Catalytic Oxidations for Pharmaceutical Synthesis

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。催化进展 氧化反应有可能对药物的发现和生产产生重大影响。的 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。拟议的 研究将开发新的氧化和氧化偶联方法，形成碳-碳和碳- 杂原子键，包括 C(sp3)–H 官能化反应。一些由此产生的方法将 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的关键挑战，而其他挑战将为简化流程提供基础 药物的工艺规模合成。本文件概述了三个互补的项目方向 提案。第一个重点是“氧化酶”型有氧氧化催化剂的开发，其特点是 过渡金属和氧化还原活性有机助催化剂。将探索新的仿生催化剂系统 表现出“二级仿生学”，简单的有机前体经过氧化自加工 创造必要的助催化剂。这个过程类似于氨基酸的翻译后修饰 侧链在自然界中产生反应性辅因子。第二个项目将追求新的电化学 用于合成难以通过经典合成获得的有机分子的氧化方法 方法。这些努力的目标是设计介体和电催化剂，使反应能够 在低电极电位下进行，从而耐受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“自由基中继”方法 提供新的 C(sp3) C–O、C–N、C–X 和 C–C 键。这些努力将应用于制药建筑—— 区块多样化、核心修改和后期功能化。在每个项目领域中， 催化反应的机理研究将补充经验反应发现工作。 在该项目的各个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着重要作用。这些项目领域中的每一个都受到支持 通过严格的动力学和机械分析，这将大大受益于专门设计的设备 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.