Chemoselective Heterogeneous Catalysts for Oxidative Amide Coupling

用于氧化酰胺偶联的化学选择性多相催化剂

• 批准号: 10370346
• 负责人: Jason S Bates
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370346
• 关键词: Active Sites; Address; Aerobic; Age; Alcohols; Aldehydes; Amides; Amines; Architecture; Binding; Binding Sites; Carbon; Catalysis; Chemical Industry; Chemicals; Chemistry; Chiroptera; Complex; Coupled; Coupling; Development; Dimensions; Dioxygen; Environment; Enzymes; Exclusion; Health; High temperature of physical object; Human; Industrialization; Intuition; Investigation; Isotopes; Kinetics; Lead; Ligands; Light; Measurement; Metals; Methodology; Methods; Modeling; Modernization; Molecular; Natural graphite; Nitrogen; Oral cavity; Outcome; Oxidants; Oxides; Pathway interactions; Peptide Synthesis; Pharmacologic Substance; Planet Earth; Process; Production; Reaction; Reagent; Recycling; Research; Rest; Role; Route; Side; Site; Solid; Structure; System; Technology; Translations; Zeolites; base; catalyst; cost; design; experimental study; functional group; improved; insight; molecular scale; nitroxyl; novel; oxidation; pressure; rational design; screening; wasting; working group

PROJECT SUMMARY (Jason Bates) Amide bonds are one of the most common functional groups present in pharmaceuticals, and reactions to form them are among the most frequently practiced by medicinal chemists. While stoichiometric methods of amide synthesis involve significant waste, current catalytic methods are limited either in their scope and chemoselectivity, use of precious metals, high temperature or pressure conditions, or often some combination of these drawbacks. Aerobic oxidative coupling of amines with alcohols is a promising route in terms of its atom economy and typically mild conditions, but heterogeneous catalysts based on earth-abundant metals have not been identified for this chemistry. Heterogeneous catalysis opens new opportunities in pharmaceutical synthesis for unique active site configurations on solids, minimized waste via ease of separation and recycling, and adaptability for flow-based production. This proposal describes the development of oxidative amide coupling strategies based on metals in nitrogen-doped carbon solids using dioxygen as oxidant. A comprehensive screening approach will be employed to identify optimal catalysts and reaction conditions for representative model substrates encompassing a range of alcohols and amines. The methodology will be applied to synthesize target pharmaceutically relevant molecules including those bearing challenging functional groups to probe the extent of chemoselectivity, and the sensitivity to stereocenters will also be explored. Detailed kinetic and mechanistic studies, Hammett studies, and H/D kinetic isotope effect experiments are proposed to elucidate the elementary steps, resting states, and rate-controlling processes involved in aerobic oxidations on the heterogeneous catalysts studied. Fundamental insights into the factors that lead to preferential alcohol activation and ultimately amide coupling can be intuitively extended to other chemistries that share similar transition states. Mechanistic investigations will be extended to probe the role of co-catalytic nitroxyl radicals that accelerate oxidation rates. Design rules for the selection of co-catalytic nitroxyls with heterogeneous catalysts will be developed, which represent a modular strategy for altering reactivity and chemoselectivity without changing any other experimental conditions. Mechanism-based intuition also suggests the rational design of new catalytic solid architectures to promote amide coupling. Nitrogen-doped carbon materials with metals confined within binding pockets of molecular dimension will be developed in order to stabilize reactive intermediates in the catalytic cycle, and to effect chemoselective catalysis based on size-exclusion. A second class of heterogeneous catalysts with well-defined ligand spheres will be synthesized to shed light on the site requirements and role of support functional groups in oxidative amide coupling catalysis. The development of heterogeneously catalyzed oxidative amide coupling reactions and fundamental understanding of their mechanisms and the active sites where they occur will enable atom-efficient synthesis of amide bonds in diverse pharmaceutical molecules that contribute to positive health outcomes, and facilitate development of related heterogeneous catalytic systems for diverse chemistries.

项目摘要（杰森·贝茨） 酰胺键是药物中最常见的官能团之一，以及形成它们的反应 是药物化学家最常使用的方法之一。虽然酰胺合成的化学计量方法涉及 大量浪费，目前的催化方法在其范围和化学选择性、贵金属的使用方面受到限制， 高温或高压条件，或者通常是这些缺点的组合。有氧氧化偶联 就其原子经济性和通常温和的条件而言，胺与醇是一种有前途的路线，但异质性 尚未发现基于地球储量丰富的金属的催化剂可用于这种化学反应。多相催化开辟新领域 在药物合成中为固体上独特的活性位点配置提供机会，通过简单的方法最大限度地减少浪费 分离和回收，以及对基于流程的生产的适应性。该提案描述了氧化的发展 基于氮掺杂碳固体中的金属的酰胺偶联策略，使用分子氧作为氧化剂。全面的 将采用筛选方法来确定代表性模型的最佳催化剂和反应条件 底物包括一系列醇和胺。该方法将用于合成目标 药学相关分子，包括那些带有挑战性官能团的分子，以探测其程度 化学选择性和立体中心的敏感性也将被探讨。详细的动力学和机理研究， 哈米特研究和 H/D 动力学同位素效应实验旨在阐明基本步骤、静止状态、 以及涉及所研究的多相催化剂有氧氧化的速率控制过程。基本见解 研究导致优先醇活化和最终酰胺偶联的因素可以直观地扩展到其他 具有相似过渡态的化学物质。机理研究将扩展到探讨助催化的作用 硝酰自由基加速氧化速度。异质共催化硝酰基选择的设计规则 将开发催化剂，它代表了一种模块化策略，可以在不改变反应性和化学选择性的情况下改变反应性和化学选择性。 改变任何其他实验条件。基于机制的直觉还表明新催化的合理设计 促进酰胺偶联的固体结构。氮掺杂碳材料，其金属限制在结合内 将开发分子尺寸的口袋，以稳定催化循环中的反应中间体，并 影响基于尺寸排阻的化学选择性催化。第二类具有明确配体的多相催化剂 将合成球体，以阐明氧化酰胺中支持官能团的位点要求和作用 偶联催化。非均相催化氧化酰胺偶联反应的进展及基础 了解它们的机制和它们发生的活性位点将使酰胺键的原子有效合成成为可能 多种药物分子有助于产生积极的健康结果，并促进相关药物的开发 适用于多种化学反应的多相催化系统。