New directions in Ni-catalyzed cross coupling

镍催化交叉偶联的新方向

• 批准号: 9897556
• 负责人: Abigail Gutmann Doyle
• 金额: $ 39.07万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897556
• 关键词: Acetals; Address; Alkenes; Amines; Area; Aziridines; Biological; Biology; Carbon; Catalysis; Complement; Complex; Coupling; Data; Development; Electrons; Ethers; Foundations; Free Radicals; Goals; Hydrogen Bonding; Ions; Laboratories; Ligands; Methods; Molecular Structure; Natural Products; Organic Synthesis; Pharmaceutical Chemistry; Phosphines; Photochemistry; Physical condensation; Play; Preparation; Reaction; Research; Role; Transition Elements; Work; biological preparation; catalyst; chemical reaction; design; human disease; molecular manufacturing; novel; predictive modeling; programs; scaffold; small molecule; success; tool

7. Project Summary/Abstract The overarching goal of this program is to facilitate the discovery and preparation of complex, biologically active small molecules by devising novel chemical reactions and elucidating new principles of catalysis in the field of transition metal-catalyzed cross coupling. Our laboratory's early work demonstrated that oxidative addition of Ni to iminium or oxocarbenium ion intermediates offers a novel entry to C(sp3)–C cross coupling. This strategy leverages the modularity of cross-coupling catalysis to deliver new bond-forming reactions with classic reactive intermediates in organic synthesis. Recently, we and others recognized that Ni catalysis presents a powerful opportunity to functionalize another class of reactive intermediate in organic synthesis: carbon-centered radicals. In the current proposal, we advance this concept, building on strong preliminary data, to develop fundamentally new bond-forming reactions under exceptionally mild conditions. An example is the development of a unified platform for the enantioselective synthesis of α- and β-substituted amines and ethers, some of the most ubiquitous scaffolds in medicinal chemistry, via Ni-catalyzed coupling with radicals derived from acetals, aziridines, and iminium ions accessed via condensation of an amine and carbonyl derivative. Such transformations are uniquely suited to late-stage diversification under mild conditions and address many challenges and limitations of ether and amine synthesis by C–O/N bond formation. Our group has also established a new paradigm for catalytic C(sp3)–H functionalization that uses photocatalysis to deliver free radical species from C(sp3)–H bonds, and Ni catalysis to functionalize these radicals. This strategy offers numerous opportunities for late-stage C(sp3)–C bond formation that complement current approaches to C–H functionalization in selectivity and scope. We describe plans to advance these reaction platforms in terms of scope of coupling partners, catalyst control of regio- and stereoselectivity, and amenability to late-stage derivatization of natural products and medicinal compounds. Critical to our success will be the development and study of three ligand classes for Ni: phosphines featuring remote steric hindrance, bioxazolines, and electron-deficient olefins. Since most effort in the field of Ni catalysis has focused on reaction discovery, we expect that the development of ligands designed specifically for Ni will play a crucial role in advancing the capabilities of this field. Similarly, we will build on our lab's prior mechanistic work with the goal of developing predictive models for the reactivity of Ni with radicals and understanding the photochemistry and photophysics of Ni that could lay the foundation for advances in numerous fields.

7. 项目总结/摘要 该计划的总体目标是促进复杂的、生物学的发现和制备 通过设计新颖的化学反应并阐明催化的新原理来制备活性小分子 过渡金属催化交叉偶联领域。我们实验室的早期工作表明，氧化 在亚胺或氧碳鎓离子中间体中添加 Ni 为 C(sp3)-C 交叉偶联提供了新的途径。 该策略利用交叉偶联催化的模块化来提供新的成键反应 有机合成中的经典反应中间体。最近，我们和其他人认识到镍催化 为有机合成中另一类反应中间体的功能化提供了强大的机会： 以碳为中心的自由基。在当前的提案中，我们在强有力的初步基础上提出了这一概念 数据，在异常温和的条件下开发全新的成键反应。一个例子 开发用于对映选择性合成 α- 和 β- 取代胺的统一平台 醚是药物化学中最普遍的支架，通过镍催化与自由基偶联 衍生自缩醛、氮丙啶和亚胺离子，通过胺和羰基的缩合获得 衍生物。这种转变特别适合温和条件下的后期多元化， 解决了通过 C-O/N 键形成醚和胺合成的许多挑战和限制。我们组 还建立了催化 C(sp3)–H 功能化的新范例，利用光催化传递 来自 C(sp3)–H 键的自由基物种，以及 Ni 催化功能化这些自由基。该策略提供 后期 C(sp3)-C 键形成的大量机会补充了当前的 C-H 方法 选择性和范围的功能化。我们描述了推进这些反应平台的计划： 偶联伙伴的范围、区域选择性和立体选择性的催化剂控制以及后期的适应性 天然产物和药物化合物的衍生化。我们成功的关键是发展 以及 Ni 的三种配体类别的研究：具有远程空间位阻的膦、双恶唑啉和 缺电子烯烃。由于镍催化领域的大部分努力都集中在反应发现上，我们 预计专为 Ni 设计的配体的开发将在推进 该领域的能力。同样，我们将以实验室先前的机械工作为基础，目标是开发 Ni 与自由基反应的预测模型并了解光化学和 镍的光物理学可以为许多领域的进步奠定基础。