Dual Electrocatalytic Enantioselective C-O Bond Formation via Benzylic C-H Functionalization

通过苄基 C-H 官能化形成双电催化对映选择性 C-O 键

• 批准号: 10589152
• 负责人: Minsoo Ju
• 金额: $ 6.95万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589152
• 关键词: Address; Alcohols; Carbon; Catalysis; Chemicals; Complex; Copper; Coupling; Cyclization; Development; Electrochemistry; Ethers; Event; Generations; Hydrogen; Ligands; Measures; Mediating; Mediator; Methods; Optics; Organic Chemistry; Oxidation-Reduction; Periodicity; Pharmacologic Substance; Phthalimides; Process; Reaction; Reporting; Research; Solvents; Transition Elements; Variant; base; carbonyl compound; catalyst; improved; oxidation; prevent

Project Summary Benzylic ethers are prominent motifs in pharmaceuticals and biologically active molecules. Previous methods for enantioselective synthesis of these motifs have relied on asymmetric reduction of a carbonyl compound with a hydride or carbon nucleophile, requiring pre- functionalized starting materials and therefore additional chemical steps. Ideally, C–O bond formation would occur through direct C–H/O–H cross-coupling, while avoiding solvent quantities of the alcohol coupling partner and tolerating a broad range of both coupling partners. Although C–H oxygenation methods have recently been developed, an enantioselective variant remains elusive. In this research strategy, we propose directly accessing optically active benzylic ethers using readily available alkyl arenes and alcohol coupling partners through dual electrocatalysis. This strategy will enable us to effectively merge hydrogen-atom transfer (HAT) mediated by phthalimide N-oxyl (PINO) radicals with copper-promoted radical alkoxylation, two established radical processes. Replacing a conventional chemical oxidation with electrochemistry will not only improve sustainability and scalability of the proposed transformation but will also address the key overoxidation problem associated with enantioselective Cu-mediated C–O bond formation. If successful, this reaction would provide the first example of enantioselective benzylic ether synthesis via C–H functionalization. This project has three specific aims: 1) investigating organic mediators such as N-hydroxyphthalimide (NHPI) for generating benzylic radicals under mild electrochemical oxidation conditions; 2) identifying conditions and chiral ligands for enantioselective C–O bond formation by Cu-catalyzed radical trapping; 3) accessing sterically hindered dialkyl ethers from racemic substrates in an enantioconvergent manner.

项目概要 苄基醚是药物和生物活性分子中的重要基序。 以前对映选择性合成这些基序的方法依赖于不对称 用氢化物或碳亲核试剂还原羰基化合物，需要预先 理想情况下，需要对起始材料进行功能化，并进行额外的化学步骤。 通过直接 C-H/O-H 交叉偶联形成，同时避免溶剂用量 醇偶联伙伴的并且耐受范围广泛的两种偶联伙伴。 最近开发了 C-H 氧化方法，但仍然存在对映选择性变体 难以捉摸。 在本研究策略中，我们建议使用直接获取光学活性苄基醚 通过双重电催化容易获得烷基芳烃和醇偶联伙伴。 该策略将使我们能够有效地合并氢原子转移（HAT）介导的 邻苯二甲酰亚胺 N-氧基 (PINO) 自由基与铜促进的自由基烷氧基化，两个已建立 用电化学取代传统的化学氧化不仅可以。 提高拟议转型的可持续性和可扩展性，但也将解决关键问题 与对映选择性铜介导的 C-O 键形成相关的过氧化问题。 成功，该反应将提供对映选择性苄基醚的第一个例子 通过 C-H 官能化合成该项目有三个具体目标：1）研究有机。 介质，如 N-羟基邻苯二甲酰亚胺 (NHPI)，可在温和条件下产生苄基自由基 电化学氧化条件；2) 确定条件和手性配体 通过 Cu 催化的自由基捕获形成对映选择性 C-O 键；3) 空间接触； 以对映体收敛的方式从种族底物中受阻二烷基醚。