Hydrogen isotope exchange (HIE) has received considerable attention in recent years. Efficient, direct replacement of C-H bonds with deuterium and tritium in potential drug candidates are critical processes for the development of new drugs. The Kerr group has carried out extensive studies using iridium catalysts to facilitate directed labelling processes within aromatic systems (Figure 1, top). However, the directed HIE of sp3-hybridised C–H bonds still remains challenging. With the pharmaceutical industry’s increased focus on drug candidates with increased sp3 character, we sought to explore the HIE of biologically relevant amino acids and peptides. Our group have recently demonstrated a successful labelling methodology for sp3-hybridised C–H bonds of α-amino acids, giving excellent isotopic incorporations. We have since expanded this work to β-amino acids due to their increased resistance to proteolytic cleavage and improved pharmacokinetic profiles. This area remains underexplored and, therefore, a mild approach for the deuteration of β-amino acid motifs is highly desirable and could aid the successful development of novel peptide therapeutics. Through extensive screening of various iridium(I) pre-catalysts and conditions, we have achieved excellent deuterium incorporations across a range of protected β-amino acids under mild conditions (Figure 1, bottom). By exploiting common amino acid protecting groups, selective labelling was attained via a proposed 5-membered metallocyclic intermediate, achieving up to 97% incorporation even at challenging tertiary centres. Additionally, we also labelled a selection of cyclic amino acid residues including the antifungal antibiotic cispentacin. Furthermore, the labelling process is stereoretentive, as confirmed by chiral HPLC studies. Additionally, preliminary studies have demonstrated impressive incorporations in β-amino acid containing dipeptides (Figure 1, bottom). High incorporations were obtained for all peptide examples even at tertiary centres. Moreover, computational studies have been carried out alongside experimental investigations to rationalise our findings.

New approaches in iridium catalysis for sp3 hydrogen isotope exchange (HIE) of amino acids and peptides

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