New Synthetic Methods Utilizing Radical Cation Intermediates Enabled by Visible Light Photocatalysis

利用可见光光催化自由基阳离子中间体的新合成方法

• 批准号: 10751166
• 负责人: Danny Thach
• 金额: $ 6.91万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751166
• 关键词: Alcohol consumption; Alcohols; Alkenes; Anions; Bypass; Catalysis; Cations; Characteristics; Chemicals; Chemistry; Complex; Coupled; Development; Electron Transport; Electrons; Generations; Glean; Goals; Health; Human; Hydrogen Bonding; Libraries; Logic; Medicine; Methodology; Methods; Modernization; Molecular; Nature; Nucleotides; Oligonucleotides; Organic Synthesis; Oxidation-Reduction; Pharmaceutical Chemistry; Phosphorylation; Protons; Reaction; Research; Research Proposals; Science; Site; Synthesis Chemistry; Technology; Training; United States National Institutes of Health; Visible Radiation; Work; analog; career; chemical reaction; design; functional group; improved; inorganic phosphate; insight; novel; nucleotide analog; nucleotide metabolism; oxidation; progenitor; small molecule; tool

Project Summary/Abstract: The development of catalytic reactions to selectively transform ubiquitous functional groups to value-added products can enable the efficient synthesis of medicinally relevant molecules. The facile generation of classical reactive intermediates such as radicals, cations, and anions via photoredox catalysis and proton-coupled electron transfer (PCET) have shifted the way chemists construct complex molecules and enabled novel bond-forming logic. However, the application of these mild photocatalytic manifolds towards the generation of alkene-derived radical cation intermediates still relies on strongly oxidative conditions to facilitate alkene oxidation. The ambiphilic nature of alkene radical cation intermediates renders these species valuable synthetic linchpins capable of rapidly building molecular complexity and streamlining the development of pharmaceutically relevant molecules. The goal of the proposed research is the development of a novel synthetic platform for the photocatalytic formation of alkene radical cation intermediates from non-canonical alcohol starting materials. This proposal seeks to leverage the mechanistic insights gleaned from the intracellular formation of alkene radical cation intermediates in concert with the capabilities of excited state redox chemistry, to generate radical cations under synthetically advantageous conditions. The development of this methodology will address three fundamental limitations of radical cation chemistry: 1) the use of harsh oxidative conditions for alkene oxidation 2) the constraint of alkenes as radical cation progenitors and 3) the use of oxidatively labile reaction partners. The research strategy outlines a rigorous approach for establishing a mechanistically distinct method to access classical alkene-radical cations from non-canonical precursors, and the development of new synthetic methods outside the scope of conventional radical cation chemistries. In aim 1, we will leverage established principles of photoredox catalysis for the development of a reductive platform for the catalytic generation and subsequent functionalization of classical alkene radical cations intermediates from non-canonical halohydrin precursors. The reductive generation of alkene radical cations will initially be applied to the development of annulative carbofunctionalizations reactions. This reductive platform will then be expanded to enable formal access to non-classical vicinal di-cation reactivity which is inaccessible via conventional alkene radical cation chemistries. In aim 2, C–H PCET will be applied for the selective homolytic activation of strong C– H bonds of simple alcohols for the direct generation of alkene radical cation intermediates. PCET generated alkene radical cations will then be applied to the direct generation and functionalization of nucleotide-derived radical cations for the expedient synthesis of nucleotide analog libraries. This work will provide a novel and synthetically advantageous approach to the generation of both classical and non-classical reactive intermediates and result in new synthetic methods that can streamline the synthesis of biologically relevant molecules and facilitate efforts to improve human health, in line with the NIH’s core values.

项目概要/摘要：发展催化反应，选择性地将无处不在的 将官能团转化为增值产品能够有效合成药用相关分子。 通过光氧化还原反应容易产生典型的活性中间体，如自由基、阳离子和阴离子 催化和质子耦合电子转移（PCET）改变了化学家构建络合物的方式， 分子和启用新的键形成逻辑。然而，这些温和的光催化歧管的应用 烯烃衍生的自由基阳离子中间体的生成仍然依赖于强氧化条件 以促进烯烃氧化。烯烃自由基阳离子中间体的两亲性使得这些物质 有价值的合成关键，能够快速构建分子复杂性， 与药物相关的分子。这项研究的目标是开发一种新的 用于由非正则光催化形成烯烃自由基阳离子中间体的合成平台 醇起始材料。这项提议旨在利用从细胞内的 与激发态氧化还原化学的能力一致的烯烃自由基阳离子中间体的形成， 以在有利的合成条件下产生自由基阳离子。这种方法的发展 将解决自由基阳离子化学的三个基本限制：1）使用苛刻的氧化条件， 烯烃氧化2）限制烯烃作为自由基阳离子前体和3）使用氧化不稳定的 反应伙伴。研究策略概述了一种严格的方法，用于建立一个机械上不同的 从非规范前体中获得经典烯烃自由基阳离子的方法，以及新的 常规自由基阳离子化学范围之外的合成方法。在目标1中，我们将利用 建立了光氧化还原催化的原理，用于开发用于催化的还原平台， 从非典型的烯烃自由基阳离子中间体生成和随后的官能化 卤代醇前体。烯烃自由基阳离子的还原生成最初将应用于 环状碳官能化反应的发展。这个简化的平台将扩展到 能够正式获得通过常规烯烃无法获得的非经典邻位双阳离子反应性 自由基阳离子化学目标2：C-H PCET将用于强C- 简单醇的H键直接生成烯烃自由基阳离子中间体。PCET生成 然后将烯烃自由基阳离子应用于直接生成和官能化核苷酸衍生的 自由基阳离子用于核苷酸类似物文库的有利合成。这项工作将提供一个新的和 产生经典和非经典反应性中间体的合成上有利的方法 并导致新的合成方法，可以简化生物相关分子的合成， 促进改善人类健康的努力，符合NIH的核心价值观。