Iridium-catalysed hydrogen isotope exchange of n-heterocycles and nucleosides

Student thesis: Doctoral Thesis

Abstract

The investigation of ADMET properties plays a crucial role in the development of any new chemical entity (NCE), with hydrogen isotope exchange heavily utilised for the late-stage labelling of target compounds. Iridium-catalysed methods, which have been extensively developed by Kerr and co-workers, have largely proceeded via directed metallacyclic intermediates with a wide range of directing groups well tolerated. This thesis describes the development of new iridium-catalysed methodologies specifically designed to label the ╬▒nitrogen position of pyridines and other heterocycles. The labelling of pyridines has been extensively optimised and explored, with methodologies developed to encompass pyridines with a variety of substitution patterns. High deuterium incorporations have been obtained across a wide range pyridine substrates and positions, with the methodologies expanded to include other N-heteroaromatics. In addition, a range of drug molecules have been subjected to both deuteration and tritiation, with a high degree of reactivity. An initial mechanistic investigation has additionally been carried out, utilising both experimental and computational studies to provide evidence towards a mechanistic proposal. Additionally, as part of a modernisation program to prior computational mechanistic studies, new insights into the nature of hydrogen fluxionality have been realised. Using a variety of computational methods, a new transition state for hydrogen fluxionality has been identified and new factors, including quantum tunnelling and relativistic effects, have been explored. In addition to the ongoing DFT studies, experimental investigations into kinetic isotope effect have revealednew considerations, such as the rate of gas exchange with reaction stirring speeds playing a particularly important role. Finally, an initial investigation has been conducted to examine hydrogen isotope exchange in nucleosides. This area of research is relatively underexplored; however, an extensive catalyst screen has permitted the development of a methodology which affords modest incorporationsacross a range of unprotected nucleosides. This provides an excellent starting platform for further development which shall continue in the future.
Date of Award15 Feb 2024
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorWilliam Kerr (Supervisor) & David Lindsay (Supervisor)

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