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.

项目总结（Jason Bates） 酰胺键是药物中最常见的官能团之一，形成它们的反应 是药物化学家最常用的方法之一。虽然酰胺合成的化学计量方法涉及 显著的浪费，目前的催化方法在它们的范围和化学选择性，贵金属的使用， 高温或高压条件下，或通常这些缺点的某种组合。好氧氧化偶联 胺与醇的反应在原子经济性和典型的温和条件方面是一种有前途的路线，但多相 基于地球上丰富的金属的催化剂还没有被确定用于该化学。多相催化开辟了新的 在药物合成中的机会，用于固体上独特的活性位点构型，通过易于 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， 酰胺偶联策略基于氮掺杂的碳固体中的金属，使用分子氧作为氧化剂。全面 筛选方法将用于确定代表性模型的最佳催化剂和反应条件 包括一系列醇和胺的底物。该方法将用于合成目标 药物相关分子，包括那些带有挑战性官能团的分子，以探测 化学选择性和对立体中心的敏感性也将被探索。详细的动力学和机理研究， Hammett研究，和H/D动力学同位素效应实验，提出了阐明的基本步骤，休息状态， 以及所研究的多相催化剂上有氧氧化的速率控制过程。基本见解 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的作用，共催化 加速氧化速率的硝酰基自由基。多相催化剂助催化剂硝基酚的选择设计规则 催化剂将被开发，这代表了一个模块化的战略，改变反应性和化学选择性， 改变其他实验条件。基于机理的直觉也表明了新催化剂的合理设计 固体结构以促进酰胺偶联。金属被约束在粘结剂内的氮掺杂碳材料 为了稳定催化循环中的活性中间体， 基于尺寸排阻实现化学选择性催化。具有明确配体的第二类多相催化剂 球将被合成，以阐明在氧化酰胺中的位置要求和支持官能团的作用 偶联催化非均相催化氧化酰胺偶联反应的研究进展及基本原理 了解它们的作用机制和活性位点，将有助于实现酰胺键的原子效率合成 在不同的药物分子，有助于积极的健康结果，并促进相关的发展， 多相催化体系用于不同的化学反应。