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.

项目概要 氧化反应是有机化学中最重要的反应之一，在化学反应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。催化氧化的进展 反应有可能对药物的发现和生产产生重大影响。大部分 现有的催化氧化方法在效率和选择性方面面临挑战，包括化学、区域氧化 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 形成碳-碳和碳-杂原子键的新氧化和氧化偶联方法，包括 C(sp3)–H 官能化反应。由此产生的一些方法将简化新发现的过程 具有多种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，而其他将为简化工艺规模合成提供基础 药品。该提案概述了三个互补的项目方向。第一个重点是 开发具有过渡金属和氧化还原活性的“氧化酶”型有氧氧化催化剂 有机助催化剂。将探索展示“二级仿生学”的新型仿生催化剂系统， 简单的有机前体通过氧化自加工产生重要的助催化剂。这 该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 在大自然中。第二个项目将寻求新的电化学氧化方法来合成有机化合物 通过经典合成方法难以获得的分子。这些努力的目标是确定 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 包容不同的功能群体并实现广泛的范围和实用性。最后，我们将开发“激进继电器” 苯甲基 C-H 氧化和氧化偶联产生新的 C(sp3) C-O、C-N、C-X 和 C-C 键的方法。 这些努力将应用于药物构建模块多样化、核心改造和后期阶段 功能化。在每个项目领域，经验反应发现工作将得到补充 催化反应的机理研究。与制药公司密切互动与合作 参与该项目各个阶段的公司将发挥重要作用，确保我们的项目产生尽可能广泛的影响 努力。