Convergent Acyliminium Methodology: Diversity in Heterocyclic Scaffolds

杂环化合物是制药和农业化学工业的基石。作为我们正在进行的研究计划的一部分，面向生物感兴趣的杂环系统的合成，我们已经把大量的重点放在设计精简和环境友好的级联和伸缩过程，导致有价值的杂环。我们现在建议开发收敛酰基化方法（CAM），以建立一个有效的“一锅法”路线，将容易获得的亚胺和羧酸转化为各种高度官能化的杂环系统。我们相信，这样一个简单而可靠的程序，导致新的杂环支架将是一个有价值的除了现有的“多样性为导向”的合成协议，并将是非常有用的合成化学家在学术界和工业界。已经进行了初步研究，确定了这一新方法的可行性;因此，该提案的主要目的是：（i）优化新的聚合酰基化方法（CAM），以开发有效的“一锅法”路线，将容易获得的亚胺和羧酸转化为各种各样的杂环体系，（ii）扩大酰化剂的范围以包括苯并稠合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富集形式的杂环，（iv）扩展亚胺底物的范围以包括无环亚胺、亚氨酸盐、恶唑啉、咪唑啉和噻唑啉，（v）在迭代意义上利用CAM序列，利用重复的环扩展以产生中等大小和大环的内酰胺和环肽，（vi）扩展制备复杂天然产物“乌戊酰胺”的方法，以展示这种新的合成方法，（vii）将新的CAM序列应用并验证于以jamtinine和loracarbef作为可能靶标的简单靶标合成中（尽管也会考虑合作者的目标）。我们的目标是将这种新方法发展成为一种强大的合成方法，在学术研究中具有深远的应用，工业药物化学和扩大规模的过程（阿斯利康和诺华（制药）和拜耳（农业）的支持信附后，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在三年内实施。

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.