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(Jason Bates) 酰胺键是药物中最常见的官能团之一，通过反应形成它们 是药物化学家最常使用的药物之一。而酰胺合成的化学计量方法包括 大量的废物，目前的催化方法在范围和化学选择性、贵金属的使用、 高温或高压条件，或这些缺点的一些组合。好氧氧化偶联 含醇的胺是一条很有前途的路线，因为它的原子经济性和通常的温和条件，但不均匀。 基于地球上丰富的金属的催化剂还没有被确定为这种化学物质。多相催化开辟了新的前景 药物合成中的机会，在固体上具有独特的活性中心配置，通过简化 分离和回收，以及流程型生产的适应性。这项建议描述了氧化剂的发展 以氧气为氧化剂的掺氮碳固体中基于金属的酰胺偶联策略。一个全面的 将采用筛选的方法来确定代表模型的最佳催化剂和反应条件 含有一系列醇和胺的底物。该方法学将应用于合成靶标 与药物相关的分子，包括那些具有挑战性的官能团，以探测 化学选择性，以及对立体中心的敏感性也将被探索。详细的动力学和机械学研究， Hammett研究和H/D动力学同位素效应实验被用来阐明基本步骤、静止状态、 以及在所研究的多相催化剂上参与有氧氧化的速率控制过程。基本见解 进入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索共催化的作用 加速氧化速率的氮氧自由基。多相共催化硝基化合物的选择设计规则 将开发催化剂，它代表了一种模块化策略，用于改变反应性和化学选择性，而不需要 改变任何其他实验条件。基于机理的直觉也暗示了新型催化剂的合理设计 促进酰胺偶联的固体结构。金属约束的氮掺杂碳材料 将开发分子维度的口袋，以稳定催化循环中的活性中间体，并 基于尺寸排斥的化学选择催化效应。具有良好配位体的第二类多相催化剂 将合成球体以阐明氧化酰胺中支持官能团的位置要求和作用 偶联催化。多相催化氧化酰胺偶联反应的研究进展及基本原理 了解它们的作用机理和它们的活性中心将有助于原子高效地合成酰胺键 在各种药物分子中，有助于积极的健康结果，并促进相关的发展 不同化学成分的多相催化体系。