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，在有机合成中起着至关重要的作用。 药物、天然产物和其他生物活性化合物的合成。催化氧化研究进展 反应在药物的发现和生产中具有潜在的重大影响。大多数 现有的催化氧化方法在其效率和选择性方面面临挑战，包括化学-、区域- 和立体选择性，限制了它们在小规模和大规模应用中的使用。该研究将开发 形成碳-碳和碳-杂原子键的新的氧化和氧化偶联方法，包括 C（sp3）-H官能化反应。一些由此产生的方法将简化新的发现 具有不同三维结构的生物活性分子，解决医学领域的关键挑战 化学和药物发现，而其他将提供基础，精简的过程规模的合成 大药厂本提案概述了三个相辅相成的项目方向。第一个重点是 开发了“氧化酶”型有氧氧化催化剂，其特征在于过渡金属和氧化还原活性 有机助催化剂。新的生物启发催化剂系统将被探索，表现出“二级仿生”， 由此简单的有机前体经历氧化自处理以产生必要的助催化剂。这 这一过程类似于氨基酸侧链的翻译后修饰，以产生反应性辅因子 in Nature自然.第二个项目将寻求新的电化学氧化方法，用于合成有机 这些分子很难通过传统的合成方法获得。这些努力的目标是查明 多功能介体和电催化剂，允许反应在低电极电位下进行，从而 容许不同的功能组，并允许广泛的范围和用途。最后，发展“激进接力” 苄基C-H氧化和氧化偶联的方法，以提供新的C（sp 3）C-O、C-N、C-X和C-C键。 这些努力将应用于药物构建模块多样化，核心修饰和后期阶段 功能化在每个项目领域，经验反应发现工作将得到以下补充： 催化反应的机理研究。与制药公司密切互动和合作 参与该项目各个阶段的公司将在确保我们的项目产生尽可能广泛的影响方面发挥重要作用 努力