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.

环状结构，包括碳环和杂环，是天然化合物的常见基序。 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 对于制备环状分子，自由基环化是最有效的方法之一 环形结构的建造。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在广谱范围内进行 溶剂并表现出显着高的官能团耐受性。此外，激进的过程已经 以级联方式执行的能力，允许快速构建复杂的分子 产生多个立体中心的结构。进一步增强合成应用 对于自由基环化，也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，特别是对映选择性，具有内在相关性的挑战性问题 具有自由基化学的“自由”性质。 在金属自由基催化（MRC）概念的指导下，这项研究探索了 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 15e 金属自由基，可以激活 重氮化合物和有机叠氮化物分别干净地产生以 C 和 N 为中心的自由基 N2 作为唯一的副产品，以受控和催化的方式产生。最初形成的以C和N为中心的 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。它们可以进行常见的自由基反应，例如自由基加成 烯烃和氢原子抽象，但有效控制反应性和立体选择性 通过卟啉配体环境。除了[Co(Por)]的自由基性质外，低离解 Co-C 和 Co-N 债券的能量对于 Co(II) 基债券的成功周转起着关键作用 催化过程，产生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手性卟啉配体，Co(II) 基 金属自由基催化（Co(II)-MRC）将用于开发各种自由基环化反应 碳环和 N-杂环化合物的立体选择性构建方法 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能够开发出具有成本效益且环保的产品 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。