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.

项目摘要/摘要：选择性转化无处不在的催化反应的发展 将官能团转化为增值产品可以实现医学相关分子的有效合成。 通过光氧化还原轻松生成自由基、阳离子和阴离子等经典反应中间体 催化和质子耦合电子转移（PCET）改变了化学家构建复合物的方式 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 促进烯烃氧化 烯烃自由基阳离子中间体的两亲性质使得这些物质具有两亲性。 有价值的合成林替平，能够快速构建分子复杂性并简化开发 拟议研究的目标是开发一种新型的药物相关分子。 从非经典光催化形成烯烃自由基阳离子中间体的合成平台 该提案旨在利用从细胞内收集的机制见解。 与激发态氧化还原化学的能力相配合形成烯烃自由基阳离子中间体， 在有利的合成条件下产生自由基阳离子。该方法的发展。 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) 烯烃作为自由基阳离子祖细胞的限制和 3) 使用氧化不稳定的 该研究策略概述了建立机械独特的严格方法。 从非经典前体中获取经典烯烃自由基阳离子的方法，以及新方法的开发 在目标 1 中，我们将利用传统自由基阳离子化学范围之外的合成方法。 建立了光氧化还原催化原理，用于开发催化还原平台 从非经典的经典烯烃自由基阳离子中间体的生成和随后的功能化 卤代醇前体的还原生成将首先应用于 然后，该还原平台将扩展到环状碳官能化反应。 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 在目标 2 中，C-H PCET 将用于强 C- 的选择性均裂活化。 简单醇的H键直接生成烯烃自由基，生成PCET中间体。 然后烯自由基阳离子将被应用于核苷酸衍生的直接生成和功能化 这项工作将为核苷酸类似物文库的便捷合成提供一种新颖且可行的方法。 生成经典和非经典反应中间体的综合有利方法 并产生新的合成方法，可以简化生物相关分子的合成 促进改善人类健康，符合 NIH 的核心价值观。