Catalytic Asymmetric Dearomative Spirocyclisations

设计合成和操作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构成了大量具有生物用途的天然产品、药品和作物保护产品的基础。特别是，能够从简单的前体快速构建复杂的3D分子结构的程序是非常重要的，因为它们促进了对潜在应用(例如，在药物发现中)的先前未探索的化学空间区域的生物测试。作为我们正在进行的旨在合成各种杂环支架的研究计划的一部分，我们非常重视设计流线型和环保的级联和伸缩工艺，从而获得具有生物活性的杂环。这项提议的核心是从简单得多的、容易获得的2D芳香族前体中形成和随后精制螺环3D支架。提出了一系列基于“去芳构化”(形成关键的3D构件)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。已经开展了非常有希望的初步研究，证实了这种新方法的可行性；关键的脱芳烃步骤使用非常少量的简单铜或银催化剂进行，并且使用温和的条件和无毒的试剂很容易执行。预计将发现许多非常通用的一锅协议。开发的方法也将是对现有的面向多样性的合成方案的宝贵补充，对学术界和工业界的合成化学家都有很大的实用价值。因此，该建议的主要目的是：(I)建立亲电的炔烃活化法作为杂芳烃脱芳烃的通用方法，从而导致新的螺环反应；(Ii)研究固载催化剂的使用和关键的脱芳烃/螺环反应的‘流动’变体；(Iii)开发不对称变体(建立在77%ee的基础上，在初步研究中获得99%的产率)；(Iv)开发通过研究额外的官能化模式产生的3D‘积木’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：沙达普坦、螺杆菌B、普利卡明、蓝花碱、螺苯并呋喃、螺螺酮A-E、兰茶碱、Mollenine A和头孢菌素都已被确定为潜在的天然产物/药物目标。此外，我们还将考虑合作者提出的药物靶标。我们的目标是，脱芳烃/官能化协议将成为构建具有生物重要性的3D支架不可缺少的工具，在学术研究、工业药物化学和放大过程中具有深远的应用。这一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.