New methods for bicyclo[1.1.1]pentane synthesis and functionalization

本项目福尔斯属于EPSRC合成有机化学研究领域。张力环系统一直是化学家感兴趣的，无论是成环策略，其有趣的结构，还是其在材料科学和医学中的独特性质。在许多张力环系统中，双环[1.1.1]戊烷（BCP）由于它们在药物化学中作为1，4-二取代的苯环、炔和叔丁基。有趣的是，药物分子的BCP类似物如Darapladib，Resveratrol和Avagacestat都被证明具有改善的活性和药代动力学特性。尽管BCP开始被确立为有效的生物电子等排体，但由于其具有挑战性的合成，它们作为“下一代”支架用于3D化学空间探索的潜在用途经常被忽视。然而，计算辅助药物发现在过去十年中在预测和虚拟筛选方面取得了巨大的进步。这在未来将导致预测具有多个向量的固定饱和环系统，例如BCP，作为Hit to Lead验证的理想候选者。不幸的是，目前还没有合适的方法来获得足够数量的桥和桥头取代的BCP用于药物开发。本研究的重点将是研究桥取代的BCP合成的策略和局限性。安德森小组已经开发了一种温和的方法，通过与三环[1.1.1.0]戊烷（TCP）的原子转移自由基加成反应获得碳/卤素取代的BCP，以提供桥头取代的BCP的多样化组合。第一种策略是将上述方法应用于已知的TCP衍生物，例如三环[2.1.0.0.]戊烷（TCP ′）。这将允许在每个桥上具有取代基的可能性，其中两个可以进一步官能化或去除，并且将是完全桥取代的BCP的第一个实例。第二个策略将扩展已经包含在BCP桥中的当前功能，例如gem dichloro。其两个主要焦点是开发足够的交叉偶联方案，以及通过一种或两种氯化物的金属插入来激活亲电体的桥。还将研究BCP的对映选择性交叉偶联/去对称化，因为它将提供对映纯桥取代的BCP的第一个实例。除了这项工作，我们还将进一步开发取代的双环丁烷，这是通过现有的二氯卡宾插入化学BCP的“已知”前体。总之，本项目中提出的工作将有助于了解自由基引发的应变消除反应，对映选择性交叉偶联和获得新的3D模板，这是医学和农业化学界感兴趣的。

This project falls within the EPSRC Synthetic Organic Chemistry research area.Strained ring systems have always been of interest to chemists, whether it be strategies for ring formation, their intriguing structures, or their unique properties in materials science and medicine.Of the many strained ring systems, bicyclo[1.1.1]pentanes (BCPs) have recently stimulated significant interest due to their potential for applications in medicinal chemistry as saturated bioisosteres for 1,4-disubstituted benzene rings, alkynes and tert-butyl groups. Interestingly, BCP analogues of drug molecules such as Darapladib, Resveratrol and Avagacestat were all shown to have either, or both, improved activity and pharmacokinetic properties from their parent compounds.Although BCPs are beginning to be established as effective bioisosteres, their potential use as 'next generation' scaffolds for 3D chemical space exploration is often overlooked due to their challenging synthesis. However, computationally assisted drug discovery has had tremendous advancements over the last decade with regards to prediction and virtual screening. This, in the future will lead to the prediction of fixed saturated ring systems with multiple vectors, such as BCPs, as ideal candidates for Hit to Lead validation. Unfortunately, there is at present no suitable method for obtaining both bridge and bridgehead substituted BCPs in quantities sufficient for drug development.The focus of this research will be to investigate the strategies and limitations of the synthesis of bridge substituted BCPs. The Anderson group has already developed a mild method to achieve carbon/halogen-substituted BCP's via atom-transfer radical addition reactions with Tricyclo[1.1.1.0]pentane (TCP) to afford a diverse portfolio of bridgehead substituted BCPs. The first strategy will be to apply the above methodology to known TCP derivatives such as Tricyclo[2.1.0.0.]pentane (TCP'). This would then allow the possibility of having a substituent on each bridge, two of which that could either be further functionalised or removed, and would be the first example of a fully bridge substituted BCP. The second strategy will expand upon current functionality that has already been incorporated into the BCP bridge, such as the gem dichloro. The two main focuses of this are to develop a sufficient cross-coupling protocol, and to activate the bridge towards electrophiles through metal insertion of one, or both, of the chlorides. Enantioselective cross- coupling/desymmetrisation of BCPs will also be investigated, as it would provide the first example of enantiopure bridge substituted BCPs. Alongside this work, we will also further develop access to substituted bicyclobutanes, which represent 'known' precursors to BCPs via existing dichlorocarbene insertion chemistry.In summary, the work proposed in this project will contribute to knowledge of radical-initiated strain relief reactions, enantioselective cross-coupling and achieving access to new 3D templates which are of interest to the medicinal and agrochemical communities.