New directions in Ni-catalyzed cross coupling

镍催化交叉偶联的新方向

• 批准号: 10364665
• 负责人: Abigail Gutmann Doyle
• 金额: $ 36.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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/10364665
• 关键词: Acetals; Address; Alkenes; Amines; Area; Aziridines; 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.项目摘要/摘要 这个计划的首要目标是促进发现和准备复杂的，生物学上的 通过设计新的化学反应和阐明新的催化原理来激活小分子 过渡金属催化交叉偶联领域。我们实验室的早期工作表明，氧化剂 镍的加入为C(SP3)-C交叉偶联提供了一种新的途径。 这一策略利用交叉偶联催化的模块化来实现新的成键反应 有机合成中经典的活性中间体。最近，我们和其他人认识到镍催化 为有机合成中的另一类活性中间体提供了一个强大的官能化机会： 以碳为中心的自由基。在目前的提案中，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从根本上开发新的成键反应。一个例子 是开发用于α和β取代胺的对映选择性合成的统一平台和 醚，药物化学中最普遍的一些支架，通过镍催化与自由基偶联 由缩醛、氮杂环丙烷和通过胺和羰基缩合得到的亚胺离子衍生而来 衍生品。这种转型特别适合于在温和条件下的后期多样化和 通过C-O/N键的形成解决了乙醚和胺合成的许多挑战和限制。我们的团队 还建立了催化C(SP3)-H功能化的新范式，使用光催化来传递 C(SP3)-H键上的自由基物种，以及Ni催化这些自由基的官能化。这一战略提供了 大量晚期C(SP3)-C键形成的机会，补充了目前的C-H方法 在选择性和范围上的功能化。我们在以下方面描述了推进这些反应平台的计划 偶联伙伴的范围，区域和立体选择性的催化剂控制，以及对后期的适应性 天然产物和药物化合物的衍生化。我们成功的关键是发展 并研究了镍的三种配位体：具有远程空间位阻的膦、双恶唑和 缺电子的烯烃。由于镍催化领域的大部分工作都集中在反应发现上，我们 预计专门为镍设计的配体的开发将在推动 这一领域的能力。同样，我们将在我们实验室之前的机械工作的基础上，以开发 镍与自由基反应活性的预测模型及对光化学和光化学的理解 镍的光物理学，可能为在许多领域的进展奠定基础。