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: 9127979
• 负责人: X. Peter ZHANG
• 金额: $ 30.99万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127979
• 关键词: Alkenes; Azides; Aziridines; Benign; Biological; Carbon; Catalysis; Chemistry; Cobalt; Complex; Cyclization; Development; Dissociation; Drug Industry; Electronics; Environment; Exhibits; Family; Goals; Health; Heterocyclic Compounds; Hydrogen Bonding; Isomerism; Lead; Ligands; Marketing; Metalloporphyrins; Methods; Molecular; Molecular Structure; Natural Products; Nature; Nitrogen; Outcomes Research; Pharmaceutical Preparations; Play; Porphyrins; Process; Reaction; Reagent; Research; Scheme; Solvents; Structure; System; Toxic effect; base; carbene; chemical reaction; cost effective; cyclopropane; design; diene; drug candidate; drug development; drug discovery; drug testing; enantiomer; functional group; improved; interest; nitrene; novel; novel strategies; programs; reaction rate; single bond; small molecule; tool

 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.

 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，自由基环化代表了构建环结构的最有效的方法之一。自由基反应具有许多固有的合成优势，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，并表现出显着高的官能团耐受性。此外，自由基过程能够以级联方式进行，允许快速构建具有多个立体中心的复杂分子结构。为了进一步增强自由基环化的合成应用， 需要新的方法来实现对其反应性和立体选择性（尤其是对映选择性）的高度控制，从而挑战与自由基化学的“自由”性质本质上相关的问题。 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以 C 和 N 为中心的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，可以激活重氮试剂和叠氮化物，分别干净地生成以C为中心的自由基和以N为中心的自由基，并以受控和催化的方式将N2作为唯一的副产物。最初形成的C-和N-中心自由基，仍然与[Co(Por)]络合，分别被称为钴-卡宾和-氮烯自由基，可以进行常见的自由基反应，例如自由基加成到烯烃上，但通过卟啉配体环境有效控制反应性和立体选择性。除了激进的 由于[Co(Por)]的性质，Co-C/Co-N键的低键解离能对于Co(II)基催化卡宾和氮宾转移的成功转换起着关键作用，从而产生有效的环化反应。通过具有可调电子、空间和手性环境的卟啉配体的支持，Co(II)基金属自由基催化的这一一般概念将 可用于开发各种自由基环化工艺，用于立体选择性构建具有不同环大小和不同分子复杂程度的碳环和 N-杂环化合物。 我们希望这些研究最终能够开发出具有成本效益且环境友好的自由基环化工艺，该工艺可以成功应用于生物重要天然产物和药学上有趣的小分子的立体选择性合成。