Copper as a Photocatalyst: Applications in Decarboxylative Fluorination

铜作为光催化剂：在脱羧氟化中的应用

• 批准号: 10627772
• 负责人: Caitlin Rebecca Lacker
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-02-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627772
• 关键词: Acidity; Acrylates; Amination; Antibiotic Resistance; Carboxylic Acids; Catalysis; Charge; Chemistry; Complex; Copper; Decarboxylation; Development; Effectiveness; Esters; Fluorine; Geometry; Goals; Health; Investigation; Ligands; Ligation; Light; Mediating; Metals; Methodology; Methods; Molecular; Molecular Conformation; Oxidants; Pharmaceutical Chemistry; Pharmacologic Substance; Property; Public Health; Reaction; Reagent; Research; Salts; Source; Spectrum Analysis; Sulfhydryl Compounds; Time; Ultraviolet Rays; Visible Radiation; absorption; cancer type; carboxylate; carboxylation; catalyst; computer studies; drug candidate; insight; invention; irradiation; lipophilicity; novel; prevent; quantum; resilience; selectfluor; small molecule

PROJECT SUMMARY Fluorination of pharmaceutical compounds has been shown to increase their potency through modulation of their lipophilicity, acidity, and conformational bias. Photoredox decarboxylative fluorination in particular has been recognized as a powerful strategy for accessing fluorinated compounds. However, these methods have typically been limited to cooperative catalysis with expensive Ir or organic photocatalysts. The Yoon lab has recently demonstrated a novel way to promote oxidative photochemical decarboxylation using simple CuII salts. Irradiation of the CuII carboxylate results in ligand-to-metal charge transfer, which leads to rapid decarboxylation to generate the alkyl radical. They applied this strategy towards the decarboxylative amination of benzylic carboxylic acids. This proposal details the application of this strategy towards oxidative decarboxylative fluorination and investigation of the reaction mechanism of this approach. In the first Aim, the photochemical oxidative decarboxylative fluorination of alkyl carboxylic acids will be developed using stoichiometric copper as both the terminal oxidant and decarboxylating agent. Both radical abstraction and nucleophilic fluorination mechanisms will be probed. The second Aim focuses on the development of a copper-catalyzed photochemical decarboxylative fluorination using Selectfluor as a source of fluorine and as an oxidant to turn over the catalyst. Use of catalytic copper allows for tuning of light absorption and copper complexation through ligand choice. UV-Vis will be used to identify ligands that form copper complexes that absorb light in the visible region and are stable in the presence of excess carboxylate. The reaction mechanism will be interrogated through quantum yield studies. Finally, upon development of the stoichiometric and catalytic methods, the mechanism and identity of the active copper species in solution will be investigated through UV-Vis, EPR, and computational studies as part of the third Aim. Development of this strategy provides a complementary approach to existing methods for the incorporation of fluorine in small molecules using simple, inexpensive reagents and affords mechanistic insight into a novel method for photochemical oxidative decarboxylation.

项目摘要 已经证明，药物化合物的氟化可以通过 调节其亲脂性，酸度和构象偏置。 Photoredox脱羧 尤其是氟化已被公认为是获得氟化的有力策略 化合物。但是，这些方法通常仅限于与 昂贵的IR或有机光催化剂。 Yoon Lab最近展示了一种新颖的促进方式 使用简单的CUII盐氧化光化学脱羧。 CUII羧酸盐的辐照 导致配体至金属电荷转移，从而导致快速脱羧以产生烷基 激进的。他们将此策略应用于苯并羧酸的脱羧胺化。 该建议详细介绍了该策略在氧化脱羧荧光方面的应用 并研究了这种方法的反应机制。在第一个目标中，光化学 将使用化学计量学开发烷基羧酸的氧化脱羧氟化 铜作为末端氧化剂和脱羧剂。从根治性抽象和 将探测亲核氟化机制。第二个目标重点是发展 使用Selectfluor作为氟的铜催化光化学脱羧氟化 并作为氧化剂翻转催化剂。催化铜的使用可以调节吸收光 和通过配体选择的铜络合。紫外线将用于识别形成铜的配体 吸收可见区域且在过量羧酸盐存在下稳定的络合物。 反应机制将通过量子产率研究审问。最后，发展 在化学计量和催化方法中，活性铜物种的机制和身份 解决方案将通过UV-VIS，EPR和计算研究研究，这是第三个目标的一部分。 这种策略的制定为现有方法提供了一种补充方法 使用简单，廉价的试剂将氟掺入小分子中，并提供机械 深入了解一种新颖的光化学氧化脱羧方法。