Catalytic Oxidations for Pharmaceutical Synthesis

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。 合成学药物、天然产物和其他生物活性化合物的合成催化剂的研究进展 氧化反应可能对药物的发现和生产产生重大影响。这个 大多数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。建议数 研究人员将开发新的氧化和氧化耦合方法，形成碳-碳和碳-碳 杂原子键，包括C(SP3)-H官能化反应。产生的一些方法将 简化具有不同三维结构的新生物活性分子的发现，解决 药物化学和药物发现方面的关键挑战，而其他挑战将为简化 药物的过程规模合成。三个相辅相成的项目方向在此概述 求婚。第一个重点是“氧化物型”好氧氧化催化剂的开发。 过渡金属和氧化还原活性有机助催化剂。将探索新的生物灵感催化剂系统， 展示了“二阶仿生作用”，即简单的有机前体经过氧化自我处理，以 创造必要的助催化剂。这一过程类似于氨基酸的翻译后修饰。 在自然界中产生反应性辅因子的侧链。第二个项目将寻求新的电化学 用于合成难以通过经典合成方法获得的有机分子的氧化方法 方法：研究方法。这些努力的目标是设计允许反应的介体和电催化剂 在低电极电位下进行，从而容忍不同的官能团并实现广泛的范围 和实用性。最后，我们将开发用于苄基C-H氧化和氧化偶联的“自由基接力”方法 以提供新的C(SP3)C-O、C-N、C-X和C-C键。这些努力将应用于医药建设-- 区块多样化、岩心改造和后期功能化。在这些项目的每个领域， 经验反应发现工作将得到催化反应的机理研究的补充。 在该项目的所有阶段与制药公司的密切互动和合作将发挥 在确保我们的努力产生尽可能广泛的影响方面发挥重要作用。这些项目领域中的每一个都受到支持 通过严格的运动学和机械分析，将从专门设计的设备中受益匪浅 监控反应进度。

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 design of 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. Each of these project areas is supported by rigorous kinetic and mechanistic analysis that will greatly benefit from dedicated equipment designed to monitor the reaction progress.