About the Project
This project will be carried out in collaboration with Pfizer and will be co-supervised by Dr David Blakemore at Pfizer. It is an EPSRC iCASE project, with four years funding.
Saturated nitrogen/oxygen heterocycles (e.g. piperidines and tetrahydropyrans) are common structures in blockbuster pharmaceuticals.1 Typical motifs of current interest to medicinal chemists include arylated piperidines and tetrahydropyrans and, as a result, the development of new methods for sp3-sp2 carbon-carbon bond formation is of much interest.2 One common approach to arylated piperidines and tetrahydropyrans involves sp2-sp2 coupling followed by alkene hydrogenation.3 However, in this project, using NBoc- or potentially O-directed -lithiation followed by transmetallation and Negishi coupling,4-6 the direct arylation of piperidines and tetrahydropyrans will be explored, as summarised in the scheme below. This will give access to a wide range of disubstituted nitrogen and oxygen heterocycles in a regio-, diastereo- and enantio-controlled manner.
Our group has much experience in the enantioselective lithiation-trapping of N-Boc activated heterocycles, including the use of in situ IR spectroscopy for optimisation studies.7-10 Building on this experience, we will explore the stereoselective arylation of 3-and 4-substituted N-Boc piperidines containing dialkylamino, alkoxy, hydroxy (which will be lithiated first) and fluoro substituents) using lithiation-trappings. With 4-substituted piperidines, diastereo- and enantioselectivity (using chiral diamine ligands such as our sparteine surrogate7) will be studied; with 3-substituted piperidines, regio- and diastereoselectivity will explored. The compatibility of the reactions with the different substituents will be determined, and a wide range of aryl halides will utilised to demonstrate the full potential of the new methodology. Optimisation of the different steps of the reactions will be carried out using our well-established in situ IR spectroscopic technique. In all cases, we will investigate -arylation and -arylation via protocols reported by Knochel5 and Baudoin.6 The methods will then be extended to other heterocycles, including 3- and 4-substituted tetrahydropyrans.
All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research. The iDTC themes are broad, interdisciplinary, and fit within the Department’s research expertise. Themes are flexible and adapt in line with the evolving research landscape. Each theme has a leader who oversees the training offered. Students may select courses from other themes where appropriate.
Training in synthetic organic chemistry will be provided to ensure a strong overall knowledge of organic chemistry as well as the synthesis of small molecules and the associated practical techniques that all synthetic chemists need to master, i.e. anhydrous techniques, chromatographic purification, compound characterisation. Group meetings will allow regular opportunities to develop skills in presenting and discussing scientific ideas. The training will develop the student’s skills in synthetic, organometallic and medicinal chemistry. Students will benefit from being a part of the organic group (invited speakers and student presentations).
The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel. Chemistry at York was the first academic department in the UK to receive the Athena SWAN Gold award, first attained in 2007 and then renewed in October 2010 and in April 2015. This project is available to study full-time or part-time (50%).
References
1 Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.
2 (a) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. W.; MacMillan, D. W. C. Science 2016, 352, 1304. (b) Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Nature Chemistry 2017, 9, 140.
3 (a) Campbell, P. S.; Jamieson, C.; Simpson, I.; Watson, A. J. B. Chem. Commun. 2018, 54, 46. (b) Hesp, K. D.; Fernando, D. P.; Jiao, W.; Londgren, A. T.; Org. Lett. 2014, 16, 413.
4 Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C.-y. J. Am. Chem. Soc. 2006, 128, 3538.
5 Seel, S; Thaler, T.; Takatsu, K.; Zhang, C.; Zipse, H.; Straub,B. F.; Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2011, 133, 4774.
6 Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Chem. Sci. 2013, 4, 2241.
7 Stead, D.; Carbone, G.; O’Brien, P.; Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260.
8 Barker, G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.; O’Brien, P. J. Org. Chem. 2011, 76, 5936
9 Sheikh, N. S.; Leonori, D.; Barker, G.; Firth, J. D.; Campos, K. R.; Meijer, A. J. H. M.; O’Brien, P.; Coldham, I. J. Am. Chem. Soc. 2012, 133, 5300.
10 Firth, J. D.; Ferris, L.; O’Brien, P. J. Am. Chem. Soc. 2016, 137, 651.
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