Catalytic Processes for Stereoselective Radical Cyclization Reactions

立体选择性自由基环化反应的催化过程

• 批准号: 10248461
• 负责人: X. Peter ZHANG
• 金额: $ 34.43万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248461
• 关键词: Address; Alkenes; Azides; Aziridines; Benign; Biological; Catalysis; Chemistry; Cobalt; Complex; Cyclization; Development; Dissociation; Drug Industry; Environment; Exhibits; Generations; Grant; Heterocyclic Compounds; Hydrogen; Isomerism; Lead; Ligands; Metals; Methods; Modernization; Molecular; Molecular Structure; Natural Products; Nature; Organic Synthesis; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Play; Porphyrins; Process; Reaction; Research; Solvents; Source; Structure; System; Testing; Toxic effect; base; catalyst; cost effective; covalent bond; cycloaddition; cyclopropane; design; diazo compound; drug candidate; drug development; drug discovery; enantiomer; functional group; improved; novel strategies; reaction rate; small molecule; stereochemistry; tool

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.

循环结构，包括碳循环和杂环，是天然的常见基序 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 为了制备环状分子，自由基循环代表了最强大的方法之一 环结构的构建。在许多固有的合成优势中，激进反应 通常在轻度和中性条件下以快速反应速率进行。 溶液和功能群的耐受性明显更高。此外，激进过程具有 以级联方式执行的能力，可以快速构造复杂的分子 产生多个立体中心的结构。进一步增强合成应用 从根本的环化化中，还需要新的方法来实现其反应性的高度控制 作为立体选择性，尤其是对映选择性，挑战本质上关联的问题 具有根本化学的“自由”性质。 在金银催化概念（MRC）的指导下，这项拟议的研究探索了 从根本上讲，以控制C-和N中心的立体选择性的新方法 反应。钴（ii）卟啉[CO（POR）]作为稳定的金属自由基，可以激活 重氮化合物和有机叠氮化物分别以干净的C-和N中心自由基生成 N2是唯一以受控和催化方式的副产品。最初形成的C和N中心 自由基分别称为A-CO（III） - 烷基自由基和A-CO（III） - 氨基自由基 与[CO（POR）]共价键合。它们可以进行共同的自由基反应，例如自由基添加 烷烃和氢原子抽象，但有效控制反应性和立体选择性 由卟啉配体环境。除了[CO（POR）]的根本性，低解离 CO – C和CO – N键的能量对于基于CO（II）的成功营业额发挥了关键作用 催化过程，导致有效的自由基环化反应。通过D2-的支持 具有可调电子，空间和手性环境的对称性手性卟啉配体，CO（II）基于CO（II） 金属自由基催化（CO（II）-MRC）将用于开发各种自由基环化 与碳纤维和N-杂环化合物的立体选择性结构的过程 不同的环尺寸和不同程度的分子复杂性。 我们希望这些研究最终将导致成本效益和环境的发展 良性的自由基环化过程，可以成功应用于立体选择性合成 生物学上重要的天然产物和药品有趣的小分子。