A Unified, Practical Synthesis of Five-Membered Aromatic Heterocycles

五元芳香杂环的统一、实用合成

基本信息

批准号：
EP/M019195/1
负责人：
Edward Anderson
金额：
$ 44.63万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FM019195%2F1
关键词：
Unified Practical Synthesis Five Membered

项目摘要

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.

2000-2012年全球最畅销的药物是降胆固醇药物立普妥，这是一种有机分子，其核心含有一个称为“吡咯”的五元环，由四个碳原子和一个氮原子组成。称为“呋喃”的相关五元含氧环是许多药物和农用化学品中发现的另一个常见基序，例如拟除虫菊酯杀虫剂灭菊酯。尽管这些和其他结构相似的有机环系统继续构成制药和农化行业研究的基石，但由于化学反应的内在结构要求，其最常见的合成方法限制了新药/农化先导化合物的设计在这个提案中，我们的目标是开发一种新的反应，可以使用一种新颖的钯催化工艺来形成环系统，从而制备四种不同类别的这些重要分子。该方法将能够访问广泛的产品（许多以前无法获得），因为它使我们能够轻松“调整”环周围不同功能组的定位。我们计划使用概念上简单、易于应用的方法，用廉价的起始材料（例如炔、醛和酮）组装反应底物，从而使该研究能够很容易地被最终用户采用。这些短的合成路线最大限度地降低了环境和经济成本，同时避免了昂贵的空气或湿气敏感催化剂和有毒试剂。总而言之，这些考虑因素完全符合 EPSRC 大挑战的主题“拨号分子”，即单一反应类型可以以简单快速的方式“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，与英国制药和农化行业工业最终用户的互动是该提案的一个组成部分。通过通过互动知识和材料交换计划与两家公司直接合作，我们将能够探索特定和当前行业相关性的目标，并确保我们开发的技术可以很容易地被这些行业采用。这可以促进新药物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生产的化合物）——这不仅从经济角度来看，而且更重要的是在改善人类健康和解决总而言之，将稳健的合成方法、廉价的起始材料和常用的催化剂相结合，可能会产生一种新的且易于部署的方法，用于合成四种重要的有机化合物类别，并具有良好的应用记录人类健康和农业。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。