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(BBSRC DTP CASE) Integrated catalysis for the regioselective functionalization of pharmaceutical precursors

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  • Full or part time
    Prof J Micklefield
    Prof M Greaney
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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 [1]. In collaboration with AztraZeneca, we aim to develop new chemoenzymatic cascade reactions which will enable functionalization of pharmaceutical scaffolds to generate compounds with improved biological activity and physical properties for further development. 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 AztraZeneca scientists and will include a placement period at AztraZeneca where the student can obtain additional training and skills in world leading industrial labs. Students from Chemistry or Biological Sciences degree programmes, who possess a desire to do cutting edge research at the Chemistry-Biology interface are encouraged to apply.

Qualification
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Contact for further Information
For more details contact Professor Jason Micklefield ([email protected])

https://www.research.manchester.ac.uk/portal/jason.micklefield.html
https://www.research.manchester.ac.uk/portal/michael.greaney.html

Funding Notes

This is a CASE studentship is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

References

Selected related recent publications:
[1] Integrated Catalysis Opens New Arylation Pathways via Regiodivergent Enzymatic C-H Activation. J. Latham, H. H. Sharif, J.-M. Henry, B. R. K. Menon, S. A. Shepherd, M. F. Greaney, J. Micklefield Nature Commun. 2016, 7, 1187 (http://dx.doi.org/10.1038/NCOMMS11873);

[2] RadH: AVersatile Halogenase for Integration into Synthetic Pathways. B Menon, E. Brandenburger, H. H. Sharif, U. Klemstein, S. A. Shepherd, M. F. Greaney, J. Micklefield Angew. Chem. Int. Ed. 2017 (http://dx.doi.org/10.1002/anie.201706342);

[3] An Engineered Tryptophan Synthetase Opens New Enzymatic Pathways to b-Methyltryptophan and Derivatives. D. Francis, M. Winn, J. Latham, M. F. Greaney, J. Micklefield ChemBioChem 2017, 18, 382-386 (http://dx.doi.org/10.1002/cbic.201600471);

[4] 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, C. Levy, D. Leys and J. Micklefield Chemical Science 2015, 6,3454-3460 (http://dx.doi.org/10.1039/C5SC00913H)

[5] Development of Halogenase Enzymes for Use in Synthesis J. Latham, E. Brandenburger, S. A. Shepherd, B. R. K. Menon and J.Micklefield Chem. Rev. 2017, in press (http://dx.doi.org/10.1021/acs.chemrev.7b00032)

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