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

项目摘要 苄基醚是药物和生物活性分子中的重要基元。 以前的这些基序的对映选择性合成方法依赖于不对称 用氢化物或碳亲核试剂还原羰基化合物，需要预先- 功能化的起始材料，因此增加了化学步骤。理想情况下，C-O键 形成将通过直接的C-H/O-H交叉偶联进行，同时避免溶剂量 对醇偶联体和广泛的两种偶联体都有耐受性。虽然 C-H氧合方法是最近发展起来的，是一种对映体选择性的变体 难以捉摸。 在此研究策略中，我们建议使用以下方法直接访问光学活性的苄基醚 易于获得的烷基芳烃和醇通过双重电催化偶联伙伴。这 策略将使我们能够有效地合并由以下因素介导的氢原子转移(HAT 邻苯二甲酰亚胺N-氧基(Pino)与铜促进的自由基烷氧基化，两个已建立 激进的过程。用电化学取代传统的化学氧化不仅会 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 与铜的对映选择性C-O键形成有关的过氧化问题。如果 如果成功，该反应将提供第一个对映体选择性的苄基醚。 C-H官能化合成。该项目有三个具体目标：1)调查有机 N-羟基邻苯二甲酰亚胺(NHPI)等介体在温和条件下产生苄基自由基 电化学氧化条件；2)识别条件和手性配体 铜催化自由基捕集生成对映体选择性C-O键；3)立体访问 以对映体收敛的方式从外消旋底物上阻挡的二烷基醚。

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.