Thesis
Novel methods to access tracelessly labelled molecules via iridium-catalysed hydrogen isotope exchange
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16492
- Person Identifier (Local)
- 201872965
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Compounds labelled with heavy isotopes of hydrogen have applications in many fields, including in the elucidation of organic reaction mechanisms, in ADMET studies, and, more recently, in deuterated marketed drugs. Metal-catalysed hydrogen isotope exchange (HIE) has risen to prominence in recent years and the Kerr group have developed a range of iridium complexes bearing sterically demanding phosphine and N-heterocyclic carbene ligands, which are highly effective at installing deuterium or tritium selectively at a position ortho to a directing group under mild conditions. A number of directing groups are tolerated within this process, including, for example, ketones, amides, an array of heterocycles, carbamates, and sulfones. To expand this methodology, in Chapter 2, a protocol has been developed for the synthesis of selectively and tracelessly labelled biaryls via a deprotection and in situ diazotisation/cross-coupling methodology. This method has been applied to the synthesis of a number of labelled biaryls (and their unlabelled analogues) with deuterium incorporation retained, including in the synthesis of labelled Flurbiprofen. In contrast to existing in situ diazotisation/cross-coupling methodologies, this method is operationally simple using commercially available catalysts, with no external ligands or additives required to facilitate the cross-coupling. Complementary to the in situ diazotisation/cross-coupling methodology, in Chapter 3, a protocol for the HIE of boronate esters will be discussed. Boronic acid derivatives have a wide synthetic utility, but their use in C–H activation protocols as the directing functionality is rare with no examples of simple boronates as directing groups. Using computational guidance a system for the HIE of boronate esters has been developed and applied to over 35 pinacol and neopentyl boronate esters. The applicability of this methodology has also been demonstrated through the synthesis of tracelessly labelled cross-coupled products including a labelled bromodomain inhibitor.
- Advisor / supervisor
- Measom, Nick
- Kerr, William
- Liwicki, Gemma
- Resource Type
- DOI
- Embargo Note
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