Synthesis and functionalisation of 1-iodo-3-substituted-bicyclo[1.1.1]pentanes

本项目福尔斯属于EPSRC合成有机化学研究领域。双环[1.1.1]戊烷（BCP）是药物分子中叔丁基、炔基和芳烃基团的有用生物电子等排体。这些基团取代药物分子中的BCP单元可以改善药物的性质，例如膜渗透性、极性、构象和代谢。BCP是1，4-取代芳烃的特别好的替代品，因为它们各自保持其取代基在180度。已经用BCP代替芳烃合成了几种药物分子的BCP类似物，改善了这些药物的药代动力学特性。因此，期望能够容易地将BCP基团插入分子中，并且具有高官能团耐受性-允许根据分子和手头提出的路线在合成的各个阶段安装。尽管这些基序具有实用性，但形成碳取代的BCP仍然具有挑战性，通常需要苛刻的反应条件。最近，我们的小组开发了三乙基硼烷引发的烷基碘和三环[1.1.1.0]戊烷（TCP，BCP的前体）之间的反应，以高产率，快速反应时间和高官能团耐受性形成1-碘-3-取代-BCP。虽然对各种各样的基团有效，但该反应不能将芳基碘化物添加到TCP中。能够形成1-碘-3-芳基-BCP将允许形成存在于多种药物化合物中的联苯系统的生物电子等排体。由于其温和的条件，跨TCP的自由基加成仍然是期望的，因此我们的兴趣最近转向使用替代的自由基反应来跨TCP加成分子。最近的工作已经成功地开始开发芳基碘跨TCP的光氧化还原催化的ATRA反应，以及杂芳基碘。这使得以前只能使用苛刻的反应条件、长反应时间和低产率合成产物。有了这些，我们希望研究BCP碘化物产品的进一步功能化的发展。该小组最近的工作开发了一种高收率的铁催化碘-BCP和芳基之间的交叉偶联反应。然而，结果表明，铁催化剂中的杂质在反应机理中发挥了作用;计划进行进一步的研究，以调查这一点，并发现更多关于该反应如何工作的信息。我们还打算进一步研究这些产品与自由基反应官能化的可能性。我们建议可以开发一种一锅法多组分体系，由此可以将化合物添加到TCP中以产生BCP基团，该基团可以反过来添加到双键中。或者，另一种方法是采用初始ATRA反应的产物并重新活化BCP-I键以形成BCP自由基，该BCP自由基再次可以添加到各种不同的官能团中。开发一种容易形成1-碘-3-取代的BCP的方法以及使这些和其他碘-BCP产物官能化的许多方法，将显著增加BCP掺入分子的工具包。这也可以允许获得广泛的取代的BCP，这些BCP以前很难或不可能制备，因此使得药物化合物的BCP类似物的合成明显更容易和更快。

This project falls within the EPSRC Synthetic Organic Chemistry research area.Bicyclo[1.1.1]pentane (BCP) is a useful bioisostere for t-butyl, alkyne and arene groups in drug molecules. Substitution of these groups for a BCP unit in a drug molecule can improve the properties of the drug such as membrane permeability, polarity, conformation and metabolism. BCPs are particularly good substitutes for 1,4-substituted arenes as they each hold their substituents at 180 degree. Several BCP analogues of drug molecules have already been synthesised with BCP in place of an arene, improving the pharmacokinetic properties of those drugs. It is therefore desirable to be able to insert BCP groups into molecules easily, and with high functional group tolerance - allowing installation at various stages of the synthesis depending on the molecule and proposed route at hand. Despite the utility of these motifs, forming carbon substituted BCPs remains challenging, often requiring harsh reaction conditions. Recently our group developed a triethylborane initiated reaction between alkyl iodides and tricyclo[1.1.1.0]pentane (TCP, the precursor to BCP) to form 1-iodo-3-substituted-BCPs in high yield, quick reaction times and high functional group tolerance. While effective for a wide variety of groups, this reaction was unable to add aryl iodides across TCP. Being able to form 1-iodo-3-aryl-BCPs would allow formation of a bioisostere for biphenyl systems which are present in a variety of drug compounds. Radical addition across TCP is still desirable due to its mild conditions and therefore our interest has recently turned to using alternative radical reactions to add molecules across TCP. Recent work has successfully begun to develop a photoredox catalysed ATRA reaction of aryl iodides across TCP, as well as heteroaryl iodides. This allows synthesis of products previously only accessible using harsh reaction conditions, long reaction times and in low yield. With these in hand, we wish to investigate the development of further functionalisation of the BCP iodide products. Recent work in the group has developed an iron catalysed cross-coupling reaction between iodo-BCPs and aryl groups in high yields. However, results have suggested that impurities in the iron catalyst have a part to play in the reaction mechanism; further studies are planned to investigate this and discover more about how this reaction works. We also intend to investigate the possibility of functionalising these products with further radical reactions. We propose that a one pot, multicomponent system could be developed, whereby a compound could be added across TCP to create a BCP radical which could in turn add into a double bond. Alternatively another approach is to take products of initial ATRA reactions and reactivate the BCP-I bond to form the BCP radical which again can add in to a wide variety of different functional groups. Developing a way to easily form 1-iodo-3-substituted BCPs as well as a number of ways to functionalise these, and other iodo-BCP products, would add significantly to the toolkit for incorporation of BCPs into molecules. This could also allow access to a wide range of substituted BCPs which were previously difficult or impossible to make and therefore make the synthesis of BCP-analogues of drug compounds significantly easier and quicker.