Proton-Coupled Electron Transfer in Organic Synthesis and Asymmetric Catalysis

描述（由申请人提供）：质子偶联电子转移（PCT）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尚未开发。该提案旨在建立协调PCET作为有机合成的底物活化的一般模式，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一致的PCET作为均裂键活化的一般机制，该机制与传统的氢原子转移（HAT）化学相比是互补的并且范围更广。具体地，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形式氢原子受体起作用，该形式氢原子受体能够选择性地氧化使用常规H原子转移催化剂平台（高达110 kcal/mol）在能量上不可接近的键。类似地，布朗斯台德酸和单电子还原剂可以共同作为正式的H原子供体，活化p键以形成与非常弱的键（<20 kcal/mol）相邻的自由基中心。考虑到协同PCET的一个独特的动力学特征，这个显着的能量范围提出了一个框架，以开发几乎任何有机官能团的直接均裂活化的方法。此外，PCET提供了独特的机会，控制自由基过程中的对映体选择性。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H-键界面通常在PCET事件之后保持完整，导致中性自由基中间体的强稳定的非共价复合物的形成。当采用手性质子供体/受体时，这种缔合可以为随后的键形成事件中的不对称诱导提供基础。最后，该建议描述了一种新的PCET机制，用于从未官能化的底物生成有机金属中间体。这项工作利用氧化还原活性金属中心均裂削弱配位体中的键的能力，使原本强的X-H键（BDE ~100 kcal）通过金属中心的伴随氧化被弱H原子受体夺取。这种“软均裂”机制提供了一种在完全中性条件下由未官能化的起始材料生成闭壳有机金属中间体的方法。总之，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重大利益。

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.