Catalytic Processes for Stereoselective Radical Cyclization Reactions

环结构，包括碳环和杂环，都是天然的 具有重要生物医学活性的产品和合成化合物。在不同的方法中 在制备环状分子方面，自由基环化是最有效的方法之一。 环形结构的施工。在一系列固有的合成优势中，自由基反应 通常在温和和中性条件下以快速反应速度进行，范围广泛 并表现出极高的官能团耐受性。此外，激进的过程具有 以级联方式执行的能力，允许快速构建复杂分子 具有多个立体产生中心的结构。进一步提升综合应用 对于自由基环化，还需要新的方法来实现对其反应性的高度控制 作为立体选择性，特别是对映体选择性，具有挑战性的问题与 具有自由基化学的“自由”性质。 在金属催化(MRC)概念的指导下，这项研究探索了一种 控制C-和N-中心自由基立体选择性的全新方法 反应。钴(II)卟啉[Co(Por)]作为稳定的~(15)E金属络合物，能激活~(15)E的活性。 重氮化合物和有机叠氮化合物，分别以清洁的方式产生C和N中心的自由基， 氮气作为唯一的副产物以受控和催化的方式进行。最初形成的C-和N-中心 分别被称为a-Co(III)-烷基和a-Co(III)-氨基的自由基仍然存在 与[Co(POR)]共价键合。它们可以进行常见的自由基反应，如自由基加成。 对烯烃和氢原子的抽提，但具有有效的反应性和立体选择性 受卟啉配基环境的影响。除了[Co(POR)]的自由基性质外，低解离 Co-C和Co-N键的能量对Co(II)基的成功成交起着关键作用 催化过程，导致有效的自由基环化反应。透过D2的支持- 具有可调节的电子、空间和手性环境的对称手性卟啉配体，基于Co(II) 金属催化(Co(II)-MRC)将应用于各种自由基环化反应的发展 碳环和N-杂环化合物的立体选择性构筑方法 不同的环大小和不同程度的分子复杂性。 我们希望这些研究最终将导致开发具有成本效益和环境保护的 可成功应用于立体选择性合成的良性自由基环化过程 具有重要生物学意义的天然产物和具有药用价值的小分子。

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.