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Integrating chemocatalysis and biocatalysis to create new synthetic pathways (iCBPATH)


Project Description

In this project, we aim to combine the power of enzymatic C-H bond functionalisation and transition metal catalysis to construct complex molecules in a single reaction providing new, more efficient and rapid routes to pharmaceuticals and other essential products. For example, bespoke engineered halogenase enzymes will be used to regioselectively install halogen substituents into complex aromatic scaffolds with in situ transition metal catalysis enabling concomitant construction of new C−C, C−N, C−F, C−CF3 bonds that are inaccessible via current state-of-the-art synthetic methods.
Previously, we demonstrated how highly regioselective flavin-dependent halogenase (Fl-Hal) enzymes, that use benign inorganic halides, are an attractive alternative to traditional toxic and nonselective chemical halogenation methods. We also used active site mutagenesis to improve catalytic activity of Fl-Hal and we were able to switch the regioselectivity of these enzymes with various non-natural substrates. In addition, we succeeded in integrating Fl-Hal with chemocatalysts to open up new reaction pathways in vitro. We demonstrated, for the first time, the integration of Fl-Hal with transition metal-catalysed cross-coupling chemistry, in one-pot, to achieve regiodivergent arylation or alkenylation of aromatic scaffolds. In this project, we aim to integrate Fl-Hal with a range of other chemocatalysts providing unprecedented C−H activation reactions for C−C, C−N, C−F, C−CF3 bond formation. In addition, we will develop other integrated cascades, with multiple different enzymes and chemocatalysts combined in a single reaction vessel (reactor).
Applicants should hold, or expect to obtain, a degree (or equivalent) in Chemistry, Biochemistry or Biological Science and should possess a strong interest in biological chemistry/chemical biology. The successful candidate will gain training and skills in organic chemistry, chemocatalysis and also biocatalysis working in a highly stimulating multidisciplinary environment with a large team of chemical biologists in the Manchester Institute for Biotechnology (http://www.mib.ac.uk) and synthetic organic chemists in the School of Chemistry.

Contact for further Information
Professor Jason Micklefield FRSC
PA Sarah Jones:

http://www.chemistry.manchester.ac.uk/aboutus/staff/show.html?ea=jason.micklefield
http://www.micklefieldlab.chemistry.manchester.ac.uk
http://www.chemistry.manchester.ac.uk/aboutus/staff/show.html?ea=michael.greaney
https://twitter.com/Micklefield_Lab
NPRONET: http://npronet.com

Funding Notes

Applications are invited from self-funded students. For UK/EU tuition fees are £8,750 and International are £25,500 for 2019/20 academic year.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or the overseas equivalent) in Chemistry, Biochemistry, Bioscience or a related area/subject. Candidates with experience in Chemical biology (biological chemistry), with an interest in enzymes (biocatalysis) and/or synthesis (chemocatalysis) are encouraged to apply.

References

• Integrated Catalysis Opens New Arylation Pathways via Regiodivergent Enzymatic C-H Activation. J. Latham, J.-M. Henry, H. H. Sharif, B. R. K. Menon, S. A. Shepherd, M. F. Greaney, J.Micklefield. Nature Commun. 2016, 7, 11873 (http://dx.doi.org/10.1038/NCOMMS11873)
• Development of Halogenase Enzymes for Use in Synthesis J. Latham, E. Brandenburger, S. A. Shepherd, B. R. K. Menon and J.Micklefield Chem. Rev 2018, 118, 232-269; (http://dx.doi.org/10.1021/acs.chemrev.7b00032)
• RadH: A Versatile Halogenase for Integration into Synthetic Pathways. B. R. K. Menon, E. Brandenburger, H. H. Sharif, U. Klemstein, S.A. Shepherd, M. F. Greaney, J. Micklefield Angew. Chem. Int. Ed. 2017, 56, 11841 –11845 (http://dx.doi.org/10.1002/anie.201706342)
• A Structure-Guided Switch in the Regioselectivity of a Tryptophan Halogenase. S. A. Shepherd, B. R. K. Menon, H. Fisk, A.-W. Struck, C. Levy, D. Leys, J. Micklefield ChemBioChem 2016, 17, 821-824 (http://dx.doi.org/10.1002/cbic.201600051)
• Extending the Biocatalytic Scope of Regiocomplementary Flavin-Dependent Halogenase Enzymes. S. A. Shepherd, C. Karthikeyan, J. Latham, A.-W. Struck, M. L. Thompson, B. Menon, M. Styles, C. Levy, D. Leys and J. Micklefield Chemical Science 2015, 6, 3454-3460 (http://dx.doi.org/10.1039/C5SC00913H)

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