Innovative Transformations of Fundamental Synthetic Building Blocks

基础合成砌块的创新改造

• 批准号: 9922930
• 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/9922930
• 关键词: Biological; 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.

项目概述：化学合成在健康相关研究中的价值与以下能力密切相关： 从容易获得的材料有效地产生药剂。这MIRA申请寻求合并 NIGMS资助的两个富有成效的项目，重点是开发创新的合成转化， 基本的构建块。该计划的长期目标是确定有前途的新模式， 化学反应性，以促进快速发现和开发小分子生物医学 应用.该应用程序的总体目标是开发一组多样化的启用转换 使用未活化的脂族C-H键或烷基亲电体。脂肪族化合物的择位转化 C-H键在简化药物合成和加速获得新的类似物方面具有巨大的前景。 通过后期官能化制备生物相关化合物。尽管有这种潜力， 存在制备价值的官能化。我们寻求开发实用的，分子间脂肪族C-H 引入不同的化学官能团并以高水平的位点选择性进行的官能化。 这项研究是基于这样的假设，即自由基介导的分子间C-H官能化提供了 与替代方法相比，具有上级位点选择性和化学选择性， 新的、一般的C-H变换的发展。我们的方法将涉及识别新的N- 功能化试剂以及光氧化还原催化的创新途径，以解锁各种各样的 有价值的，目前无法使用杂原子为中心的自由基的C-H变换。 另一个主要目标是发展过渡金属催化的立体选择性构建方法 碳碳键的合成，否则很难实现除了少数例外，使用未激活的 卤代烷在催化C-C键形成反应中涉及活性自由基中间体。这种限制 防止在立体选择性C-C键形成反应中使用烷基卤化物， 合成并提供获得有药用价值的官能化小分子的途径。我们试图建立 金属催化中的新范例，其能够使未活化的烷基的立体选择性直接偶联 亲电试剂和广泛可获得的化学原料。我们假设烷基的双电子活化 亲电试剂将解锁一系列立体选择性C-C结构。我们的目标包括发展 未活化的烷基的立体选择性、羰基化转化和立体选择性碳环化 亲电体拟议研究的基本原理是，所产生的实际和选择性反应将 有助于获得多种合成的和有药用价值的小分子。我们的研究计划是 创新，因为它涉及未充分利用的化学反应模式，以产生新的，强大的键- 形成反应。这些贡献是重要的，因为它们将提供一系列的转换， 发现和开发下一代具有生物活性的天然产物和药物。