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: 9543478
• 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/9543478
• 关键词: Alkenes; Azides; Aziridines; Benign; Bicycling; Biological; Carbon; Catalysis; Chemistry; Cobalt; Complex; Cyclization; Development; Dissociation; Drug Industry; Environment; Exhibits; Family; Goals; Heterocyclic Compounds; Hydrogen Bonding; Isomerism; Lead; Ligands; Metalloporphyrins; Methods; Molecular; Molecular Structure; Natural Products; Nature; Nitrogen; Outcomes Research; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; 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; nitrene; novel; novel strategies; programs; public health relevance; 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（由应用提供）：立体选择性自由基环反应的催化过程循环结构，包括碳循环和杂环，是天然产物的常见基序和具有重要生物医学活性的合成化合物。在制备循环分子的不同方法中，自由基循环代表了构造环结构的最强大方法之一。具有许多固有的合成优势，在各种溶液中，在轻度和中性条件下，基本反应通常以快速反应速率之前先于快速反应速率之前，并显示出明显高的功能群耐受性。此外，激进过程具有以级联形式执行的能力，可以快速构建具有多个立体源性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， 要高度控制其反应性以及立体选择性，尤其是对映选择性，挑战与自由基化学的“自由”本质上相关的挑战问题，将需要新的方法。在金属自由基催化的概念的指导下，这项拟议的研究采用了一种从根本上进行新的方法来控制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使重氮试剂和叠氮化物的激活分别能够干净地产生C-和N为中心的自由基，而N2是唯一以受控和催化方式的副产物。最初形成的C-和N中心的自由基与[CO（POR）]保持络合，分别称为钴 - 碳酸盐和二硝基自由基，可以在烷烃中进行共同的自由基反应，例如对反应性和反应性的有效控制，而孢子素的控制性则可以通过棒球素ligand ligand ligand环境进行控制。除了激进 [CO（POR）]的性质，CO-C/CO-N键的低键解离能对于成功的基于CO（II）的基于CO（II）的催化碳和硝基转移的转移起着关键作用，从而导致有效的环化反应。通过具有可调电子，空间和手性环境的卟啉配体的支撑，这种基于CO（II）的金属自由基催化的一般概念将 应用于开发各种自由基环化过程，以立体选择性结构具有不同的环尺寸和不同程度的分子复杂度的碳循环和N-杂环化合物。我们希望这些研究最终将导致具有成本效益和环境良性的自由基环化过程的发展，这些过程可以成功地应用于对生物学上重要的天然产物和药品有趣的小分子的立体选择合成。