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.

项目摘要 苄醚是药物和生物活性分子中的重要基序。 先前用于这些基序的对映选择性合成的方法依赖于不对称合成。 用氢化物或碳亲核试剂还原羰基化合物，需要预处理， 官能化的起始材料和因此额外的化学步骤。理想情况下，碳氧键 形成将通过直接C-H/O-H交叉偶联发生，同时避免溶剂量 并且耐受宽范围的两种偶联配偶体。虽然 C-H氧合方法最近已经发展，一种对映选择性变体仍然存在 难以捉摸。 在这项研究策略中，我们建议直接访问光学活性苄醚， 通过双重电催化，容易获得烷基芳烃和醇偶联伙伴。这 策略将使我们能够有效地合并氢原子转移（HAT）， 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，两个建立 激进的过程。用电化学代替传统的化学氧化不仅 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Cu介导的C-O键形成相关的过氧化问题。如果 如果成功，该反应将提供对映选择性苄醚的第一个实例 通过C-H官能化合成。本项目有三个具体目标：1）研究有机 介体如N-羟基邻苯二甲酰亚胺（NHPI），用于在温和条件下产生苄基自由基， 电化学氧化条件; 2）鉴定用于电化学氧化的条件和手性配体。 通过Cu催化的自由基捕获的对映选择性C-O键形成; 3）空间访问 以对映收敛的方式从外消旋底物得到受阻二烷基醚。