Thesis
New approaches in iridium catalysis for sp3 hydrogen isotope exchange of amino acid and peptides
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T16836
- Person Identifier (Local)
- 201981234
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Hydrogen isotope exchange (HIE) reactions are exceptionally valuable to the pharmaceutical industry. The ability to incorporate deuterium or tritium atoms within drug candidate molecules at the late stages of synthesis has revolutionised the drug discovery process. Specifically, the Kerr group has carried out extensive studies using iridium-based complexes, which have emerged as some of the most active systems in the area to facilitate directed labelling processes. In a response to the pharmaceutical industry’s recent focus on drug candidates with increased sp3 character, the Kerr research team have been driven to explore hydrogen isotope exchange reactions of amino acids and peptide-based structures. The chemistry detailed within this PhD Thesis builds on the team’s experiments with ɑ-amino acids, and delivers a corresponding robust and efficient method for the HIE of β-amino acids. β-Amino acids have increased resistance to proteolytic cleavage and improved pharmacokinetic profiles therefore, a mild approach for the deuteration of β-amino acid motifs could aid the successful development of novel peptide therapeutics. Through extensive screening of various iridium(I) pre-catalysts and conditions, excellent deuterium incorporations have been achieved across a range of protected β-amino acids under mild conditions (Scheme 1). By exploiting common amino acid protecting groups, selective labelling was attained via a proposed 5-membered metallocyclic intermediate, achieving up to 99% incorporation even at challenging centres. Additionally, a selection of cyclic amino acid residues were also labelled including the antifungal antibiotic cis-pentacin. Furthermore, the labelling process is stereoretentive, as confirmed by chiral HPLC studies. [graphic element - Scheme 1: Iridium-catalysed HIE of β-amino acids.] Additionally, preliminary studies demonstrated impressive incorporations in β-amino acid containing dipeptides including the labelling of challenging methine sites (Scheme 2). Further investigations confirmed that larger tri- and tetra- peptides were successfully deuterated following additional optimisation. Moreover, computational density functional theory (DFT) studies were carried out alongside experimental investigations to rationalise our findings throughout. [graphic element - Scheme 2: Iridium-catalysed HIE of small peptides.]
- Advisor / supervisor
- Kerr, William J
- Resource Type
- DOI
- Date Created
- 2023
- Embargo Note
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File | 2024-03-08 | Embargo |