Using a computationally guided rational ligand design approach, a novel chelated NHC-P iridium(I) catalyst system has been identified for the directed hydrogen isotope exchange (HIE) of aryl sulfones. The catalyst design process was aided primarily through DFT binding energy calculations. The solvent scope of the reaction was studied, and the optimised conditions applied to the successful deuterium labelling of a broad range of 20 aryl sulfones. The catalyst system was also shown to be highly active in the HIE of aryl sulfones at sub-atmospheric pressures of deuterium. Additionally, the catalyst system was applied in the tritiation of aryl sulfones, affording tritiated samples of methylphenyl sulfone, as well as a GPR119 agonist, in high levels of specific activity.This chelated catalyst system was then further refined for the labelling of highly substituted sulfonamides. A more focussed approach to the catalyst design process was taken at this stage, with a combination of binding energy calculations and binding mode analysis being used to guide the modification of the ligand. This resulted in a novel, chelated NHC-Py system, which proved to be highly active in the HIE of a broad range of highly substituted sulfonamides. A total of 22 sulfonamide substrates were synthesised, and labelled using this novel catalyst system. Additionally, this complex was shown to be highly effective in the deuteration of sulfoximines, for which the means of labelling are severely under met.Finally, our studies in the labelling of aryl sulfones led us to the serendipitous discovery of ether-directed HIE. This process was investigated with our novel NHC-P catalyst system, and a substrate scope established. Additionally, a potential application in form of labelling natural products, and natural product-like molecules has been proposed, with a series of three natural product-like molecules having been synthesised for attempts towards labelling.
|Date of Award||15 Mar 2019|
- University Of Strathclyde
|Sponsors||EPSRC (Engineering and Physical Sciences Research Council)|
|Supervisor||William Kerr (Supervisor) & Nick Tomkinson (Supervisor)|