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）：质子耦合电子转移（PCET）是非常规的氧化还原过程，其中电子和质子在协调的基本步骤中一起交换。虽然 PCET 现在被认为在生物氧化还原催化和无机太阳能转换技术中发挥着核心作用，但其在有机化学中的应用在很大程度上仍未得到探索。该提案旨在建立协同PCET作为有机合成底物活化的通用模式，为自由基化学、不对称催化和有机金属化学领域长期存在的重大合成挑战提供新颖的解决方案。 这项工作的中心目标是建立一致的 PCET 作为均裂键激活的通用机制，该机制与传统氢原子转移 (HAT) 化学互补且范围更广。具体来说，协同 PCET 提供了一种机制，通过该机制，布朗斯台德碱和单电子氧化剂可以一起作为正式的氢原子受体，能够选择性地氧化使用传统氢原子转移催化剂平台（高达 110 kcal/mol）在能量上难以接近的键。类似地，布朗斯台德酸和单电子还原剂可以共同充当正式的氢原子供体，激活 p 键以形成邻接至极弱键（<20 kcal/mol）的自由基中心。与协同 PCET 的独特动力学特征结合在一起，这种非凡的能量范围提供了一个框架，用于开发几乎任何有机官能团的直接均裂活化方法。此外，PCET 为控制自由基过程中的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。这些氢键界面通常在 PCET 事件后保持完整，导致形成高度稳定的中性自由基中间体非共价复合物。当使用手性质子供体/受体时，这种缔合可以为后续成键事件中的不对称诱导提供基础。最后，该提案描述了一种新颖的 PCET 机制，用于从非功能化基质生成有机金属中间体。这项工作利用了氧化还原活性金属中心均裂削弱配位配体中键的能力，使原本较强的 X-H 键（BDE ~100 kcal）能够通过金属中心的伴随氧化被弱 H 原子受体夺走。这种“软均解”机制提供了一种在完全中性条件下从未官能化的起始材料生成闭壳有机金属中间体的方法。总而言之，这些技术有可能简化和改进药物和其他生物功能小分子探针的合成，为人类健康和相关生物医学科学创造重大利益。