Radical Relay Methods for Selective C-H Oxidation

选择性 C-H 氧化的自由基接力方法

• 批准号: 9767243
• 负责人: Shannon S Stahl
• 金额: $ 29.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767243
• 关键词: Acids; Alkylating Agents; Architecture; Biological; Boronic Acids; Carbon; Chemicals; Collaborations; Complement; Complex; Coupled; Coupling; Development; Dimensions; Electron Transport; Electrons; Esters; Exhibits; Generations; Hybrids; Hydrogen; Hydrogen Bonding; Mediating; Mediator of activation protein; Metabolic; Methodology; Methods; Modification; Natural Products; Nitrogen; Oxidants; Oxygen; Pathway interactions; Peroxides; Pharmaceutical Preparations; Pharmacologic Substance; Protons; Reaction; Reagent; Research; Site; Structure; Targeted Research; Therapeutic Agents; base; c new; comparative; drug candidate; drug discovery; drug efficacy; method development; novel therapeutics; oxidation

Project Summary Oxidation reactions exhibit significant value in the synthesis of pharmaceuticals, natural products and other bioactive compounds. The proposed studies will develop powerful new synthetic methods for selective oxidative functionalization of C(sp3)–H bonds. Benzylic C–H bonds represent a strategic target: such bonds are ubiquitous in pharmaceuticals and they are comparatively weak relative to most other C–H bonds. The latter feature provides the basis for selective functionalization of these sites via radical intermediates. In addition, benzylic sites often contribute to the metabolic instability of pharmaceuticals, and their selective modification will confer enhanced biological potency. Our efforts target the development of synthetic methods that may be readily adapted to pharmaceutical discovery and facilitate access to drug candidates with more-complex three dimensional architectures. The project will employ two complementary experimental strategies. One will make use of chemical oxidants that initiate selective hydrogen-atom abstraction from benzylic sites, while the second will exploit electrochemical methods that utilize catalytic electron-, electron/proton-, or hydrogen-atom-abstraction mediators to generate radical intermediates. Both the chemical and electrochemical methods will target benzylic C–H coupling reactions that generate diversely functionalized products. The electrochemical methodology will also target the generation of radicals that undergo addition reactions with (hetero)aromatic rings to produce medicinally relevant aromatic molecules. Several of the benzylic C–H oxidative coupling reactions show effective reactivity with the benzylic coupling partner as the limiting reaction, thereby making them highly appealing for late-stage functionalization of complex molecules. Opportunities toward this end will be explored in collaboration with Merck. Overall, the complementary chemical and electrochemical C–H oxidation methods are poised to greatly impact drug discovery efforts.

项目摘要 氧化反应在药物、天然产物的合成中显示出重要价值， 其他生物活性化合物。这些研究将为选择性地合成具有生物活性的化合物提供有力的新方法。 C（sp3）-H键的氧化官能化。苄基C-H键代表了一个战略目标： 在药物中普遍存在，并且相对于大多数其他C-H键，它们相对较弱。的 后一特征提供了通过自由基中间体选择性官能化这些位点的基础。在 此外，苄基位点通常导致药物的代谢不稳定性，并且它们的选择性不稳定。 修饰将赋予增强的生物效力。我们的努力目标是开发合成 可以容易地适应药物发现并促进获得候选药物的方法 更复杂的三维结构。该项目将采用两个互补的 实验策略。人们将利用化学氧化剂，引发选择性的氢原子 提取从苄基网站，而第二个将利用电化学方法，利用催化 电子-、电子/质子-或氢原子-夺取介体以产生自由基中间体。两 化学和电化学方法将针对苄型C-H偶联反应， 双官能化产物。电化学方法还将针对生成 与（杂）芳环进行加成反应以产生药用相关芳族化合物的基团 分子。几种苄基C-H氧化偶联反应显示出与苯甲酸的有效反应性。 苄基偶联配偶体作为限制反应，从而使它们对后期阶段非常有吸引力。 复杂分子的功能化。为此目的，将与下列机构合作探讨各种机会： 默克总的来说，互补的化学和电化学C-H氧化方法准备用于 对药物研发工作产生了很大影响。

项目成果

Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space.

• DOI: 10.1021/acs.accounts.3c00580
• 发表时间: 2023-12
• 期刊: Accounts of chemical research
• 影响因子: 18.3
• 作者: Si-Jie Chen;S. Krska;S. Stahl