Innovative Transformations of Fundamental Synthetic Building Blocks

基础合成砌块的创新改造

• 批准号: 10397531
• 负责人: Erik John Alexanian
• 金额: $ 49.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397531
• 关键词: Catalysis; Chemicals; Coupling; Development; Electrons; Funding; Goals; Health; Hydrogen Bonding; Mediating; Metals; National Institute of General Medical Sciences; Natural Products; Pathway interactions; Preparation; Process; Public Health; Reaction; Reagent; Research; Site; Transition Elements; analog; base; chemical function; chemical synthesis; drug synthesis; innovation; next generation; novel; prevent; programs; small molecule; small molecule therapeutics; tool

Project Summary: The value of chemical synthesis in health-related research is closely tied to the ability to efficiently generate medicinal agents from readily available materials. This MIRA application seeks to merge two productive NIGMS-funded projects centered on the development of innovative synthetic transformations of fundamental building blocks. The long-term goal of this program is to identify promising new modes of chemical reactivity to facilitate the rapid discovery and development of small molecules for biomedical applications. The overall objective of this application is to develop a diverse set of enabling transformations using either unactivated aliphatic C–H bonds or alkyl electrophiles. Site-selective transformations of aliphatic C–H bonds hold enormous promise in streamlining drug synthesis and expediting access to novel analogs of biologically relevant compounds via late-stage functionalization. Despite this potential, few intermolecular C–H functionalizations of preparative value exist. We seek to develop practical, intermolecular aliphatic C–H functionalizations that introduce diverse chemical functionality and proceed with high levels of site selectivity. This research is based on the hypothesis that radical-mediated intermolecular C–H functionalizations offer the potential for superior site selectivities and chemoselectivities as compared to alternative approaches, enabling the development of new, general C–H transformations. Our approach will involve the identification of new N- functionalized reagents as well as innovative pathways in photoredox catalysis to unlock a diverse set of valuable, currently inaccessible C–H transformations using heteroatom-centered radicals. Another major goal is to develop transition metal catalyzed processes for the stereoselective construction of C–C bonds that would otherwise be challenging to accomplish. With few exceptions, the use of unactivated alkyl halides in catalytic C–C bond-forming reactions involves reactive radical intermediates. This limitation prevents the use of alkyl halides in stereoselective C–C bond-forming reactions that would streamline drug synthesis and provide access to medicinally valuable, functionalized small molecules. We seek to establish new paradigms in metal catalysis that enable the stereoselective direct coupling of unactivated alkyl electrophiles and widely available chemical feedstocks. We hypothesize that two-electron activation of alkyl electrophiles will unlock a range of stereoselective C–C constructions. Our objectives include the development of stereospecific, carbonylative transformations and stereoselective carbocyclizations of unactivated alkyl electrophiles. The rationale of the proposed research is that the practical and selective reactions produced will facilitate access to diverse synthetically and medicinally valuable small molecules. Our proposed research is innovative because it involves underutilized modes of chemical reactivity to generate new, powerful bond- forming reactions. These contributions are significant because they will offer a range of transformations for the discovery and development of next generation, biologically active natural products and medicinal agents.

项目摘要：化学合成在与健康相关研究中的价值与能力紧密相关 有效地从可用的材料中产生药用剂。此Mira应用程序试图合并 两个生产性诺格姆资助的项目以创新合成转型为中心 基本构建块。该计划的长期目标是确定有希望的新模式 化学反应性以促进生物医学的小分子的快速发现和发展 申请。该应用程序的总体目的是开发一套可实现转型的多样 使用未激活的脂肪族C – H键或烷基电力。脂肪族的现场选择性转换 C – H键在简化药物合成并加快获得新颖的类似物方面具有巨大的希望 通过晚期功能化的生物学相关化合物。尽管有潜力，但很少分子C – H 存在准备值的功能化。我们寻求开发实用的，分子间的脂肪族C – H 引入潜水员化学功能的功能化并具有高水平的现场选择性。 这项研究基于以下假设：自由基介导的分子间C – H功能化提供了 与替代方法相比 新的，一般的C – H转换的发展。我们的方法将涉及对新n-的识别 光电毒素催化中的功能化试剂以及创新途径，以解锁一组多样的 使用以杂种为中心的自由基的有价值的，目前无法访问的C – H变换。 另一个主要目标是开发过渡金属催化的工艺，以进行立体选择性结构 否则将要挑战的C – C债券。除了少数例外，使用未激活 催化C – C键形成反应中的烷基卤化物涉及反应性自由基中间体。这个限制 防止在立体选择性C – C形成反应中使用烷基卤化物，以简化药物 合成并提供对有价值的功能化小分子的访问。我们试图建立 金属催化中的新范例，使未活化烷基的立体选择性直接耦合 亲电的和广泛可用的化学原料。我们假设烷基的两电子激活 亲电器将解锁一系列立体选择C – C结构。我们的对象包括开发 立体特异性，羰基转化和未活化烷基的立体选择性羰基化 电力。拟议的研究的理由是，产生的实际和选择性反应将 促进合成和有价值的小分子的潜水员进入潜水员。我们提出的研究是 创新的，因为它涉及未充分利用的化学反应性模式，以产生新的，强大的键 - 形成反应。这些贡献很重要，因为它们将为 下一代，生物活跃天然产品和医疗药物的发现和开发。