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.

项目摘要 对映体富集的胺是在各种生物活性化合物中发现的普遍官能团， 大药厂目前用于获得它们的方法具有局限性，诸如差的原子经济性、差的能量消耗、低的能量消耗、低的能量消耗和低的能量消耗。 选择性差、反应性差或需要高压气体。过渡金属催化的交叉偶联 反应代表了获得对映体富集的胺化合物的强有力的方法， 克服了当前最先进技术的一些固有问题。然而， 过渡金属催化的方法通常需要详尽的配体筛选和寻找一组最佳的 能够实现满意的活性、化学选择性和立体选择性的条件。在某些过程中， 所用的金属催化剂是没有任何添加的配体或具有不含手性等价物的配体的那些 存在，呈现对映体诱导的挑战性情景。该提案概述了一种替代办法 发展新的过渡金属催化方法，利用氢键供体（HBD） 催化以活化C（sp3）-O键朝向Ni催化的交叉偶联反应。这个双重催化平台 是一种概念上尚未探索的交叉偶联化学方法，其中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。 然而，这些作用传统上被分配给配体性质作为反应发展的驱动力， 这项拟议的研究将证明利用两种催化模式进行合作的可行性 温和的亲电体在对映会聚的C（sp3）-C（sp2）交叉偶联中生成胺化合物。铃木- Miyaura和Mizoroki-Heck型偶联容易获得的半缩醛胺底物将通过以下方法进行探索： 利用HBD介导的底物电离产生亚胺离子。HBD已被证明 是用于生成亚胺离子的有效催化剂，以及它们随后参与对映选择性反应的催化剂。 被标准亲核试剂捕获。与这些传统的反应曲线不同， 金属在此提出。有趣的是，C（sp3）-O键的各种立体选择性Ni催化偶联具有以下优点： 据报道，在“无配体”条件下或使用不易于与配体反应的烯属配体时， 转化为手性等价物，从而突出了这种方法的策略。成功执行本 该提案将揭示一种获得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。