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

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.