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Brønsted Acid Catalysed Asymmetric Synthesis of Cyclic Ethers

  • Full or part time
    Dr P Clarke
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Over recent years there has been a drive by medicinal chemists to explore more 3-dimensional areas of chemical space. Cyclic ethers, such as the tetrahydropyran (THP) and the tetrahydrofuran (THF) rings, are the most common and 6th most common saturated heterocyclic function present in marketed pharmaceuticals. They are also present in a significant number of biologically active natural products. Hence, there has been considerable attention devoted to the development of new strategies to enable their synthesis with greater efficiency, , especially as single enantiomers. Over the last 15 years our group has played a major role in the development of some of these strategies, especially for the synthesis of THPs present in natural products (phorboxazole B, centrolobine, diospongin B, lasonolide A ). However, until this year we had not attempted to develop a general strategy which could be applied to both THPs and THFs with differing substitution patterns and stereochemical arrangements. We have recently developed a Brønsted acid and a fluoride catalysed oxy-Michael cyclisation onto -unstaturated thioesters to generate either the cis- or the trans-THP product selectively (Scheme 1). Preliminary investigations into the scope of the Brønsted acid-catalysed cyclisation has shown that when a chiral Brønsted acid is used, THP 2 can be formed in 13% e.e. and THF 4 can be formed in 42% e.e. (Scheme 2).

The project will have 4 goals:
(i) The optimisation of our preliminary asymmetric results to enable to enantioselective synthesis of THFs and THPs;
(ii) Extending the methodology to the kinetic resolution of racemic substrates to deliver single enantiomers of both ether and starting material;
(iii) The asymmetric desymmeterisation of achiral and meso-substrates.
(iv) Application of this methodology to the synthesis of cyclic ether containing natural products.

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.

The Clarke group trains all members in contemporary synthetic organic chemistry techniques, including the spectroscopic identification of compounds. The student on this project will also be trained in the theory and use of automated synthesis using the Chemspeed apparatus within the department. The student will attend weekly group meetings focusing on the development of literature awareness, presentation of results, problem solving and mechanistic skills. Guidance will also be given on project management and project specific scientific issues. As part of the Organic Chemistry section the student will be exposed to a wide range of visiting speakers through a vibrant external seminar program. The student will also be encouraged to present their work as a poster and as oral presentations at least two different national or international meetings.

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.



Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to those from countries outside the UK. Wild Fund Scholarships offer up to full tuition fees for those from countries from outside the European Union. EU students may also be offered £6,000 per year towards living costs. For further information see: View Website

References

1 a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752. b) F. Lovering, Med. Chem. Commun. 2013, 4, 515.
2 M. Aldeghi, S. Malhotra, D. L. Selwood and A. W. E. Chan, Chem. Bio. Drug. Des. 2014, 83, 450.
3 N. M. Nasir, K. Ermanis and P. A. Clarke, Org. Biomol. Chem. 2014, 12, 3323.
4 A. Lorente, J. Lamariano-Merketegi, F. Albericio and M. Álvarez, Chem. Rev. 2013, 113, 4567.
5 For review see: a) F. Vetica, P. Chauhan, S. Dochain and D. Enders, Chem. Soc. Rev. 2017, 46, 1661. For recent advances see: b) N. Cox, M. R. Uehling, K. T. Haelsig and G. Lalic, Angew. Chem. Int. Ed. 2013, 52, 4878. c) G. C. Tsui, L. Liu and B. List, Angew. Chem. Int. Ed. 2015, 54, 7703. d) M. Iqbal, N. Mistry and P. A. Clarke, Tetrahedron, 2011, 67, 4960. e) G. Hu, F. Wu, R. Zhou, L. Ouyand and B. Han, Adv. Synth. Catal. 2014, 356, 2311.
6 a) P. A. Clarke and K. Ermanis, Org. Lett. 2012, 14, 5550. b) P. A. Clarke, S. Santos, N. Mistry, L. Burroughs and A. C. Humphries, Org. Lett. 2011, 13, 624.
7 P. A. Clarke and W. H. C. Martin, Tetrahedron, 2005, 61, 5433.
8 P. A. Clarke, N. M. Nasir, P. B. Sellars, A. M. Peter, C. A. Lawson and J. L. Burroughs, Org. Biomol. Chem. 2016, 14, 6840.
9 P. A. Clarke, P. B. Sellars and N. M. Nasir, Org. Biomol. Chem. 2015, 13, 4743.
10 K. Ermanis, U. Kaya, A. Jeuken, Y.-T. Hsiao and P. A. Clarke, Chem. Sci. 2017, 8, 482.

Related Subjects

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

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