Proton-Coupled Electron Transfer in Organic Synthesis and Asymmetric Catalysis

说明书(申请人提供)：质子耦合电子转移(PCET)是一种非传统的氧化还原过程，其中一个电子和质子在一个协调的基本步骤中交换在一起。尽管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，但它在有机化学中的应用在很大程度上仍未被探索。这项建议旨在建立协调的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的重大和长期存在的合成挑战提供新的解决方案。这项工作的中心目标是建立协调的PCET作为均解键激活的一般机制，与传统的氢原子转移(HAT)化学相辅相成，范围更广。具体地说，协同PCET提供了一种机制，通过该机制，Bronsted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H原子转移催化剂平台(高达110千卡/摩尔)在能量上无法获得的键。类似地，Bronsted酸和单电子还原剂可以作为正式的H原子供体，激活p键以形成非常弱的键附近的自由基中心(&lt；20千卡/摩尔)。结合协同PCET的独特动力学特征，这一显著的能量范围为开发几乎任何有机官能团的直接均解激活方法提供了一个框架。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体发生。在PCET事件发生后，这些氢键界面通常保持不变，导致中性自由基中间体形成强稳定的非共价络合物。当使用手性质子供体/受体时，这种缔合可以为随后的成键事件中的不对称诱导提供基础。最后，这项建议描述了一种新的PCET机制，用于从未功能化的底物中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一地削弱配位配体中的键的能力，使原本较强的X-H键(BDE~100kcal)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的条件下从未功能化的原料中合成闭壳有机金属中间体的方法。综上所述，这些技术有可能简化和改进药物和其他具有生物功能的小分子探针的合成，为人类健康和相关的生物医学科学创造巨大的好处。

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.