Thiyl Radicals and Isocyanides: A New Approach Towards Biologically Active Heterocycles

制药业面临着巨大的压力，需要改善新疗法的供应，同时降低成本，并缩短从发现到应用的过渡时间。如果不开发新的合成方法或新技术，这个问题很难解决，拟议的研究将解决这两个方面。大多数药物和农用化学品都是基于杂环的，因此，寻找新的有效方法来合成它们，避免使用保护基团是至关重要的。一个关键的被忽视的反应类别，是这个问题的明显解决方案，是自由基化学，它使用温和的条件，不需要保护基团。然而，自由基化学几乎没有受到制药行业的关注，因为大多数反应涉及到有机锡衍生物的使用，并且经常在高稀释条件下进行。虽然这对于药物化学所需的克量是可以接受的，但当移动到过程化学所需的千克量时，这显然是不切实际的。合成路线经常被重新设计，并删除自由基化学物质，以最大限度地减少去除有毒副产品所需的纯化步骤。为了应对这一挑战，流动化学技术已成为执行多种类型的化学转化的可行手段，因为反应可以随着时间的推移或并行进行，以产生克量或千克量。因此，从药物实验室到过程实验室的转变已经变得不那么成本密集，流动化学引起了制药行业的相当大的关注。不幸的是，尽管自由基化学具有潜力，但由于其对有机锡化合物的依赖，它在制药工业中并没有经历同样的转变。在初步研究中，我们已经证明了基于无毒的硫自由基/异氰化物的三环杂环环化是可行的，并且它是有机锡衍生物的可靠替代品。在拟议的研究中，我们将探索这一过程的范围，以合成一系列关键的生物活性杂环，包括目前正在进行临床试验的抗癌化合物。与此相结合，我们将把我们的化学应用于流动反应器技术，以证明自由基化学可以作为一种为制药工业生产更大规模材料的方法而被重新审视。

The pharmaceutical industry is under intense pressure to improve the supply of new therapeutics whilst at the same time, reducing both cost and transition-time from discovery to application. This problem is hard to resolve without the development of new synthetic methodology or new technology and the proposed research will address both aspects of this.Most medicines and agrochemicals are based on heterocycles and as a result, the search for new efficient methodology for their syntheses that avoids the use of protecting groups is essential. One key neglected class of reaction that is an obvious solution to this problem is radical chemistry, which uses mild conditions without the need for protecting groups. However, radical chemistry has received little attention from the pharmaceutical industry because the majority of reactions involve the use of organotin derivatives and are often carried out at high dilution. Whilst this is acceptable for the gram amounts required for medicinal chemistry, this is clearly impractical when moving to the kilogram quantities required in process chemistry. Synthetic routes are often redesigned and radical chemistry removed to minimise the purification steps required to remove the toxic by-products. To address this challenge, flow chemistry technology has emerged as a viable means for performing many types of chemical transformations as reactions can be run over time or in parallel, to produce either gram or kilogram quantities. Therefore, the transition from medicinal to process laboratories has become less cost-intensive and flow-chemistry has attracted considerable attention from the pharmaceutical industry. Unfortunately, despite its potential, radical chemistry has not undergone the same transition in the pharmaceutical industry due to its reliance on organotin compounds. In preliminary studies, we have demonstrated that a non-toxic sulfur radical/ isocyanide based cyclisation of tricyclic heterocycles is viable and that it is a credible replacement for organotin derivatives. In the proposed research, we will explore the scope of this process to synthesise a range of key biologically active heterocycles, including anti-cancer compounds currently undergoing clinical trials. In conjunction with this, we will apply our chemistry to flow reactor technology to demonstrate that radical chemistry can be revisited as a method to produce larger scale quantities of material for the pharmaceutical industry.