Novel strategies for transition metal catalysis in living cells

The ability to carry out efficient transition metal catalysis inside living cells has the potential to unlock a diverse range of new-to-nature transformations, and provides the opportunity to gain insight into the working of biological systems by providing new routes towards biomolecular labelling and imaging, as well as to specific and controlled prodrug activation. However, there is often poor biocompatibility of metal catalyst with the cellular environment. The irreversible poisoning of metal catalysts by biomolecules, in particular intracellular thiols, results in deactivated complexes which are no longer catalytically active. Another hurdle is that very low catalyst concentrations and loadings are required to circumvent cytotoxicity induced by the metal complex. Together, this has the result that the majority of transition metal catalysed reactions carried out in living cells exhibit very poor catalytic activity, with low turnover numbers and low yields. Therefore, it is apparent that new strategies need to be developed in order to make progress towards achieving efficient in vivo transition metal catalysis. In this thesis we present two new strategies to improve the reactivity of transition metal catalysts under biological conditions. Firstly, encapsulation of a gold catalyst within the cavity a supramolecular cage protects the catalyst by providing a physical barrier which can hinder large biomolecules from reaching the metal centre. The second strategy is kinetic protection. Increasing the reaction kinetics of a metathesis catalyst allows productive catalysis to occur faster than catalyst decomposition pathways, and therefore improving the yield of catalysis in the presence of biological poisons.