New directions in Ni-catalyzed cross coupling

7.项目总结/摘要 该计划的总体目标是促进发现和制备复杂的，生物 通过设计新颖的化学反应和阐明催化的新原理， 过渡金属催化的交叉耦合领域。我们实验室的早期工作表明，氧化 Ni与亚胺鎓或氧代碳鎓离子中间体的加成提供了C（sp3）-C交叉偶联的新途径。 该策略利用交叉偶联催化的模块性来提供新的成键反应， 有机合成中典型的活性中间体。最近，我们和其他人认识到，镍催化 为有机合成中另一类反应性中间体的官能化提供了强大的机会： 以碳为中心的自由基在目前的提案中，我们提出了这一概念，建立在强大的初步 数据，在非常温和的条件下开发全新的成键反应。例 是开发用于α-和β-取代胺的对映选择性合成的统一平台， 醚，一些在药物化学中最普遍的支架，通过镍催化与自由基偶联 由缩醛、氮丙啶和亚胺鎓离子通过胺和羰基缩合得到 衍生物这种转变特别适合于温和条件下的后期多样化， 解决了通过C-O/N键形成的醚和胺合成的许多挑战和限制。我们集团 还建立了催化C（sp3）-H功能化的新范式， 来自C（sp3）-H键的自由基物质，以及使这些自由基官能化的Ni催化剂。该战略提供 后期C（sp3）-C键形成的许多机会，补充了目前的C-H方法 功能化的选择性和范围。我们描述了推进这些反应平台的计划， 偶联配偶体的范围、催化剂对区域和立体选择性的控制以及对后期反应的适应性 天然产物和药用化合物的衍生化。我们成功的关键在于 研究了镍的三种配体：具有远位阻的膦，双恶唑啉， 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 我预计，专门为Ni设计的配体的开发将在推进镍的研究中发挥至关重要的作用。 这个领域的能力。同样，我们将建立在我们实验室先前的机械工作的基础上， 镍与自由基反应性的预测模型，并了解光化学和 镍的电子物理学可以为许多领域的进步奠定基础。

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.