The persistence of high attrition rates within drug discovery has driven a need for early metabolism studies to enable assessment of the properties of drug candidates. In this area, isotopic labelling via hydrogen isotope exchange (HIE) has played a central role. Previous work within our laboratory has resulted in the development of a range of novel iridium(I)-based catalysts 1, combining sterically encumbered N- heterocyclic carbene and phosphine ligands, to facilitate HIE directed by a broad range of functional groups. While isotopically labelled aromatics are accessed effectively in metabolism studies, the emergence of peptidic drugs brings a requirement for isotopically labelled peptides and amino acids. However, this area remains relatively unstudied. Thus, we have initiated studies aimed at deuteration of such moieties. Amino acids, bearing common protecting groups, are labelled with high incorporation. Additionally, retention of stereochemistry is achieved. Extension of our methodology has enabled the labelling of tripeptides such as 2. Chemo-selective deuteration at the glycine residue through judicious choice of conditions offers the opportunity to selectively target specific residues within larger peptide molecules. Additionally, small deuterated dipeptides 3 containing tertiary residues have been accessed in a chemo-selective manner.

Iridium-catalysed hydrogen isotope exchange of amino acid and peptide molecules

2019 Fall National Meeting

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