Convergent Acyliminium Methodology: Diversity in Heterocyclic Scaffolds

杂环化合物是制药和农化工业的基石。作为我们正在进行的旨在合成具有生物学意义的杂环体系的研究计划的一部分，我们非常重视设计流线型和环境友好的级联和伸缩过程，以获得有价值的杂环。我们现在建议开发聚合丙烯酰亚胺方法(CAM)，以建立一种有效的“一锅”方法，将现成的亚胺和羧酸转化为各种高度官能化的杂环体系。我们相信，这种简单可靠的合成方法将是对现有的“多样性导向”合成方案的有益补充，对学术界和工业界的合成化学家都有很大的帮助。已经进行了初步研究，确定了这一新方法的可行性；因此，该建议的主要目的是：(I)优化新的收敛丙烯酰胺方法(CAM)，以开发有效的“一锅”路线，将容易获得的亚胺和羧酸转化为各种杂环体系；(Ii)扩大酰化剂的范围，以包括与苯环有关的实例和官能化的磺酸、膦酸、氯甲酸酯和异氰酸酯；(Iii)探索不对称催化，以制备对映体丰富的杂环；(Iv)扩大亚胺底物的范围，以涵盖环亚胺、亚胺、恶唑、咪唑和噻唑(V)在迭代意义上开发CAM序列，利用重复扩环来生产中、大环内酰胺和环肽；(Vi)扩展制备复杂天然产物‘upenamide’的方法学，以展示这一新的合成方法；(Vii)将新的CAM序列应用于简单目标合成中，并因此验证新的CAM序列(尽管来自合作者的目标也将被考虑)。我们的目标是将这一新过程发展成一个在学术研究中具有深远应用的强大的合成过程，工业药物化学和扩大流程(附上阿斯利康、诺华(制药)和拜耳(农业)的支持函，与这些公司的合作计划进展顺利)。这一雄心勃勃的方案将由PDRA在3年内执行。

Heterocyclic compounds are the cornerstone of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of biological interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to valuable heterocycles. We now propose to develop Convergent Acyliminium Methodology (CAM) to establish an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of highly functionalised heterocyclic systems. We believe that such a simple and reliable procedure leading to novel heterocyclic scaffolds will be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry. Preliminary studies have been carried out which establish the viability of this novel approach; the main aims of the proposal are therefore: (i) to optimise the novel Convergent Acyliminium Methodology (CAM) to develop an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of heterocyclic systems, (ii) to expand the range of acylating agents to include benzannelated examples and functionalized sulfonic acids, phosphonic acids, chloroformates and isocyanates,(iii) to explore asymmetric catalysis to prepare heterocycles in enantio-enriched forms,(iv) to extend the range of imine substrates to encompass acyclic imines, imidates, oxazolines, imidazolines and thiazolines,(v) to exploit the CAM sequence in an iterative sense utilising repeated ring-expansions to produce medium-sized and macrocyclic lactams and cyclic peptides,(vi) to extend the methodology to prepare the complex natural product, 'upenamide, in order to showcase this new synthetic approach,(vii) to apply, and therefore validate, the new CAM sequence in simple target synthesis with jamtinine and loracarbef as possible targets (although targets from collaborators will also be considered).It is our aim to develop this new procedure into a powerful synthetic procedure with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes (letters of support from AstraZeneca and Novartis (pharma) and Bayer (Agro) are attached and plans for collaborations with these companies are well advanced). This ambitious programme will be carried out by a PDRA over a 3 year period.