Anion-Gated Dual Catalysis: Alkene Difunctionalization Accelerated by High Throughput Experimentation

催化多组分反应将烯烃原料的C=C键转化为复杂分子，用于生物系统的研究，是现代合成的基石。C=C键固有的多方面反应性可以通过多种催化活化方式解锁。当与普遍存在的烯烃原料类固有的结构和功能多样性相结合时，这些激活模式为复杂结构的可编程合成提供了显著的灵活性在这些反应的许多类别中，形成新的C-C和C-N键的转化是涉及过渡金属催化的氨基化的新方法的一个有吸引力的起点。最近，我们报道了一种独特的催化平台，可以实现烯烃、芳基亲电试剂和NaN3的多组分偶联，从而一步合成多功能和功能多样化的β -芳基乙胺衍生物。在可见光的驱动下，两个独立的cu催化剂协调ar自由基的形成和叠氮基团的转移步骤，这是烯烃叠氮基芳基化（AAA）过程的基础。该反应在烯烃和ar组分中表现出广泛的范围，叠氮阴离子作为氮源和通过球内电子转移介导氧化还原-中性双催化平台发挥多方面的作用。这种阴离子介导的AAA的合成能力及其相关反应的发展可能在各种药学相关和更广泛的合成应用中具有实用价值。尽管取得了一些显著的进步，但绝大多数合成化学都是以“一次一次”的批量方式进行的，使用的设备自1828年通过Wöhler首次合成尿素以来基本上没有改变。大多数合成化学仍然基于通常涉及常规操作的工作流程，并且是劳动密集型和耗时的。在过去的四年里，PI和团队已经建立了一个ns-HTE平台，这样我们就可以在广泛的化学反应空间中执行和分析1000个并行和离散可编程反应。该平台由液体处理机器人（lhr）提供便利，使反应能够在微或纳摩尔尺度上进行。为了分析384孔或1536孔板的反应混合物，我们可以选择定量和半定量LC-MS，高通量（HT） qNMR和平行HT- tlc。这些技术可以在短时间内对产品进行无与伦比的定量和结构测定。我们的目标是利用HTE来探索一种新型的烯烃合成复杂分子的催化剂。“阴离子门控双催化”平台将三种现成的构建模块结合在一起，最终由一个简单的阴离子控制。该产物可以在生物系统中发展为具有未开发特性的功能分子，为探索新的化学和生物学空间提供了一种手段。

Catalytic multicomponent reactions that transform the C=C bonds of alkene feedstocks into complex molecules for the interrogation of biological systems are a cornerstone of modern synthesis. The intrinsic multifaceted reactivity of C=C bonds can be unlocked by many catalytic activation modes. When combined with the structural & functional diversity inherent to the ubiquitous classes of alkene feedstock, these activation modes offer remarkable flexibility for programmable synthesis of complex architectures.1 Among many classes of these reactions, transformations that form new C-C & C-N bonds are an attractive starting point for new methodologies involving transition metal-catalyzed aminoarylation. Recently, we reported a distinct catalysis platform that enables a multicomponent coupling of alkenes, aryl-electrophiles & NaN3, providing single-step access to synthetically versatile & functionally diverse beta-arylethylamine derivatives. Driven by visible-light, two discrete Cu-catalysts orchestrate Ar-radical formation & azido-group transfer steps, which underpin an alkene azido-arylation (AAA) process. The reaction exhibits broad scope in alkene & Ar-components & the azide-anion performs a multifaceted role as both nitrogen source & in mediating the redox-neutral dual-catalysis platform via inner-sphere electron transfer. The synthetic capabilities of this anion-mediated AAA & development of its related reactions is likely to be of utility in a variety of pharmaceutically relevant & wider synthetic applications.Despite several notable advances, the vast majority of synthetic chemistry is conducted in 'one-at-a-time' batch fashion using equipment that has not, essentially, changed since urea was first synthesized by Wöhler in 1828. Most synthetic chemistry is still based on a work flow that often involves routine operations and is labour-intensive & time consuming. Over the last four years, the PI & team have established a ns-HTE platform, such that we can execute & analyse 1000s of parallel & discretely programmable reactions across a wide range of chemical reaction space. The platform is facilitated by liquid handling robots (LHRs), which enables reactions to be set up on a micro or nanomolar scale. To analyse reaction mixtures from 384 or 1536-well plates, we can choose from quantitative & semi-quantitative LC-MS, high-throughput (HT) qNMR & parallel HT-TLC. Together these techniques allow unparalleled quantification & structure determination of products on a short timescale. Together we aim to use HTE to epxlore a new type a catalysis for the synthesis of complex molecules from alkenes. The 'anion-gated dual catalysis' platform brings together three readily available building blocks in a process controlled, ultimately, by a simple anion. The products can be advnaced to functional molecules that have unexplored properties in biologial systems, providing a means to explore new chemical and biology space.