New Synthetic Methods Enabled by Excited-State Redox Chemistry

激发态氧化还原化学实现的新合成方法

• 批准号: 10542406
• 负责人: Robert R Knowles
• 金额: $ 54.21万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542406
• 关键词: Address; Alcohols; Alkenes; Amides; Amines; Biological Process; Catalysis; Cations; Chemistry; Complex; Coupled; Development; Electron Transport; Equilibrium; Event; Generations; Goals; Health; Human; Hydrogen Bonding; Isomerism; Light; Literature; Mediating; Methods; Organic Chemistry; Organic Synthesis; Outcome; Oxidation-Reduction; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Photons; Process; Protocols documentation; Protons; Reaction; Science; Site; Sulfonamides; Technology; Technology Transfer; Variant; Work; absorption; carbonyl compound; catalyst; community engagement; design; manufacture; novel; novel strategies; pharmacophore; small molecule; tool

Project Summary The work described in this proposal aims to develop novel synthetic methods enabled by excited-state redox events to address longstanding challenges in catalysis and synthetic organic chemistry. A primary focus of this proposal is the continued development of proton-coupled electron transfer (PCET) technologies in organic synthesis. In particular we focus on developing PCET-based methods for the catalytic functionalization of aliphatic C-C bonds, including redox-neutral isomerization reactions of cyclic alcohols to form linear carbonyl compounds, and novel methods for the catalytic ring-expansion and ring-contraction of carbocyclic alcohols. We also discuss efforts to develop a new class of chiral amide-based catalysts that can be activated by PCET to generate transient amidyls, which can then mediate enantioselective and site-selective functionalization of aliphatic C-H bonds. A second goal of this work is the development of out-of-equilibrium synthetic methods enabled by excited-state redox events. These technologies provide opportunities to use photon absorption events to drive reaction against a thermochemical gradient, but without requiring generation of excited state substrates. Importantly, these methods provide novel approaches to achieve non-Boltzmann product distributions and reaction outcomes that are not, by definition, possible to obtain using conventional ground- state methods. Applications to the development of light-driven deracemization reactions are presented. A third goal is to advance our efforts in developing photocatalytic methods for olefin hydroamination and hydroetherification. We propose to develop the first general catalytic protocol for intermolecular anti- Markovnikov hydroamination reactions between unactivated olefins with primary alkyl amines to yield secondary amine products, selectively, based on the chemistry of aminium radical cations. PCET-based methods for enantioselective hydroaminations with sulfonamides are also proposed, wherein the asymmetric induction is proposed to arise from direct non-covalent interactions between a chiral H-bond donor and a neutral N-centered radical intermediate. We also present plans to develop analogous intermolecular hydroetherification methods and their enantioselective variants. If successful, these efforts will provide valuable new reactions and concepts for the chemistry communities engaged in the discovery, synthesis, and manufacture of pharmaceuticals and other small-molecule probes of biological function, and thus create a significant benefit to human health.

项目摘要 这项提案中描述的工作旨在开发利用激发态氧化还原实现的新的合成方法 为解决催化和合成有机化学方面的长期挑战而举办的活动。这是一个主要的关注点 建议继续发展有机中的质子耦合电子转移(PCET)技术 综合。特别是，我们专注于开发基于PCET的方法来催化官能化 脂肪族C-C键，包括环醇的氧化还原中性异构化反应生成直链羰基 化合物，以及碳环醇催化扩环和缩环的新方法。 我们还讨论了开发一类可被PCET活化的新型手性酰胺类催化剂的努力。 来产生瞬时的酰胺，然后它可以介导对映体选择性和位置选择性的官能化 脂肪族C-H键。这项工作的第二个目标是开发非平衡合成方法。 受激发态氧化还原事件的影响。这些技术提供了利用光子吸收的机会 在不需要产生激发态的情况下驱动热化学梯度反应的事件 底物。重要的是，这些方法提供了实现非玻尔兹曼产品的新方法 根据定义，使用常规地面无法获得的分布和反应结果- 国家方法。介绍了其在光驱动去消旋化反应发展中的应用。三分之一 目标是推动我们在开发烯烃氢胺化和光催化方法方面的努力。 氢醚化反应。我们建议开发第一个通用的分子间抗病毒催化方案。 未活化的烯烃与伯烷基胺的Markovnikov氢胺化反应 仲胺产品，选择性地，基于铵自由基阳离子的化学。基于PCET的 还提出了与磺胺类化合物进行不对称氢胺反应的方法，其中不对称 被认为是由手性氢键供体和a之间的直接非共价相互作用引起的。 中性N中心自由基中间体。我们还提出了开发类似分子间的计划 氢醚化方法及其对映体选择性变体。如果成功，这些努力将提供有价值的 新的反应和概念的化学界从事发现，合成，和 制造药物和其他具有生物功能的小分子探针，从而创造出一种 对人类健康大有裨益。