Stereoselective Transition Metal Catalysis Enabled by Hydrogen-Bond Donor Mediated Electrophile Activation

氢键供体介导的亲电子试剂活化实现立体选择性过渡金属催化

• 批准号: 10605979
• 负责人: Sepand K Nistanaki
• 金额: $ 6.87万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605979
• 关键词: Acceleration; Alkenes; Amines; Anions; Carbon; Catalysis; Cations; Chemicals; Chemistry; Complex; Computer Analysis; Coupling; Development; Drug Industry; Gases; Generations; Goals; Health; Human; Hydrogen Bonding; Ions; Libraries; Life; Ligands; Ligation; Mediating; Medicine; Metals; Methodology; Methods; Modeling; National Institute of General Medical Sciences; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Property; Reaction; Reporting; Research; Role; Source; System; Thinking; Transition Elements; bioactive natural products; catalyst; cost; discount; experimental analysis; experimental study; functional group; interest; ionization; metal complex; novel strategies; pressure; reaction rate; screening

Project Summary Enantioenriched amines are prevalent functional groups found in various bioactive compounds and pharmaceuticals. Current methods for accessing them come with limitations, such as poor atom-economy, poor selectivity, poor reactivity, or requirement for high-pressure gases. Transition metal catalyzed cross-coupling reactions represent a powerful approach towards accessing enantioenriched amine compounds, which could overcome some of the inherent issues with current state-of-the-art. However, the discovery of new asymmetric transition metal catalyzed processes often requires exhaustive ligand screening and search for an optimal set of conditions that enable satisfactory activity, chemoselectivity, and stereoselectivity. In some processes, the best metal catalysts employed are those without any added ligands or with ligands to which no chiral equivalents exist, presenting challenging scenarios for enantioinduction. This proposal outlines an alternative approach towards the development of new transition metal catalyzed methodology, utilizing hydrogen-bond donor (HBD) catalysis to activate C(sp3)–O bonds towards a Ni-catalyzed cross-coupling reaction. This dual catalytic platform is a conceptually unexplored approach towards cross-coupling chemistry, wherein the role of the HBD is to accelerate the oxidative addition while simultaneously imparting stereoselectivity to the step through ion pairing. These roles have traditionally been assigned to ligand properties as the driver of reaction development, however this proposed research will demonstrate the feasibility of leveraging both catalytic modes to cooperatively engage mild electrophiles in an enantioconvergent C(sp3)–C(sp2) cross-coupling to generate amine compounds. Suzuki- Miyaura and Mizoroki-Heck type couplings of readily-accessible hemiaminal substrates will be explored by leveraging HBD-mediated substrate ionization for the generation of iminium ions. HBDs have been demonstrated to be effective catalysts for the generation of iminium ions, and their subsequent engagement in enantioselective trapping by standard nucleophiles. Unlike these traditional reaction profiles, the trapping of iminium ions by a metal is proposed here. Interestingly, various stereoselective Ni-catalyzed couplings of C(sp3)–O bonds have been reported to perform the best under “ligandless” conditions or with olefinic ligands that are not easily converted to chiral equivalents, thus highlighting the strategy of this approach. Successful execution of this proposal will reveal a new method for accessing enantioenriched amines and establish a proof-of-concept for the synergistic cooperation of HBD-catalysis with transition metal catalysis.

项目概要 对映体富集胺是各种生物活性化合物中常见的官能团， 目前获取它们的方法存在局限性，例如原子经济性较差、较差。 选择性、反应性差或需要过渡金属催化交叉偶联。 反应代表了获取对映体富集胺的有效方法，这些化合物可以 然而，新的不对称的发现克服了当前最先进技术的一些固有问题。 过渡金属催化过程通常需要详尽的配体筛选并寻找一组最佳配体 在某些过程中，能够实现令人满意的活性、化学选择性和立体选择性的条件是最好的。 使用的金属催化剂是没有任何添加配体或配体没有手性等价物的那些 存在，提出了对映诱导具有挑战性的场景，该提案概述了一种替代方法。 利用氢键供体 (HBD) 开发新的过渡金属催化方法 催化激活 C(sp3)–O 键以进行 Ni 催化的交叉偶联反应。 是一种概念上尚未探索的交叉偶联化学方法，HBD 的作用是 加速氧化加成，同时通过离子配对赋予该步骤立体选择性。 传统上，这些作用被分配给配体特性作为反应发展的驱动力，然而 这项拟议的研究将证明利用两种催化模式合作参与的可行性 温和的亲电子试剂在对映体 C(sp3)–C(sp2) 交叉偶联中生成胺化合物。 易于接近的半缩醛胺底物的 Miyaura 和 Mizoroki-Heck 型耦合将通过 利用 HBD 介导的底物电离来产生亚胺离子已被证明。 成为产生亚胺离子及其随后参与对映选择性的有效催化剂 与这些传统的反应曲线不同，通过标准亲核试剂捕获亚胺离子。 这里提出了各种立体选择性 Ni 催化的 C(sp3)-O 键偶联。 据报道，在“无配体”条件下或使用不易分解的烯属配体时表现最佳 转换为手性等价物，从而突出了该方法的成功执行。 该提案将揭示一种获取对映体富集胺的新方法，并建立概念验证 HBD 催化与过渡金属催化的协同作用。