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.

项目概要 该提案中描述的工作旨在开发由激发态氧化还原实现的新型合成方法 旨在解决催化和合成有机化学领域长期存在的挑战的活动。本次活动的一个主要焦点 该提案是在有机领域继续开发质子耦合电子转移（PCET）技术 合成。我们特别专注于开发基于 PCET 的催化功能化方法 脂肪族C-C键，包括环醇形成直链羰基的氧化还原中性异构化反应 化合物，以及碳环醇催化扩环和缩环的新方法。 我们还讨论了开发可被 PCET 活化的新型手性酰胺基催化剂的努力 产生瞬时酰胺基，然后可以介导对映选择性和位点选择性官能化 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 由激发态氧化还原事件启用。这些技术提供了利用光子吸收的机会 驱动逆热化学梯度反应的事件，但不需要产生激发态 基材。重要的是，这些方法提供了实现非玻尔兹曼积的新方法 根据定义，使用常规接地不可能获得分布和反应结果 状态方法。介绍了光驱动去消旋反应开发的应用。第三个 目标是推进我们在开发用于烯烃加氢胺化和光催化方法的努力 加氢醚化。我们建议开发第一个分子间抗的通用催化方案 未活化烯烃与伯烷基胺之间的马尔可夫尼科夫氢胺化反应生成 基于铵自由基阳离子的化学选择性仲胺产品。基于PCET 还提出了与磺酰胺进行对映选择性氢胺化的方法，其中不对称 感应被认为是由手性氢键供体和手性氢键供体之间的直接非共价相互作用产生的。 中性N中心自由基中间体。我们还提出了开发类似分子间化合物的计划 加氢醚化方法及其对映选择性变体。如果成功的话，这些努力将提供有价值的 化学界从事发现、合成和研究的新反应和概念 制造药物和其他具有生物功能的小分子探针，从而创建 对人类健康有重大益处。