We focussed on the biocatalytic synthesis of chiral thiols and thioethers, which are a functional group found in many APIs but with very limited enzymatic strategies for their synthesis. We explored a plethora of potential strategies which led us to find the ability of a certain class of enzyme, ene reductases, to generate α-acyl radicals as a new strategy for the synthesis of thioethers. We carried out mechanistic studies to understand this unique ability of ene reductases to control the highly reactive intermediates formed during the catalysis. This reaction was scaled up and the product isolated (10.26434/chemrxiv-2024-shnqc; 10.1021/jacs.5c00761).
In the ThioBioCat project, we also developed several other new biocatalytic strategies for the synthesis of chiral molecules, not limited to thiols and thioether. We developed a cascade combining three different types of enzymes to create a fragment of the API BMS-986278 which is currently in clinical trials, starting from a cheap and readily available precursor. Combing C-H activation by unspecific peroxygenase to install an allylic ketone, ene reduction by ene reductase, and finally keto reduction by alcohol dehydrogenase, we synthesised the final fragment containing two stereocentres with high purity (10.1021/acscatal.4c00177).
This research was also presented at several international conferences, one of which I helped organise every year since 2022, NextGenBiocat which aims to bring together early career researchers in biocatalysis. I was involved in the training of master and PhD students, and in turn received training in several techniques, most notably stopped-flow spectroscopy which allows us to follow fast processes to better understand enzyme mechanisms.
