Cu(II)-Catalysed C-H Activation Routes to Heterocycles; Applications in Target Synthesis

杂环化合物是制药和农化工业的中流砥柱。作为我们正在进行的旨在合成具有药用价值的杂环系统的研究计划的一部分，我们非常重视设计简化和环境友好的合成程序。因此，我们已经成功地开发了一些利用级联和伸缩过程来获得杂环构建块的改进路线。作为这项计划的一部分，我们最近开发了一种高产率、对湿度和空气不敏感的方法，通过正式的双C-H活化法，在DMF中使用极其便宜和容易获得的一水醋酸铜(ACS级，GB 1/10 g)，从简单的苯胺衍生的起始原料制备3，3‘-二取代氧吲哚。这种产生第四级立体中心的直接方法值得注意。2010年，我们发现了一种大大改进的方法，它使用催化量的乙酸铜在甲苯或均三甲苯中作为溶剂，在不需要排除空气和湿度的情况下获得同样高的氧化吲哚产品产量。我们现在完全专注于展示改进的一水醋酸铜方法的广泛用途，我们相信这种方法的潜力是巨大的，特别是考虑到当今的许多药物都是基于氧吲哚的(例如，轰动一时的抗癌药物Sutent)。因此，该建议的主要目的是：(I)进一步开发新型的铜基C-H活化化学，以开发一条合成螺环氧吲哚的路线；(Ii)探索所有底物类别的不对称变体的开发；(Iii)将方法学扩展到相关杂环体系的合成；以及，非常重要的是，(Iv)在复杂的药物和天然产物的目标合成中应用并验证新的铜催化环化过程。我们的目标是将这一新程序开发成真正强大的合成工具，在学术研究和工业药物化学以及放大过程中具有深远的应用。这一雄心勃勃的方案将由PDRA在3年内执行。

Heterocyclic compounds are the mainstay of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of medicinal interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly synthetic procedures. Thus, we have successfully developed a number of improved routes to heterocyclic building blocks utilising cascade and telescoped processes. As part of this programme, we recently developed a high yielding moisture- and air-insensitive procedure for the preparation of 3,3'-disubstituted oxindoles from simple aniline-derived starting materials via a formal double C-H activation approach using an extremely cheap and readily available reagent, cupric acetate monohydrate (ACS grade, < £1/10 g), in DMF as solvent. Such a straightforward method of generating quaternary stereogenic centres is noteworthy. In 2010, we discovered a much improved procedure which uses catalytic amounts of cupric acetate monohydrate in toluene or mesitylene as solvent and gives equally high yields of oxindole products without the need to exclude air and moisture.We are now fully focused on demonstrating the broad utility of the improved cupric acetate monohydrate procedure and we believe that the potential of this methodology is enormous, particularly, given that many of today's drugs are based on oxindoles (e.g. the blockbuster anti-cancer drug, Sutent). The main aims of this proposal are therefore: (i) to further exploit the novel copper-based C-H activation chemistry to develop a route to spirocyclic oxindoles, (ii) to explore the development of asymmetric variants for all substrate classes, (iii) to extend the methodology to the synthesis of related heterocyclic systems, and, very importantly, (iv) to apply, and therefore validate, the new copper-catalysed cyclisation procedure in complex pharmaceutical and natural product target synthesis. It is our aim to develop this new procedure into a truly powerful synthetic tool with far-reaching applications in both academic research and industrial medicinal chemistry and scale-up processes. This ambitious programme will be carried out by a PDRA over a 3 year period.