Intermolecular Aliphatic C-H Functionalization Using Heteroatom-Centered Radicals

使用杂原子中心自由基进行分子间脂肪族 C-H 官能化

• 批准号: 9330868
• 负责人: Erik John Alexanian
• 金额: $ 27.28万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330868
• 关键词: Acids; Address; Alkylation; Biological; Biological Sciences; Chemicals; Complex; Computer Simulation; Coupled; Data; Development; Electron Transport; Future; Generations; Goals; Health; Hydrogen Bonding; In Situ; Mediating; Metals; Methods; Modification; N hydroxylation; Natural Products; Natural regeneration; Nitrogen; Outcome; Oxidation-Reduction; Preparation; Process; Protons; Public Health; Reaction; Reagent; Research; Route; Site; Technology; Therapeutic Agents; Variant; Visible Radiation; Work; analog; base; bioactive natural products; c new; carbene; catalyst; chemical function; chemical synthesis; decalin; design; drug synthesis; halogenation; improved; innovation; next generation; novel; novel therapeutics; small molecule; small molecule therapeutics; tool

Project Summary: The utility of chemical synthesis in health-related research is closely tied to efficient access to therapeutic agents. The synthesis of these compounds using standard approaches often involves lengthy, inefficient synthetic routes, hindering the discovery and development of new drugs. Synthetic transformations that selectively functionalize aliphatic C–H bonds hold significant promise in streamlining drug synthesis and providing access to novel analogs of biologically relevant compounds that would otherwise be challenging to obtain. Despite the potential for site-selective C–H functionalization, few intermolecular processes of preparative value exist. This gap in reaction development fundamentally limits the use of C–H functionalization in the synthesis of medicinally valuable, functionalized small molecules. The long-term goal of this research is the development of practical, intermolecular aliphatic C–H functionalizations that introduce diverse chemical functionality and proceed with high levels of selectivity. The overall objective of this application is to develop a new C–H functionalization that unlocks a diverse set of currently inaccessible, valuable C–H transformations, and to further enhance the site selectivities and chemoselectivities of our approach using heteroatom-centered radicals. We will also develop catalytic variants, offering new opportunities in both reagent design and reaction development. Our research is based on the central hypothesis that radical-mediated intermolecular C–H functionalizations offer superior site selectivities and chemoselectivities and will enable the development of new transformations that are inaccessible via metal-catalyzed approaches. The rationale of the proposed research is that these practical and selective reactions will facilitate access to diverse synthetically and medicinally valuable small molecules. This work involves three specific aims: (1) to develop an aliphatic C–H xanthylation (dithiocarbonation) as a platform technology for C–H functionalization; (2) to increase the site selectivity and chemoselectivity of intermolecular C–H functionalizations using heteroatom-centered radicals; and (3) to develop catalytic variants of the radical-mediated C–H functionalizations. Under the first aim, we will develop a practical, efficient method for aliphatic C–H xanthylation. In the second aim, we will enhance both the site selectivity and chemoselectivity of our platform using heteroatom-centered radicals. Under the third aim, we will develop catalytic, intermolecular aliphatic C–H functionalizations. Our proposed research is innovative because it will establish the unique capabilities of intermolecular aliphatic C–H functionalization using tuned radical species in unlocking new, practical transformations of aliphatic C–H bonds with superior levels of site selectivity and chemoselectivity. These contributions are significant because they will offer a range of practical and predictable aliphatic C–H transformations for late-stage functionalizations, catalyzing the discovery and development of next generation biologically active natural products and medicinal agents.

项目摘要：化学合成在健康相关研究中的效用与有效获取密切相关 到治疗剂。使用标准方法合成这些化合物通常涉及冗长的， 合成路线效率低下，阻碍了新药的发现和开发。综合变换 选择性官能化脂肪族C-H键在简化药物合成和 提供获得生物相关化合物的新类似物的途径，否则将难以 获取。尽管有可能有选择性的C-H官能化，但很少有分子间过程 准备价值是存在的。反应发展中的这种差距从根本上限制了C-H官能化的使用 在合成有药用价值的官能化小分子方面。这项研究的长期目标是 引入多种化学物质的实用分子间脂肪族C-H官能化的研究进展 功能，并以高水平的选择性进行。这个应用程序的总体目标是开发一个 新的C-H功能化，解锁了一组目前无法访问的、有价值的C-H变换， 为了进一步提高以杂原子为中心的方法的位置选择性和化学选择性 激进分子。我们还将开发催化变种，为试剂设计和反应提供新的机会 发展。我们的研究是基于一个中心假设，即自由基介导的分子间C-H 功能化提供了卓越的部位选择性和化学选择性，并将使 通过金属催化的方法无法实现的新转变。建议的理由是 研究表明，这些实际和选择性的反应将有助于获得不同的合成和 具有药用价值的小分子。这项工作涉及三个具体目标：(1)开发一种脂肪族C-H 黄烷化(二硫代碳化)作为C-H官能化的平台技术；(2)增加位置 以杂原子为中心的分子间C-H官能化的选择性和化学选择性 以及(3)开发自由基介导的C-H官能化的催化变体。在第一个目标下，我们将 开发一种实用、高效的脂肪族C-H黄原化方法。在第二个目标中，我们将加强这两个方面 我们的平台使用杂原子为中心的自由基的位置选择性和化学选择性。在第三层以下 目的，我们将开发催化的分子间脂肪族C-H功能化。我们建议的研究是 创新是因为它将建立分子间脂肪族C-H官能化的独特能力 利用调谐自由基物种解锁新的、实用的脂肪族C-H键 位置选择性和化学选择性的水平。这些贡献意义重大，因为它们将提供 用于后期功能化的一系列实用和可预测的脂肪族C-H转化，催化 新一代生物活性天然产物和医药制剂的发现和开发。