Subproject Investigator: Dong Wang

子项目研究员：王栋

• 批准号: 10004089
• 负责人: Dong Wang
• 金额: $ 21.47万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004089
• 关键词: Active Sites; Affect; Affinity; Agrochemicals; Alkynes; Azides; Binding; Biochemical Reaction; Biological; Biomimetics; Carbon; Chemistry; Cleaved cell; Clinical; Development; Diamond; Enzymes; Generations; Goals; Hydrocarbons; Hydrogen Bonding; Hydroxylation; Ligands; Metabolic; Metals; Methane; Methane hydroxylase; Methanol; Mononuclear; Nuclear; Oxidants; Oxidation-Reduction; Oxides; Pathway interactions; Pharmacologic Substance; Planet Earth; Process; Reaction; Reagent; Research; Research Personnel; Specificity; Structure; System; Transition Elements; alpha ketoglutarate; base; biological systems; catalyst; cycloaddition; design; drug candidate; functional group; improved; metal complex; metalloenzyme; next generation; oxidation; scaffold

Project Summary: Title: M2O2 "Diamond Core": the Next Generation of Biomimetic Transition-metal Catalyst for Effective and Selective Aliphatic Hydrocarbon Functionalization. The selective installation of functional groups onto inert aliphatic carbon centers is a key step in many metabolic transformations, and finds many uses in the synthesis of pharmaceuticals, clinical reagents, materials and agrochemicals. For example, the halogenated biomolecules and drug candidates are expected to be more metabolically stable and have improved target-binding affinities. The introduction of the azide group, on the other hand, provides a convenient way to access a variety of functionalities through redox chemistry and the azide-alkyne cycloaddition reaction (“click chemistry”). In biological systems the functionalization of C–H bonds is catalyzed by metalloenzymes that utilize mono- or multi-nuclear active sites and employ earth-abundant transition metals. One representative example is the α-ketoglutarate dependent nonheme halogenase SyrB2 that activates O2 as the natural oxidant and specifically converts a C–H bond to a C–Cl bond through a high-valent Cl–FeIV=O intermediate. A recent development has even shown that SyrB2 could carry out aliphatic C–N bond formation reactions, suggesting that this radical-based reaction pathway might be considered as a universal strategy for aliphatic C–H bond functionalization. While this enzymatic strategy appears highly attractive in designing biomimetic catalytic systems; great challenges exist for synthetic systems, which lack the enzymatic scaffold, in controlling the transfer of the functional group selectively onto the target carbon center. Competition between the functional group –X and the –OH group generated by the initial C–H bond cleavage from the substrate normally resulted in a reaction mixture composed of multiple products. In order to tackle these challenges, the proposed research is inspired by natural metalloenzymes that utilize dinuclear active sites possessing a specific M2(µ-O)2 “diamond core” structure, and recent biomimetic studies showing that the M2(µ-O)2 “diamond core” could be activated to release higher oxidizing ability upon interacting with Lewis bases. The proposed dinuclear synthetic catalysts would have a M2(µ-O)2 “diamond core”, where the two metals function in a cooperative manner in the catalytic cycle. This project also integrates attractive features of high-valent metal-oxo chemistry for late-transition metals (Co, Ni) as active C–H bond cleaving oxidants. Specifically, the project contains three aims. The goal of the first aim is to design and evaluate the catalytic system, including synthesizing and characterizing ligands and catalysts, optimizing experimental conditions, expanding the substrate scope and the identity of the functional group, and investigating the reaction mechanism and the ligand effect on the catalytic activity. In the second aim, efforts will be devoted to the independent generation and characterization of high-valent late-transition metal-oxo intermediates involved in the catalytic cycle. The focus of the third aim is to investigate discriminating factors that affect functional group transfer and the selectivity, including the oxidation state of the metal and the configuration of the open core structure upon interacting with the functional group.

项目摘要： 标题：M2O2“钻石核心”：下一代仿生过渡金属催化剂有效 选择性脂肪族烃官能化。 官能团在惰性脂肪族碳中心上的选择性安装是许多代谢的关键步骤 转化，并在制药，临床试剂，材料和 例如，农产品。 可满足的稳定，并改善了目标结合的亲和力。 手，提供了一种方便的方法来访问氧化还原化学和你的各种功能 叠氮化物环节反应（“单击化学”）。 由利用单核或多核活性位点的金属酶催化并使用地球丰富 过渡金属。 这将O2作为天然氧化剂，并专门将C -H键通过A转换为C -Cl键 高价值Cluarfeiv = O中级。 C – N键形成反应，建议基于自由基的反应途径可能被认为是 脂肪性C- H键功能的普遍策略。 在设计生物模型的催化系统方面有吸引力； 酶支架，在控制官能团的转移到目标碳中心时。 功能组-X与-OH组之间由初始C -H键裂解产生的-OH组之间的竞争 从底物中，通常导致由多种产物组成的反应混合物。 为了解决这些Challlenges，拟议的研究的灵感来自天然金属酶的启发 具有特定M2（µ-O）2“钻石核”结构的二十个活跃位点和最近的仿生研究 表明M2（µ-O）2“ Diamond Core”可以激活以释放相互作用时释放高氧化能力 刘易斯基地。 两个金属在催化周期中以合作的方式运行。 用于晚过渡金属（CO，Ni）的高价值金属氧化物化学作为活性C-H键切割氧化剂。 具体来说，该项目包含三个目标。 系统，包括合成和表征配体和催化剂，优化经验条件， 扩展底物范围和功能组的身份，并研究反应机理 配体对催化活性的影响。 涉及催化的高价值晚期金属氧的产生和表征 周期。 选择性，包​​括金属的氧化状态以及开放核心结构的配置 与功能组相互作用。