New methods for bicyclo[1.1.1]pentane synthesis and functionalization

该项目属于EPSRC合成有机化学研究领域的福尔斯。生物电子等排体是设计药物候选物的重要工具，在保持生物活性的同时提供改进的理化特性。二取代双环[1.1.1]戊烷（BCPs）在药物设计中作为三维间隔基单元，常被用作取代1，4-取代芳烃、叔丁基和炔基的结构单元。虽然BCP基序是否真正是“等排的”是值得怀疑的，但是它已经显示出赋予有吸引力的性质，例如代谢稳定性、水溶性和相对于母体含芳烃化合物的膜渗透性。BCP通常通过与三环[1.1.1]戊烷（TCP）的应变消除加成反应获得。碳/卤素取代的BCP已经通过插入C-X键合成，尽管所使用的方法通常遭受苛刻的反应条件或差的官能团耐受性。我们的小组已经证明了一种温和的方法，通过原子转移自由基加成（ATRA）反应与TCP实现碳/卤素取代的BCP的。杂原子取代的BCP的形成比C-取代的类似物更不确定，通常需要多个步骤。本研究的重点将是通过一步ATRA级联反应形成杂碘BCP化合物。在我们的初步工作中，我们已经成功地实现了氮中心自由基与TCP的ATRA反应，得到卤代氨基BCP产物，但需要优化以减少不需要的副产物的形成并提高反应产率。我们将通过改变我们的起始材料的取代基和通过使用替代的氮中心自由基来建立反应范围，这将提供获得广泛的期望的含BCP的衍生物的途径。另一个研究领域是在TCP上添加其他杂原子;虽然TCP以前已经与二硫化物、二硒化物、硫醇和磷酰基反应得到杂BCP化合物，但有许多机会可以扩展这一范围。探索ATRA与磺酰基自由基的反应将是一个有吸引力的起点。碘-BCP产物可以通过锂-卤素交换经典地官能化;但可能更有用的是通过自由基再生或交叉偶联方法，以得到类似于母体芳烃化合物的杂碳取代的BCP。我们已经证明，碘-BCP可以重新经受反应条件以重新引发反应性中间体;因此，将第三组分并入我们的ATRA反应中并朝向目前未实现的跨TCP的多组分ATRA偶联以得到杂碳取代的BCP将是有吸引力的。最后，将开发的方法应用于药物类似物，展示这项工作的实用性将是有趣的。这些产品的生物学测试也很有意义。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，获得新的3D模板，这将是医学和农业化学界感兴趣的。

This project falls within the EPSRC Synthetic Organic Chemistry research area.Bioisosteres are important tools for the design of pharmaceutical drug candidates, offering improved physicochemical profiles whilst maintaining biological activity. Di-substituted bicyclo[1.1.1]pentanes (BCPs) act as a three dimensional spacer units in drug design, and are often used as a substitute for 1,4-substituted arenes, tert-butyl groups and alkynyl groups. While it is questionable whether the BCP motif is truly 'isosteric', it nonetheless has been shown to impart attractive properties such as metabolic stability, aqueous solubility and membrane permeability over the parent arene-containing compound. BCPs are typically accessed through strain relief addition reactions to tricyclo[1.1.1]pentane (TCP). Carbon/halogen-substituted BCPs have been synthesised through insertion into C-X bonds, although the methods used usually suffer from harsh reaction conditions or poor functional group tolerance. Our group has demonstrated a mild method to achieve carbon/halogen-substituted BCP's via atom-transfer radical addition (ATRA) reactions with TCP. The formation of heteroatom-substituted BCPs is less established than the C-substituted analogues, often requiring multiple steps. The focus of this research will be to form hetero-iodo-BCP compounds via one step ATRA cascades. In our preliminary work, we have successfully achieved ATRA reactions of nitrogen centred radicals with TCP to give halo-amino-BCP products, but optimisation to reduce the formation of unwanted side products and to improve reaction yield is required. We will establish reaction scope by varying the substituents of our starting material and by using alternative nitrogen centred radicals, this will provide access to a wide range of desirable BCP containing derivatives. Another area of investigation would be the addition of other heteroatoms across TCP; while TCP has been previously reacted with disulfides, diselenides, and thiols and phosphoranyl radicals to give hetero-BCP compounds, many opportunities are available for expansion of this scope. Exploration of ATRA reaction with sulfonyl radicals would be an attractive starting point. Iodo-BCP products can be functionalised classically through lithium-halogen exchange; but perhaps more usefully by radical re-generation or cross coupling methods to give hetero-carbon substituted BCPs analogous to the parent arene compounds. We have demonstrated that iodo-BCPs can be re-subjected to the reaction conditions to re-initiate the reactive intermediate; it would therefore be attractive to incorporate a third component to our ATRA reaction, and head towards currently unachieved multi-component ATRA couplings across TCP to give hetero-carbon-substituted BCPs. Finally, it would be interesting to apply the developed methodology to drug analogues, showcasing the utility of this work. Biological testing of these products is also of interest. In summary, the work proposed in this project will contribute knowledge of radical-initiated strain relief reactions, achieving access to new 3D templates which will be of interest to the medicinal and agrochemical communities.