A Unified, Practical Synthesis of Five-Membered Aromatic Heterocycles

2000年至2012年全球销量最高的药物是降胆固醇药物立普妥（Lipitor），它是一种有机分子，核心是一个名为“吡咯”的五元环，由四个碳原子和一个氮原子组成。与之相关的五元含氧环称为“呋喃”，这是在许多药物和农用化学品中发现的另一个常见基序，如拟除虫菊酯杀虫剂resmethrin。尽管这些和其他结构类似的有机环系统继续成为制药和农化工业研究的基石，但由于用于构建环的化学反应的内在结构要求，它们的最常见合成方法限制了新药/农化先导物的设计。在本提案中，我们的目标是开发一种新的反应，可以制备四种不同类别的这些重要分子，使用一种新的钯催化过程来形成环系统。该方法将能够获得广泛的产品（许多以前无法获得），因为它允许我们轻松地“调整”环周围不同官能团的位置。我们计划使用概念上简单，易于应用的方法从廉价的起始材料（如炔，醛和酮）组装反应底物，从而使研究易于被最终用户采用。这些短合成路线最大限度地降低了环境和经济成本，同时也避免了昂贵的空气或水分敏感催化剂和有毒试剂。综上所述，这些考虑正好符合EPSRC大挑战的主题“拨号分子”，即一个单一的反应类型可以直接和快速地“拨号”许多不同的产品。为了最大限度地发挥这项研究的影响，与英国制药和农用化学工业的工业最终用户的互动构成了本提案的一个组成部分。透过互动的知识和资料交换计划，与两家公司直接合作，我们将能够探索具体和当前工业相关的目标，并确保我们开发的技术可以很容易地被这些行业采用。这可以促进新药品和农用化学品的开发（尤其是通过测试我们将在项目过程中制造的化合物）——这不仅从经济角度来看有好处，而且更重要的是在改善人类健康和应对粮食安全的全球挑战方面有好处。总之，强大的合成方法、廉价的起始材料和常见的催化剂相结合，可能会产生一种新的、易于部署的方法，用于合成四种重要的有机化合物类别，并在人类健康和农业方面有良好的应用记录。这项工作将简化这些领域的研究，这些领域是21世纪的主要全球挑战。

The world's top-selling pharmaceutical of 2000-2012 was the cholesterol-lowering drug Lipitor, an organic molecule containing at its core a five-membered ring called a 'pyrrole', which comprises four carbon atoms and one nitrogen atom. A related five-membered oxygen-containing ring called a 'furan' is another common motif found in many drugs and agrochemicals, such as the pyrethroid insecticide resmethrin. Although these and other structurally similar organic ring systems continue to form a cornerstone of research in the pharmaceutical and agrochemical industry, the most common methods for their synthesis restrict the design of new drug / agrochemical leads, due to the intrinsic structural requirements of the chemical reactions used to build the ring.In this proposal, we aim to develop a new reaction that can prepare four different classes of these important molecules, using a novel palladium-catalyzed process to form the ring system. The method will be able to access a wide range of products (many previously unattainable), as it allows us to easily 'tune' the positioning of different functional groups around the ring. We plan to use conceptually simple, easily applied methods to assemble the reaction substrates from cheap starting materials (such as alkynes, aldehydes and ketones), thus enabling the research to be readily adopted by end users. These short synthetic routes minimise environmental and economic cost, as does the avoidance of expensive air or moisture sensitive catalysts, and toxic reagents. Taken together, these considerations fit neatly into the EPSRC Grand Challenge theme of 'Dial-a-Molecule', whereby a single reaction type can 'dial up' many different products in a straightforward and rapid fashion.To maximize the impact of this research, interactions with industrial end-users in the UK pharmaceutical and agrochemical industry form an integral part of this proposal. By directly collaborating with two companies through an interactive knowledge and material exchange programme, we will be able to explore targets of specific and current industrial relevance, and also ensure that the technology we develop can be readily adopted by these industries. This could facilitate the development of new pharmaceuticals and agrochemicals (not least through testing of compounds we will make in the course of the project) - which has consequent benefits not only from an economic perspective, but more importantly in improving human health and in tackling the global challenge of food security.In summary, a combination of robust synthetic methodology, cheap starting materials, and commonly available catalysts could lead to a new and readily deployed method for the synthesis of four important organic compound classes with a proven track record of application in human health and agriculture. This work will streamline research in these fields, which are major global challenges of the 21st century.