Photocatalytic Reductive Coupling of Iminiums: New Umpolung Strategy for Tertiary Amine Synthesis

该项目属于EPSRC合成有机化学研究领域。生物相关的a-功能化胺功能在许多天然产物，药物制剂和农用化学品的结构中无处不在。因此，开发一种新颖有效的方法，通过碳-碳键的形成快速获取这些结构，与学术和工业应用高度相关。胺功能化的一个常见接入点是使用有机金属试剂将亲核加成固有的亲电性的铝官能团。然而，开发一种新的合成策略，可以逆转亚胺离子的自然极性，为多样化可获得的化学转化和叔胺支架提供了机会。因此，我们提出了一种前所未有的策略，即将铱催化的叔酰胺还原与随后的光催化还原偶联步骤结合在一起。由于其固有的稳定性，叔酰胺具有作为a-功能化胺构建的强大起点的潜力。Vaska的催化剂(IrCl（CO)(PPh3)2）与TMDS（1,1,3,3-四甲基二硅氧烷）还原剂一起，最初将酰胺还原为半胺中间体，从而消除了原位形成的亚胺物种。在光催化、单电子还原条件下，中间体转化为亲核的a-氨基自由基，它可以与合适的亲电试剂偶联，形成a-官能化叔胺产物。该项目的目标是获得充分优化的反应条件，使用n -甲基苯胺衍生物作为模型底物，并通过将一系列叔酰胺与烯烃偶联伙伴（即迈克尔受体，苯乙烯衍生物等）结合来扩大底物范围。此外，提出了密度泛函理论（DFT）计算，以微调光催化剂的选择，以合成具有挑战性的衬底。在这个项目的后期，我们的目标是利用计算化学来阐明这种转化的机制。除了开发一种新的合成方法外，该项目还将专注于将光催化，还原策略应用于生物相关化合物的合成和衍生化。例如，通过将这种分子间系统适应为分子内变体，我们的目标是从叔酰胺中获得二取代的n -杂环。此外，我们计划利用这种方法的高度化学选择性，通过选择性地通过叔酰胺基序引入衍生化，对天然产物和药物制剂（如Vassopresin）进行后期功能化。总的来说，我们希望开发一种有效的、广泛适用的策略，这将对药物化学领域和制药工业产生相当大的兴趣。

This project falls within the EPSRC Synthetic Organic Chemistry research area.The biologically-relevant a-functionalised amine functionality is ubiquitous within the structures of numerous natural products, pharmaceutical agents and agrochemicals. As a result, the development of a novel and efficient methodology that would allow for rapid access to these structures through carbon-carbon bond formation is highly relevant for academic and industrial applications. A commonplace access point for amine functionalisation has been nucleophilic addition into the inherently electrophilic iminium functional group using organometallic reagents. However, developing a new synthetic strategy that would reverse the natural polarity of iminium ions provides an opportunity to diversify the range of accessible chemical transformations and tertiary amine scaffolds. Hence, we propose an unprecedented strategy that entails the combination an iridium-catalysed tertiary amide reduction with a subsequent photocatalytic, reductive coupling step in one pot. Due to their inherent stability, tertiary amides hold potential as powerful starting points for a-functionalised amine construction. Vaska's catalyst (IrCl(CO)(PPh3)2), in tandem with the TMDS (1,1,3,3-tetramethyldisiloxane) reductant, initially reduces the amide to give a hemiaminal intermediate, which eliminates to form the iminium species in situ. Under photocatalytic, single electron reductive conditions, this intermediate is transformed into a nucleophilic a-amino radical, which can couple with an appropriate electrophilic reagent resulting in the formation of the a-functionalised tertiary amine product. The goal of this project is to obtain the fully optimised reaction conditions, using a N-methyl anilide derivative as a model substrate, and expand the substrate scope by combining a range of tertiary amides with alkene coupling partners (i.e. Michael acceptors, styrene derivatives, etc.). Furthermore, it is proposed to employ density functional theory (DFT) calculations in order to fine-tune the photocatalyst selection for synthetically challenging substrates. In the later stages of this project, we aim to use computational chemistry to elucidate the mechanism of this transformation. In addition to developing a novel synthetic method, this project will also focus on applying the photocatalytic, reductive strategy to the synthesis and derivatisation of biologically relevant compounds. For example, by adapting this intermolecular system to an intramolecular variant, we aim to obtain di-substituted N-heterocycles from tertiary amides. Moreover, we plan to utilise the highly chemoselective nature of this method for late stage functionalisation of natural products and pharmaceutical agents, such as Vassopresin, by selectively introducing derivatisation via the tertiary amide motif. Overall, we hope to develop and efficient and widely applicable strategy that would be of considerable interest for the medicinal chemistry field and the pharmaceutical industry.