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

中环（8-12元）杂环形成一系列天然存在的生物活性化合物的核心支架，其中由环状结构施加的构象约束归因于改善含中环化合物与其靶蛋白的结合。因此，这些环是药物化学的有吸引力的合成靶标。然而，这些支架的合成仍然非常具有挑战性，由于环闭合后的不利的跨环相互作用;这可能是药物发现中中环显著代表性不足的原因。因此，需要新的方法来获得这些结构，从而使药物化学家能够将中等大小的环纳入片段筛选库和新的药物设计中。扩环策略是制备中等大小的环化合物的一种有吸引力的方法，因为这可以部分减少形成中等大小的环的熵罚，并且五至七元杂环是广泛可用的。Clayden小组先前的工作已经证明，容易获得的含芳烃的酰胺或脲底物可以进行分子内芳基迁移以生成中环化合物。本研究项目旨在利用这种强大的扩环策略实现烯基迁移，而不是芳基迁移，这将扩大范围，丰富可获得的潜在生物活性中环支架库。该项目将开始，建立一个强大的路线，使各种含烯烃的起始材料。对此进行了一些调查，作为一个本科生的硕士研究项目的一部分，这将在这个项目中进一步发展，以产生一个更多样化的基板。下一阶段将是确定通过烯烃迁移的扩环在这些类型的基底上是可行的。设想可以使用实验设计来进行这种转化的优化，这可以通过使用布里斯托自动化合成设施的Chemspeed平台来加速。在找到环扩张的稳健条件后，将其应用于一系列基材，以研究该过程的官能团公差和范围。使用Chemspeed机器人可以快速提供其他方法难以获得的中环产品，这也可能加快速度。扩环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化，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目标支架的选择，并有助于确保这种化学从学术实验室到药物发现研究的可转移性。烯烃迁移是一个非常不寻常的反应，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开发进一步的新转化有价值。

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.