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Synthesis of saturated nitrogen heterocycles and alkaloids by using organolithiums or dipolar cycloaddition chemistry


Department of Chemistry

About the Project

Our research group focuses on the synthesis of nitrogen-containing heterocyclic compounds, especially with chiral organometallic compounds and dipolar cycloaddition reactions. The chemistry can be used for the synthesis of biologically active alkaloids and molecules of interest to the pharmaceutical industry.

One area of research in our group is centred on the formation of chiral organometallic compounds.[1,2] We have found that deprotonation occurs readily in the 1-position of N-Boc-tetrahydroisoquinolines (Boc = CO2tBu) and we can trap the resulting organolithium with electrophiles. For example, the organolithium derived from the 1-phenyl derivative does not racemise readily (t1/2 73 min at –10 °C) and provides a way to prepare the NMDA antagonist FR115427 with high enantioselectivity. The metallation is dependent on coordination of n-BuLi to the Boc group and therefore on the rate of rotation of the Boc group. We can follow the reaction by using in situ ReactIR spectroscopy and have determined the kinetics for rotation of the Boc group by variable temperature NMR spectroscopy. Recent work has focused on the highly enantioselective kinetic resolution of racemic substrates, such as N-Boc-2-phenyltetrahydroquinoline. This project will study proton abstraction of a new heterocycle followed by electrophilic quench. By using kinetic resolution, we will achieve the asymmetric synthesis of drug-like structures.

Funding Notes

This is a self-funded project. The applicant should have or expect to gain at least an upper second class degree, or equivalent overseas qualification, in a relevant subject.

If you have the correct qualifications and access to your own funding, either from your home country or your own finances, your application to work with this supervisor will be considered.

References

1. N. Carter, X. Li, L. Reavey, A. J. H. M. Meijer, I. Coldham, Chem. Sci. 2018, 9, 1352.
2. X. Li, I. Coldham, J. Am. Chem. Soc. 2014, 136, 5551.

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