Heterocyclic inflation - efficient routes to medium rings by migratory ring expansion of alkenes

中环（8-12元）杂环形成了一系列天然存在的生物活性化合物的核心支架，环结构施加的构象约束归因于改善中环含化合物与其靶蛋白的结合。因此，这些环是药物化学中有吸引力的合成靶点。然而，由于环闭合时不利的跨环相互作用，这些支架的合成仍然非常具有挑战性；这可能是药物发现中介质环代表性明显不足的原因。因此，需要新的方法来提供对这些结构的访问，从而使药物化学家能够将介质环纳入片段筛选文库和新型药物设计中。环展开策略是制造中型环化合物的一种吸引人的方法，因为这可以部分减少形成中型环的熵损失，并且五到七元杂环广泛可用。Clayden小组先前的工作已经证明，容易接近的含芳烃的酰胺或尿素底物可以经历分子内芳基迁移以产生中环化合物。本研究项目旨在利用这种强大的扩环策略来实现烯基迁移，而不是芳基迁移，这将扩大范围，丰富潜在生物活性的培养基环支架库。该项目将首先建立一条稳健的路线，以生产各种含烯烃的原料。作为本科生MSci研究项目的一部分，已经对此进行了一些调查，该项目将进一步发展，以产生更多样化的基板。下一阶段将是确定通过烯烃迁移的环扩张在这些类型的底物上是可行的。设想这种转变的优化可以使用实验设计来进行，可以通过使用布里斯托尔自动合成设施的Chemspeed平台来加速。在找到环扩展的稳健条件后，它们将应用于一系列衬底，从而研究该工艺的官能团公差和范围。使用Chemspeed机器人也可能加速这一过程，以快速提供其他方法难以获得的中环产品。环扩张的产物将具有进一步反应的潜在位点，因此，我们希望展示特定的衍生物，以证明中环产物的多功能性及其对药物发现的适用性。在整个项目中，与英国癌症研究中心的定期会议将指导靶向支架的选择，并帮助确保这种化学从学术实验室转移到药物发现研究。烯烃运移是一种非常罕见的反应，因此我们希望对其机理进行研究。我们可以使用的工具包括实验动力学研究、原位红外光谱测量和计算建模。从这些研究中获得的信息可能对进一步发展新的转变有价值。

Medium ring (8-12 membered) heterocycles form the core scaffold of a range of naturally occurring biologically active compounds, with the conformational constraints imposed by the cyclic structure attributed to improving the binding of medium ring-containing compounds to their target protein. Thus, these rings are attractive synthetic targets for medicinal chemistry. However, the synthesis of these scaffolds remains very challenging, due to the unfavourable transannular interactions upon ring closure; this is the likely reason for the marked underrepresentation of medium rings in drug discovery. Therefore, new methods are required to provide access to these structures, thereby enabling medicinal chemists to incorporate medium rings into fragment screening libraries and novel drug designs.A ring expansion strategy is an appealing way to make medium-sized ring compounds, since this can partially reduce the entropic penalty in forming the medium-sized ring, and five- to seven-membered heterocycles are widely available. Previous work in the Clayden group has demonstrated that readily accessible arene-containing amide or urea substrates can undergo an intramolecular aryl migration to generate medium ring compounds. This research project aims to employ this powerful ring expansion strategy to achieve alkenyl migration, rather than aryl migration, which would broaden the scope and enrich the library of potentially bioactive medium ring scaffolds that could be accessed.The project will begin with establishing a robust route to make a variety of alkene-containing starting materials. Some investigation into this has been carried out as part of an undergraduate's MSci research project, which will be further developed in this project to generate a more diverse set of substrates. The next stage will be to establish that the ring expansion via alkene migration is feasible on these types of substrates. It is envisaged that optimisation of this transformation could be carried out using Design of Experiments, which could be accelerated through use of Bristol Automated Synthesis Facility's Chemspeed platform. After robust conditions for the ring expansion have been found, they will be applied to a range of substrates, so as to investigate the functional group tolerance and scope of the process. This too could potentially be expedited using the Chemspeed robot to rapidly provide medium ring products that would be difficult to access by other methods. The products of the ring expansion would have potential sites for further reaction, and therefore, we would like to showcase particular derivatisations that would demonstrate the versatility of medium ring products and their applicability to drug discovery. Regular meetings with Cancer Research UK throughout the project will guide the choice of scaffolds targeted and help ensure the transferability of this chemistry from academic laboratories to drug discovery research. The alkene migration is a very unusual reaction, and so we hope to undertake investigations its mechanism. The tools we could use to do this include experimental kinetic studies, in situ infrared spectroscopy measurements and computational modelling. The information gained from these studies could be valuable in developing further novel transformations.