Model Systems for C-H Bond Transformations through Multiple-Site Concerted Proton-Electron Transfer

通过多位点协同质子-电子转移进行 C-H 键转变的模型系统

• 批准号: 10453794
• 负责人: Scott Christopher Coste
• 金额: $ 5.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453794
• 关键词: Acids; Active Sites; Address; Affect; Alkenes; Amides; Anaerobic Bacteria; Betula Genus; Biochemical; Biochemical Reaction; Biochemistry; Biological; Biological Models; Carbon; Cell Respiration; Coenzyme A; Complex; Coupling; Dependence; Development; Distant; Educational process of instructing; Electron Transport; Energy Metabolism; Energy Transfer; Environment; Enzymes; Faculty; Fostering; Foundations; Free Energy; Future; Goals; Heart; Hydrogen Bonding; Hydrogenation; Institution; Kinetics; Learning; Measurement; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Microbe; Modeling; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Photosynthesis; Process; Protons; Reaction; Research; Research Personnel; Respiration; Series; Site; Sulfonamides; System; Training; Universities; Variant; Writing; base; career; cofactor; cost; design; driving force; insight; kinetic model; methyl group; molecular modeling; morphogens; novel strategies; oxidation; post-doctoral training; reaction rate; skills; teacher; thioester; unsaturated bonds

Project Summary/Abstract C–H bond transformations lie at the heart of numerous metabolic pathways throughout the biosphere. Oxidoreductase enzymes manipulate strong X–H bonds (X = C, N, O) with limited free energy expenditure through a process known as multiple-site concerted proton-electron transfer (MS-CPET) which underlies photosynthesis, respiration, and complex biomolecule synthesis. In many of these reactions, the proton transfer coordinate is guided by pre-aligned hydrogen bonding interactions, which are absent with C–H bonds. Consequently, the mechanisms of many CH-CH oxidoreductase enzymatic reactions are not known despite the large number that rely on distant electron transfer cofactors. Therefore, deriving principles behind MS-CPET involving C–H bonds would be immensely informative to unveiling how a significant amount of enzymes function in the biosphere. In this proposal, we seek to understand how the proton transfer coordinate governs C–H bond reactivity through MS-CPET using molecular models. Specifically, we will probe how key aspects such as proton transfer pre-alignment and proton tunneling distance affect C–H bond cleavage through structural variation. We will also derive essential thermochemical principles for reductive C–H bond formation in a stable radical system to develop kinetic free energy relationships. Finally, we will build upon these kinetic and thermochemical models to assess the reductive hydrogenation mechanism of aromatic substrates central to anaerobic microbe metabolism. Our goal is to develop a mechanistic understanding of MS-CPET with C-H bonds in our model systems to illuminate unknown CH-CH oxidoreductase reactivity. This research will help elucidate how enzymes perform difficult C–H bond transformations and guide synthetic chemists towards new approaches for manipulating strong bonds. My postdoctoral training in the Mayer group will expand my research skillset through learning mechanistic and kinetic studies as well as allowing me to hone my mentorship, writing, and presenting skills. Importantly, this training will teach me new ways to think and approach scientific problems allowing me to expand the scope of research I can address in my future independent career. Yale University fosters an ideal environment to train me with its exceptional facilities, seminar and teaching opportunities, and prominent faculty who are experts in synthetic organic, theoretical, and biological chemistry. I believe my training will sufficiently equip me to be a leading independent researcher and teacher at an academic institution in the future.

项目概要/摘要 C-H 键转变是整个机体众多代谢途径的核心 生物圈。氧化还原酶利用有限的游离态操纵强 X-H 键 (X = C、N、O) 通过多位点协同质子电子转移过程消耗能量 (MS-CPET) 是光合作用、呼吸和复杂生物分子合成的基础。在 在许多这样的反应中，质子转移坐标是由预先排列的氢引导的 键合相互作用，而 C-H 键不存在这种相互作用。因此，许多机制 尽管大量依赖于CH-CH氧化还原酶的酶促反应，但CH-CH氧化还原酶的酶促反应尚不清楚 远距离电子转移辅助因子。因此，推导涉及 C-H 的 MS-CPET 背后的原理 键对于揭示大量酶如何发挥作用将提供大量信息 在生物圈中。 在这个提案中，我们试图了解质子转移坐标如何控制 C-H 键 使用分子模型通过 MS-CPET 进行反应。具体来说，我们将探讨关键方面如何 例如质子转移预对准和质子隧道距离影响C-H键断裂 通过结构变异。我们还将推导出还原反应的基本热化学原理 在稳定的自由基体系中形成 C-H 键以发展动能自由能关系。最后， 我们将基于这些动力学和热化学模型来评估还原 芳香族底物的氢化机制对厌氧微生物代谢至关重要。我们的 目标是在我们的模型系统中建立对带有 C-H 键的 MS-CPET 的机械理解 阐明未知的 CH-CH 氧化还原酶反应性。这项研究将有助于阐明如何 酶进行困难的 C-H 键转变，并指导合成化学家走向新的方向 操纵强债券的方法。 我在梅耶小组的博士后培训将通过学习扩展我的研究技能 机械和动力学研究，以及让我磨练我的指导、写作和 展示技巧。重要的是，这次培训将教会我思考和接近科学的新方法 允许我扩大研究范围的问题，我可以在未来的独立研究中解决 职业。耶鲁大学以其卓越的设施为我提供了理想的培训环境， 研讨会和教学机会，以及合成有机专家的杰出教师， 理论和生物化学。我相信我的训练足以使我成为领导者 未来在学术机构担任独立研究员和教师。