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。生物同位体是设计候选药物的重要工具，在保持生物活性的同时提供改进的物理化学特征。二取代双环[1.1.1]戊烷（bcp）在药物设计中作为三维间隔单元，常被用作取代1,4-取代芳烃、叔丁基和炔基。虽然BCP基序是否真的是“等构”尚存疑问，但它已被证明具有比母体含芳烃化合物更吸引人的特性，如代谢稳定性、水溶性和膜渗透性。bcp通常通过三环[1.1.1]戊烷（TCP）的应变应变加成反应获得。碳/卤素取代的bcp通过插入C-X键来合成，尽管使用的方法通常受到苛刻的反应条件或较差的官能团耐受性的影响。我们的团队展示了一种通过原子转移自由基加成（ATRA）与TCP反应获得碳/卤素取代BCP的温和方法。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，得到了halo-氨基- bcp产物，但需要优化以减少不必要的副产物的形成并提高反应收率。我们将通过改变起始材料的取代基和使用替代的氮中心自由基来建立反应范围，这将提供广泛的含BCP衍生物的途径。另一个研究领域是跨TCP添加其他杂原子；虽然TCP以前已经与二硫化物、二硒化物、硫醇和磷酰自由基反应，得到杂基bcp化合物，但有很多机会可以扩大这一范围。探索ATRA与磺基自由基的反应将是一个有吸引力的起点。碘- bcp产品可通过锂-卤素交换实现经典功能化；但也许更有用的是通过自由基再生或交叉偶联的方法来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可以重新受到反应条件的影响，以重新引发反应中间体；因此，在我们的ATRA反应中加入第三个组分是有吸引力的，并朝着目前尚未实现的跨TCP的多组分ATRA偶联，以获得杂碳取代的bcp。最后，将开发的方法应用于药物类似物将是有趣的，展示了这项工作的效用。对这些产品的生物学测试也令人感兴趣。总之，本项目提出的工作将有助于了解自由基引发的应变缓解反应，实现对医学和农化界感兴趣的新3D模板的访问。

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.