Chemoenzymatic cascades for one carbon functionalization of pharmaceutical scaffolds

The project aims to integrate novel enzymes (biocatalysts) with synthetic catalysts (chemocatalysts) to develop new methods for more efficient, lower cost and environmentally sustainable production of pharmaceuticals which are urgently required to combat disease. Currently most pharmaceuticals are produced by multi-step synthetic methods, with deleterious reagents and solvents, from non-renewable petrochemicals, all of which come at significant cost. In this project we aim to develop more sustainable processes, combining biocatalysts and chemocatalysts to deliver key pharmaceutically relevant compounds under mild conditions, in water, utilising more benign reagents and renewable feedstocks. Many biocatalysts and chemocatalysts are incompatible. A key challenge in this project is the development of technology that will enable multiple different enzymes and chemocatalysts to be combined in one reaction vessel. The combination of multiple catalytic transformations in a single reaction cascade represents a potential step-change improvement in efficiency, avoiding multiple work-up and purifications steps required to isolate intermediates. To address this major challenge, we recently developed the first example of integrated chemobiocatalytic cascades, including enzymes with transition-metal catalysed (TM) cross-coupling chemistry, in one reaction vessel, to achieve regiodivergent arylation or alkenylation of aromatic scaffolds.
In collaboration with GlaxoSmithKline, the UKs largest pharmaceutical company, we aim to develop new chemoenzymatic cascade reactions to install nitrile (one-carbon) groups into target compounds. The nitrile group has considerable value as it is present in numerous pharmaceutical products, and it is also a highly versatile functional
group for derivatisation. We will therefore develop further integrated enzymatic and chemocatalytic transformations to derivatise the nitrile containing intermediates to the corresponding amides, carboxylic acids, amines, amidines, and heterocyclic moieties all of which that are found in a number of pharmaceutical products. To achieve this we will need to develop new and improved enzymes (biocatalysts), with enhanced activity, stability and altered substrate specificity. In addition, new chemocatalytic reactions will need to be developed that are compatible with the enzymes. Training will be provided in biological chemistry/biocatalysis and in chemocatalysis under the supervision of Prof. Jason Micklefield and Prof. Michael Greaney. The project will also involve close interactions with GSK scientists and will include a placement period at GSK where the student can obtain additional training and skills in world leading industrial labs.