Artificial metalloenzymes for novel C(sp3)-H activation

Enzymes are nature`s promoters, carrying out all essential chemical reactions in every living organism. These promoters - or rather catalysts - are exceptionally selective in their reactions, efficiently orchestrating specific transformations while avoiding unwanted side reactions. They are particularly admired by organic chemists for their selectivity in forming only one of two possible mirror images of the product. Mirror-image molecules are made up of the same atoms and bonds, have the same energy, but are not the same as their mirror-image and can therefore behave differently in the body. In the laboratory, it is extremely difficult to exert this level of control over chemical reactions and products are often obtained as mixtures. A disadvantage of enzymes, however, is that they are limited to reactions within the natural repertoire. Transition metal catalysts developed by organic chemists, on the other hand, offer a wide range of reactivity, enabling a plethora of chemical transformations. Artificial metalloenzymes are catalysts in which an unnatural metal centre is installed in an enzymatic environment. By merging two worlds, artificial metalloenzymes capitalise on nature`s selectivity while introducing new and exciting reactivity into the mix. Directed evolution technology plays a crucial role in maximising the potential of engineered metalloenzymes. It allows a large number of enzymatic environments to be explored simultaneously, greatly increasing the chances of discovering catalysts with the desired properties for specific reactions. Artificial metalloenzymes have immense potential to revolutionise various scientific and technological fields, providing efficient, selective and sustainable catalysts that pave the way for a greener future of synthesis.

The method of C-H activation has revolutionized organic synthesis by providing more economical and environmentally friendly alternatives to construct complex molecules. Traditionally, chemists have depended heavily on synthetic sequences that rely on pre-functionalised materials with significant synthetic effort. With the development of C-H functionalisation, this ubiquitous bond has been realised itself as a reactive handle that - if controlled correctly - drastically shortening syntheses of complex structures. However, therein lies the challenge: the control of selectivity or the art to select only one specific C-H bond in a wide number of possible C-H bonds. At the outset of this project, the potential of a class of artificial metalloenzyme should be interrogated which combine of a new-to-nature metal catalyst known for a high reactivity in C-H activation with an enzyme scaffold known for their excellent selectivity. After initial setbacks using biocatalysis, the focus was redirected to a different strategy namely the utilization of a second C-H bond as a directing group. This approach allows not one but two C-H bonds in proximity to be functionalised at the same time. Importantly, it also allows to stich the two C-G bonds together resulting in a ring formation in a very efficient manner. The main goal was to improve the versatility of this method to enable a wide range of coupling partners to be used. Indeed, several new ring forming reactions were achieved which revealed an interesting, diverted product selectivity depending on the steric and electronic nature of the reaction partners. While usually a 6-membered ring was the preferred product, 5 membered rings could also be obtained with high selectivity when using a different class of unsaturated coupling partners. Moreover, with stabilising groups present, C-C bond cleavage in between the two C-H bonds could be observed revealing yet another avenue for increasing molecular complexity. Optimisation of reaction conditions to favour this mode of reactivity revealed that the presence of water drastically increased the selectivity for C-C bond cleavage. Although there is still much to learn, this work has opened up new possibilities for using dual C-H activation to create complex molecules more efficiently and sustainably from simple starting materials.