Developing access to new areas of molecular space is a key objective for chemists,1 particularly to three-dimensional, sp3-rich compounds which show improved bioactivity compared with flat, sp2-rich structures favoured by recent strategies within the pharmaceutical sector.2 While this importance is increasingly known, prompting the development of software to predict the “three-dimensional novelty” of structures, there remains a lack of reliable methodologies for creating this diversity; metal-catalysed cross-coupling processes show great ability to form carbon-carbon bonds but remain associated with flat molecular architectures (Scheme 1a). Further, nitrogen remains a key element in bioactive molecules, appearing in every major pharmacological class despite its inclusion representing an established synthetic challenge. A methodology forming novel, three-dimensional structures which incorporate nitrogen would therefore be of great importance to medicinal chemists,1a-b,3 equipping the field of drug discovery with another tool to combat antibiotic resistance. Tsuji-Trost reactions (Scheme 1b) show promise in creating stereochemically-complex structures,1b and recent developments permit the activation of carbon-nitrogen bonds. This project will develop the related catalytic rearrangement of allylic amines to convert simple starting materials into highly complex, bi- and tri-cyclic structures. The deliberate use of amines as the reactive component will turn a synthetic problem into an advantage, while ensuring this key group is retained. Such rearrangements are inherently equilibria, and control will therefore be achieved through the design of selective termination strategies, permitting only one state to undergo further reaction (Scheme 1c). This will allow single step syntheses of complex, stereo-defined structures that score highly in terms of novelty and three-dimensionality. The resulting compounds are well suited to further derivatisation, allowing the testing of small compound libraries against cellular targets (cancer, bacterial, CNS) through collaboration with groups at Northumbria and Bristol universities. The automated scale-up of these reactions will also be explored, permitting application within industrial research.4
Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.
• Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere.
For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/
Please note: Applications that do not include a research proposal of approximately 1,000 words (not a copy of the advert), or that do not include the advert reference (e.g. RDF20/…) will not be considered.
Deadline for applications: Friday 24 January 2020
Start Date: 1 October 2020
Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.
1) For examples from my own work, see: a) C. J. Gerry, B. K. Hua, M. J. Wawer, J. P. Knowles, S. D. Nelson, Jr., O. Verho, S. Dandapani, B. K. Wagner, P. A. Clemons, K. I. Booker-Milburn, Z. V. Boskovic, S. L. Schreiber, J. Am. Chem. Soc., 2016, 138, 8920; b) E. E. Blackham, J. P. Knowles, J. Burgess and K. I. Booker-Milburn, Chem. Sci, 2016, 7, 2302; c) P. J. Koovits, J. P. Knowles and K. I. Booker-Milburn, Org Lett., 2016, 18, 5608; d) K. G. Maskill, J. P. Knowles, L. D. Elliott, R. W. Alder and K. I. Booker-Milburn, Angew. Chem. Int. Ed., 2013, 52, 1499. 2) F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52, 6752. 3) For examples from my own work, see: a) R. L. Connelly, J. P. Knowles and K. I. Booker-Milburn, Org. Lett. 2019, 21, 18; b) J. P. Knowles and K. I. Booker-Milburn, Chem. Eur. J., 2016, 22, 11429. 4) For my experience in scale-up using flow reactors, see: a) L. D. Elliott, J. P. Knowles, P. J. Koovits, K. G. Maskill, M. J. Ralph, G. Lejeune, L. J. Edwards, R. I. Robinson, I. R. Clemens, B. Cox, D. D. Pascoe, G. Koch, M. Eberle, M. B. Berry and K. I. Booker-Milburn, Chem. Eur. J., 2014, 20, 15226; b) L. D. Elliott, J. P. Knowles, C. S. Stacey, D. J. Klauber and K. I. Booker-Milburn, React. Chem. Eng., 2018, 3, 86