical cyclization processes for stereoselective construction of both carbocyclic 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 toward the stereoselective synthesis of biologically important natural products and pharmaceutically interesting small molecules.