Catalytic Oxidations for Pharmaceutical Synthesis

药物合成的催化氧化

• 批准号: 10319588
• 负责人: Shannon S Stahl
• 金额: $ 59.51万
• 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: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319588
• 关键词: 3-Dimensional; Address; Aerobic; Architecture; Area; Carbon; Collaborations; Complement; Coupling; Development; Electrodes; Ensure; Exhibits; Face; Mediator of activation protein; Methods; Modification; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Oxidases; Oxidation-Reduction; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Play; Posttranslational Amino Acid Modification; Process; Production; Reaction; Research; Role; Side; System; Therapeutic Agents; Transition Elements; catalyst; cofactor; drug discovery; functional group; oxidation

Project Summary Oxidation reactions are among the most important reactions in organic chemistry and play a crucial role in the synthesis of pharmaceuticals, natural products, and other bioactive compounds. Advances in catalytic oxidation reactions have potential for major impact in the discovery and production of pharmaceuticals. The majority of existing catalytic oxidation methods face challenges in their efficiency and selectivity, including chemo-, regio- and stereoselectivity, limiting their use in small- and large-scale applications. The proposed research will develop new oxidation and oxidative coupling methods that form carbon-carbon and carbon-heteroatom bonds, including C(sp3)–H functionalization reactions. Some of the resulting methods will streamline the discovery of new bioactive molecules with diverse three-dimensional architectures, addressing key challenges in medicinal chemistry and drug discovery, while others will provide the basis for streamlined process-scale synthesis of pharmaceuticals. Three complementary project directions are outlined in this proposal. The first focuses on the development of "oxidase"-type aerobic oxidation catalysts that feature a transition metal and a redox active organic co-catalyst. New bioinspired catalyst systems will be explored that exhibit "second-order biomimicry", whereby simple organic precursors undergo oxidative self-processing to create the essential co-catalysts. This process resembles the post-translational modification of amino acid side chains to generate reactive cofactors in Nature. The second project will pursue new electrochemical oxidation methods for the synthesis of organic molecules that are difficult to access via classical synthetic methods. These efforts target the identification of versatile mediators and electrocatalysts that permit the reactions to proceed at low electrode potentials, thereby tolerating diverse functional groups and enabling broad scope and utility. Finally, we will develop "radical relay" methods for benzylic C–H oxidation and oxidative coupling to afford new C(sp3) C–O, C–N, C–X, and C–C bonds. These efforts will be applied to pharmaceutical building-block diversification, core-modification, and late-stage functionalization. In each of these project areas, empirical reaction discovery efforts will be complemented by mechanistic studies of the catalytic reactions. Close interactions and collaborations with pharmaceutical companies in all phases of this project will play an important role in ensuring the broadest possible impact of our efforts.

项目摘要 氧化反应是有机化学中最重要的反应之一，在 药物，天然产物和其他生物活性化合物的合成。催化氧化的进步 反应可能在药物的发现和生产中产生重大影响。大多数 现有的催化氧化方法在其效率和选择性方面面临着挑战，包括化学，区域 和立体选择性，限制了它们在小型和大规​​模应用中的使用。拟议的研究将发展 新的氧化和氧化耦合方法，形成碳碳和碳杂质键，包括 C（SP3） - H功能化反应。一些结果的方法将简化新的发现 具有潜水员三维体系结构的生物活性分子，应对医学上的关键挑战 化学和药物发现，而其他人则将为简化的过程规模合成提供基础 药品。该提案中概述了三个完整的项目指示。第一个重点是 开发“氧化酶” - 型有氧氧化催化剂，具有过渡金属和氧化还原活性 有机共催化剂。将探索新的生物启发的催化剂系统，这些系统提取“二阶仿生”， 因此，简单的有机前体经历氧化物自我处理以创建必需的共催化剂。这 过程类似于氨基酸侧链的翻译后修饰，以产生反应性辅助因子 本质。第二个项目将采用新的电化学氧化方法来合成有机 难以通过经典合成方法获得的分子。这些努力针对的是确定 多功能介质和电催化剂，允许反应在低电极电位上进行，从而 容忍潜水员的功能组并实现广泛的范围和效用。最后，我们将开发“激进的继电器” 苯并C -H氧化和氧化偶联的方法，可提供新的C（SP3）C – O，C – N，C – X和C – C键。 这些努力将应用于药物建筑块多样性，核心修饰和后期 功能化。在每个项目领域中，经验反应发现工作将由 催化反应的机械研究。与药品的紧密互动和合作 该项目的各个阶段的公司将在确保我们的最大可能影响方面发挥重要作用 努力。