Thesis
New iridium-catalysed methods for the hydrogen isotope exchange of pharmaceutically-relevant compounds
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16604
- Person Identifier (Local)
- 201850734
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- A carbonyl-directed C(sp3)−H hydrogen isotope exchange (HIE) methodology has been disclosed within this thesis using [Ir(COD)(IMesMe)(PBn3)]BArF (5 mol%) in MTBE at 50 °C. Over 25 N-benzyl lactams have been labelled with up to 94% benzylic deuterium incorporation, while being tolerant of different ring sizes (5-7) and aryl substitution. Select N-benzyl lactams have also demonstrated aryl deuteration, allowing the incorporation of up to 4 deuterium atoms from a single directing group. Incorporation of deuterium into the aryl group of N-benzyl lactams can be minimised by limiting the reaction time to 1-4 h. Non-benzylic N-substituted lactams have also been subjected to this sp3-labelling procedure with excellent results. Indeed, 20 non-benzylic lactams have demonstrated up to 98% deuterium incorporation covering a variety of lactam ring sizes and substituent chain lengths while tolerating functionality such as alcohols, esters, and sulfonamides. These substrates included bioactive molecules such as Nefiracetam, Unifiram, and Praziquantel. An expansion of the sp3-HIE substrate scope was realised using cyclic urea and carbamate directing groups, with moderate C(sp3)−H deuterium incorporation observed with N-benzyl carbamate substrates (47-67%). Lastly, open chain amides furnished exceptional levels of C(sp3)−H deuteration, even in highly sterically demanding environments. Density functional theory has been used to investigate the difference in reactivity between lactams and carbamates of different ring sizes. One longstanding challenge with the HIE field is the ability to conduct homogenous HIE in the presence of strongly coordinating functionality, especially nitrile groups. Two nitrile tolerant HIE procedures are reported here, furnishing excellent levels of deuterium incorporation under mild reaction conditions via benzylamines, ketones, anilines, or N-heterocyclic directing groups. Importantly, both a para- and meta-relationship is tolerated between the directing group and the nitrile. Preliminary investigations have been conducted on tertiary amine-directed HIE, with initial results indicating that the commercially available catalyst [Ir(COD)(IMes)(PPh3)]BArF readily facilitates the HIE of benzylamines.
- Advisor / supervisor
- Kerr, William
- Resource Type
- DOI
- Embargo Note
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File | 2023-06-16 | 限制运用 |