New approaches in iridium catalysis for sp 3 hydrogen isotope exchange (HIE) of amino acids and peptides Megan Cuthbert 1 , Sumei Ren 2 , Neil Strotman 2 , David M. Lindsay 1 and William J. Kerr 1 * 1 University of Strathclyde, UK, 2 Department of Process Research & Development, Merck Research Laboratories (MRL),USA Hydrogen isotope exchange (HIE) has received considerable attention in recent years due to the requirement for isotopically labelled compounds for use in pharmaceutical ADMET assays and in the study of organic reaction mechanisms. 1 In particular, Lewis base-directed, iridium catalysed HIE is of particular importance in drug discovery, given the ability of this process for late-stage introduction of deuterium or tritium directly into drug candidates. Efficient, direct replacement of C-H bonds with deuterium and tritium in potential drug candidates are critical processes for the development of new drug candidates. The Kerr group has carried out extensive studies on iridium(I) pre-catalysts bearing bulky N-heterocyclic carbene (NHC) and phosphine ligands to facilitate directed labelling processes within aromatic systems (Scheme 1). 1,2 A range of directing groups (DG), such as amides, heterocycles, ketones and sulfonamides, could be successfully employed under mild conditions to selectively activate the ortho- position, yielding the desired labelled products in high isotopic incorporations. Although these highly effective catalysts have been developed for a range of sp 2 -hybridised systems, the directed HIE of sp 3 -hybridised C–H bonds still remains challenging. 2 With the pharmaceutical industry’s increased focus on drug candidates with increased sp 3 character, we sought to explore the HIE of biologically relevant amino acids and peptides.
Our group have recently demonstrated a successful labelling methodology for sp 3 -hybridised C–H bonds of α -amino acids, giving excellent isotopic incorporations. 3 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 (Scheme 2). By exploiting common amino acid protecting groups, selective labelling was attained via a proposed 5-membered metallocyclic intermediate, achievingup 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 (Scheme 3). High incorporationswere obtained for all examples even at tertiary centres within the peptides.Moreover, computational density functional theory (DFT) studies have been carried out alongside experimental investigations to rationalise our findings.
References 1. J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem., Int. Ed ., 2018, 57 , 1758–1784. 2. J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem., Int. Ed. , 2018, 57 , 3022–3047. 3. A. E. Queen, PhD Thesis , The University of Strathclyde, 2020.
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