New Strategies for Copper-Catalyzed Cross-Coupling of Alkyl Electrophiles

铜催化烷基亲电试剂交叉偶联的新策略

• 批准号: 10650863
• 负责人: Wei Liu
• 金额: $ 39.58万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650863
• 关键词: Agrochemicals; Alcohols; Alkylation; Carbon; Catalysis; Characteristics; Complex; Copper; Coupling; Development; Disease; Elements; Generations; Goals; Human; Hydrogen Bonding; Life; Medicine; Metals; Natural Products; Organic Chemistry; Pathway interactions; Pharmacologic Substance; Planet Earth; Play; Prevention; Reaction; Research; Role; Transition Elements; Work; catalyst; chemical reaction; improved; invention; novel; public health relevance; small molecule; tool

Project Summary/Abstract The overarching goal of the Liu group is to facilitate the discovery and synthesis of complex bioactive small molecules by developing novel copper-catalyzed reactions and to elucidate the reactive intermediates in copper-catalyzed bond-forming reactions. The selective construction of carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds remains the most important synthetic tool in organic chemistry, with these reactions playing a vital role in the synthesis of natural products, pharmaceuticals, and agrochemicals. However, most such transformations rely on the least abundant elements in Earth's crust. Owing to their many attractive characteristics, copper catalysts represent an appealing alternative to precious-metal catalysts, although copper-catalyzed cross-coupling reactions still have various limitations. Recently, we and others recognized that copper catalysis provides a powerful strategy for the functionalization of sp3-hybridized carbon radicals to construct C–C and C–heteroatom bonds. To date, our group has developed a menu of copper-catalyzed coupling reactions for alkyl electrophiles via the activation of C–COOH, C–N, C–H, and C–O bonds, with an initial focus on the installation of fluoroalkyl groups into medicinally relevant moieties. These promising results led us to envision the emergence of copper-catalyzed, radical-activated cross-coupling reactions as a powerful tool for solving a range of long-standing synthetic problems. In this proposal, we will demonstrate that merging the copper-catalyzed functionalization of C(sp3) radicals with different radical generation pathways offers a viable approach for the cross- coupling of unactivated alkyl electrophiles. Specifically, we aim to develop reactions such as the deoxygenative cross-coupling of alcohols, the selective alkylation of C(sp3)–H bonds, and the cross-coupling of unactivated alkyl halides. These transformations are either unknown or have limited reaction scope. The development and mechanistic understanding of these transformations will make a significant contribution toward advancing the field of transition- metal catalysis.

项目摘要/摘要 刘小组的首要目标是促进复合体的发现和合成 通过开发新的铜催化反应来开发生物活性小分子并阐明 铜催化成键反应中的活性中间体。选择的建筑 碳-碳(C-C)和碳-杂原子(C-X)键的组成仍然是最重要的 有机化学中的合成工具，这些反应在合成 天然产品、药品和农用化学品。然而，大多数这样的转变 依赖于地壳中最不丰富的元素。由于它们有许多吸引人的地方 特点，铜催化剂是贵金属催化剂的一种有吸引力的替代品， 尽管铜催化的交叉偶联反应仍有各种局限性。最近，我们 和其他人认识到，铜催化为 SP3杂化碳自由基官能化构筑C-C和C-杂原子键。 到目前为止，我们的小组已经开发了一系列铜催化的烷基偶联反应。 通过C-COOH、C-N、C-H和C-O键激活的亲电性，最初的重点是 将氟烷基安装到与药物相关的部分中。这些有希望的结果 使我们预见到铜催化、自由基活化的交叉偶联的出现 反应是解决一系列长期存在的合成问题的有力工具。在这 建议，我们将证明将铜催化的C(SP3)官能化 具有不同自由基生成途径的自由基为杂交提供了一种可行的方法 未活化烷基亲电体的偶联。具体地说，我们的目标是发展反应，如 醇的脱氧交叉偶联，C(SP3)-H键的选择性烷基化，以及 未活化的烷基卤化物的交叉偶联。这些转换要么是未知的，要么是 反应范围有限。这些问题的发展和机理认识 转型将为推进过渡领域做出重大贡献- 金属催化。