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

亚胺的光催化还原偶联：叔胺合成的新 Umpolung 策略

• 批准号: 1923532
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1923532
• 关键词: Photocatalytic; Reductive; Coupling; Iminiums; New

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.

该项目属于EPSRC合成有机化学研究领域。与生物相关的α-官能化胺官能团普遍存在于许多天然产品、药剂和农用化学品的结构中。因此，开发一种新颖而有效的方法，允许通过碳-碳键的形成快速获得这些结构，对于学术和工业应用具有非常重要的意义。胺功能化的一个常见的接入点是使用有机金属试剂将亲核加成到固有的亲电性的金属官能团中。然而，开发一种新的合成策略来逆转亚胺离子的自然极性，为使可获得的化学转化和叔胺支架的范围多样化提供了机会。因此，我们提出了一种史无前例的策略，需要在一个锅中结合Ir催化的叔胺还原和随后的光催化还原耦合步骤。由于其固有的稳定性，叔胺具有作为a-官能化胺构建的有力起点的潜力。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，首先将酰胺还原为半胺类中间体，再在原位消除形成亚胺物种。在光催化、单电子还原的条件下，该中间体转化为亲核的α-氨基，它可以与适当的亲电试剂偶联，从而形成α-官能化叔胺产品。该项目的目标是使用N-甲基苯胺衍生物作为模型底物，获得完全优化的反应条件，并通过将一系列叔胺与烯烃偶联伙伴(即Michael受体、苯乙烯衍生物等)相结合来扩大底物范围。此外，建议使用密度泛函理论(DFT)计算来微调用于合成挑战底物的光催化剂的选择。在这个项目的后期阶段，我们的目标是用计算化学来阐明这种转变的机制。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，通过使分子间体系适应分子内变体，我们的目标是从叔胺中获得双取代N-杂环。此外，我们计划利用这种方法的高度化学选择性的性质，通过叔胺基序选择性地引入衍生化，用于天然产品和药物的后期功能化，如硫代树脂。总体而言，我们希望开发出高效和广泛适用的战略，这将是药物化学领域和制药行业非常感兴趣的战略。