Proton-Coupled Electron Transfer in Organic Synthesis and Asymmetric Catalysis

有机合成和不对称催化中的质子耦合电子转移

• 批准号: 8989128
• 负责人: Robert R Knowles
• 金额: $ 27.34万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989128
• 关键词: Acids; Address; Alcohols; Alkenes; Amides; Ammonium; Area; Biological; Biological Process; Carbamates; Catalysis; Chemistry; Complex; Coupled; Coupling; Development; Electron Transport; Electrons; Event; Free Radicals; Generations; Goals; Health; Human; Hydrogen; Hydrogen Bonding; Ions; Ketones; Kinetics; Ligands; Literature; Mediating; Metals; Methods; Organic Chemistry; Organic Synthesis; Organometallic Chemistry; Oxidants; Oxidation-Reduction; Pharmacologic Substance; Play; Process; Protocols documentation; Protons; Reaction; Reducing Agents; Role; Science; Solar Energy; Sulfoxide; Synthesis Chemistry; Technology; Work; abstracting; base; catalyst; design; drug synthesis; functional group; improved; innovation; metal complex; novel; novel therapeutics; oxidation; small molecule; stereochemistry; tool

DESCRIPTION (provided by applicant): Proton-coupled electron transfers (PCETs) are unconventional redox processes in which an electron and proton are exchanged together in a concerted elementary step. While PCET is now recognized to play a central a role in biological redox catalysis and inorganic solar energy conversion technologies, its applications in organic chemistry remain largely unexplored. This proposal aims to establish concerted PCET as a general mode of substrate activation for organic synthesis, providing novel solutions to significant and long-standing synthetic challenges in the areas of free radical chemistry, asymmetric catalysis, and organometallic chemistry. The central goal of this work is to establish concerted PCET as a general mechanism for homolytic bond activation that is complementary to and broader in scope than conventional hydrogen atom transfer (HAT) chemistry. Specifically, concerted PCET provides a mechanism by which a Bronsted base and a one-electron oxidant can function together as a formal hydrogen-atom acceptor capable of selectively oxidizing bonds that are energetically inaccessible using conventional H-atom transfer catalyst platforms (up to 110 kcal/mol). Similarly, Bronsted acids and one-electron reductants can function jointly as formal H-atom donors, activating p bonds to form radical centers vicinal to extraordinarily weak bonds (<20 kcal/mol). Taken together with a unique kinetic feature of concerted PCET, this remarkable energetic range presents a framework to develop methods for the direct homolytic activation of nearly any organic functional group. In addition, PCET presents unique opportunities for controlling enantioselectivity in radical processes. PCET typically occurs through a hydrogen-bond complex between the substrate and a proton donor/acceptor. These H-bond interfaces often remain intact following the PCET event, resulting in the formation of strongly stabilized non-covalent complexes of neutral radical intermediates. When chiral proton donors/acceptors are employed, this association can provide a basis for asymmetric induction in subsequent bond forming events. Lastly, this proposal describes a novel PCET mechanism for the generation of organometallic intermediates from unfunctionalized substrates. This work exploits the ability of redox active metal centers to homolytically weaken the bonds in coordinated ligands, enabling otherwise strong X-H bonds (BDE ~100 kcal) to be abstracted by weak H-atom acceptors through concomitant oxidation of the metal center. This 'soft homolysis' mechanism provides a method to generate closed-shell organometallic intermediates from unfunctionalized starting materials under completely neutral conditions. Taken together, these technologies have the potential to simplify and improve the synthesis of drugs and other small-molecule probes of biological function, creating a significant benefit for human health and the associated biomedical sciences.

描述（由申请人提供）：质子耦合的电子传输（PCET）是非常规的氧化还原过程，其中电子和质子在协同的基本步骤中交换在一起。虽然PCET现在被认为在生物氧化还原催化和无机太阳能转化技术中发挥着重要作用，但其在有机化学中的应用仍未得到探索。该提案旨在将协同的PCET作为有机合成的底物激活的一般模式，为自由基化学，不对称催化和有机化化学方面的重要和长期的合成挑战提供新的解决方案。 这项工作的核心目标是建立一致的PCET作为均应键激活的一般机制，与常规氢原子转移（HAT）化学相比，均与范围更广泛。具体而言，协同的PCET提供了一种机制，通过该机制，Bronsted碱基和单电子氧化剂可以作为正式的氢原子受体一起起作用，能够使用常规的H原子传递催化剂平台（最高110 kcal/mol）选择性地氧化能在能量上无法访问的键。同样，布朗斯特酸和单电子还原剂可以作为形式的H原子供体共同发挥作用，激活P键以形成激进的中心，直至非常弱键（<20 kcal/mol）。结合了协同PCET的独特动力学特征，这个非凡的能量范围为开发了几乎所有有机官能团的直接均溶性激活的方法提供了一个框架。此外，PCET为在激进过程中控制对映选择性提供了独特的机会。 PCET通常通过底物和质子供体/受体之间的氢键复合物发生。 PCET事件发生后，这些H键界面通常保持完整，从而形成了中性自由基中间体的强稳定的非共价复合物。当使用手性质子供体/受体时，该关联可以为随后的键形成事件提供不对称诱导的基础。最后，该提案描述了一种新型的PCET机制，用于从未实施的底物产生有机金属中间体。这项工作利用了氧化还原活性金属中心的能力，可以通过弱的H原子受体通过同伴氧化来使氧化配体中的键削弱键削弱的键，从而使其他强大的X-H键（BDE〜100 kcal）被金属中心的氧化。这种“软均利分解”机制提供了一种在完全中性条件下从未实施的起始物质中产生封闭壳有机金属中间体的方法。综上所述，这些技术具有简化和改善药物和其他小分子探针的合成，从而为人类健康和相关的生物医学科学带来了重大益处。