Catalytic Processes for Stereoselective Radical Cyclization Reactions

项目摘要/摘要 立体选择性自由基环化反应的催化过程 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 制备环状分子，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)力学原理的指导下，本研究提出了 探索一种完全不同的方法来控制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金属络合物，能使~(15)E 重氮化合物和有机叠氮化合物的活化以干净地产生以C和N为中心的自由基， 分别以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中心自由基，称为a-Co(III)-烷基和a-Co(III)-氨基， 分别与[Co(POR)]保持共价键合。它们可以经历常见的自由基反应， 如烯烃自由基加成和氢原子抽提，但要有效控制 卟啉配体环境对反应活性和立体选择性的影响。除了激进的性质之外， [Co(Por)]，Co-C和Co-N键的低解离能对反应的成功起着关键作用 基于Co(II)的催化过程的周转，导致有效的自由基环化反应。 通过D2对称的手性氨基卟啉配体与可调的电子、空间和 手性环境，Co(II)基金属催化剂(Co(II)-MRC)将应用于 两种碳环类化合物立体选择性构筑的各种自由基环化工艺研究进展 以及具有不同环大小和不同分子复杂程度的N-杂环化合物。 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。

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.