Catalytic Asymmetric Dearomative Spirocyclisations

设计合成和操纵复杂杂环分子的新方法是极其重要的，特别是考虑到这些化合物形成了大量生物学上有用的天然产物、药物和作物保护产品的基础。特别是，允许复杂的3D分子结构从简单的前体快速构建的程序是非常重要的，因为它们有利于生物测试以前未探索的区域的“化学空间”的潜在应用（例如，在药物发现）。作为我们正在进行的研究计划的一部分，面向不同的杂环支架的合成，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，导致生物活性杂环。该提案集中于从更简单、容易获得的2D芳香族前体形成螺环3D支架并随后进行阐述。提出了一系列基于“脱芳构化”（以形成关键的3D构建块）和“官能化”（以利用其高反应性并进一步增加分子复杂性）的两步方案。已经进行了非常有前途的初步研究，其确立了这种新方法的可行性;关键的脱芳构化步骤使用非常少量的简单铜或银催化剂进行，并且易于进行，采用温和的条件和无毒试剂。预计会发现许多非常通用的一锅法协议。开发的方法也将是一个有价值的除了现有的“多样性为导向的”合成协议，并将在学术界和工业合成化学家的巨大效用。因此，该提案的主要目的是：（i）建立亲电炔活化作为杂芳族化合物脱芳化产生新型螺环的通用方法;（ii）研究关键脱芳/螺环化反应的固体负载催化剂和“流动”变体的使用;（iii）开发不对称变体。（基于初步研究中获得的77%ee，99%产率）;（iv）开发通过检查另外的功能化模式产生的3D“构建块”的合成潜力，包括与一系列亲核试剂的反应、交叉偶联反应和氧化还原过程;（v）研究替代的亲电活化模式;（vi）开发级联反应序列并将这些方法应用于目标合成：沙伐普坦、螺杆菌烯B、普利卡明、天蓝素、螺苯并呋喃、薏苡螺烯酮A-E、rychnophylline、mollenine A和三尖杉碱都已被鉴定为潜在的天然产物/药物靶标。除此之外，我们还将考虑合作者提出的药物靶点。我们的目标是，脱芳/功能化方案将成为构建具有生物重要性的3D支架不可或缺的工具，在学术研究、工业药物化学和规模化过程中具有深远的应用。这个雄心勃勃的计划将由PDRA在3年内实施。

The design of new methods to synthesize and manipulate complex heterocyclic molecules is extremely important , especially given that such compounds form the basis of a vast array of biologically useful natural products, pharmaceuticals and crop protection products. In particular, procedures which allow complex 3D molecular architectures to be constructed quickly from simple precursors are of great importance, as they facilitate the biological testing of previously unexplored regions of 'chemical space' for potential applications (e.g. in drug discovery). As part of our on-going research programme geared towards the synthesis of diverse heterocyclic scaffolds, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to biologically active heterocycles. This proposal centres on the formation and subsequent elaboration of spirocyclic 3D scaffolds from far simpler, readily available 2D aromatic precursors. A series of two-step protocols based of 'dearomatisation' (to form the key 3D building block) and 'functionalisation' (to exploit its high reactivity and further increase molecular complexity) are proposed. Highly promising preliminary studies have been carried out which establish the viability of this novel approach; the key dearomatsation step is performed using a very small quantity of a simple copper or silver catalyst and is easy to perform, employing mild conditions and non-toxic reagents. The discovery of a number of extremely versatile one-pot protocols is anticipated. The methods developed will also be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry. The main aims of the proposal are therefore:(i) to establish electrophilic alkyne activation as versatile method for the dearomatisation of heteroaromatics leading to novel spirocycles;(ii) to investigate the use of solid supported catalysts and 'flow' variants of the key dearomatisation / spirocyclisation reaction;(iii) to develop asymmetric variants (building on the 77% ee, 99% yield obtained in preliminary studies);(iv) to exploit the synthetic potential of the 3D 'building blocks' generated by examining additional functionalisation modes, including reactions with a range of nucleophiles, cross-coupling reactions and redox processes;(v) to investigate alternative electrophilic activation modes; (vi) to develop cascade reaction sequences and to apply these methods in target synthesis: Satavaptan, spirobacillene B, plicamine, coerulescine, spirobenzofuran, coixspiroeneones A-E, rychnophylline, mollenine A and cephalotaxine have all been identified as potential natural product/pharmaceutical targets. In addition, medicinal targets suggested by collaborators will also be considered.It is our aim that the dearomatisation/functionalisation protocols will become indispensable tools for the construction of biologically important 3D scaffolds, with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes.This ambitious programme will be carried out by a PDRA over a 3 year period.