New Approaches in Iridium Catalysis for Appreciably Expanded Isotope Labelling Processes

To date, detailed studies within Strathclyde laboratories have led to the discovery and establishment of a family of novel iridium catalysts, possessing N-heterocyclic carbene (NHC) units alongside bulky phosphine ligands, which are capable of delivering heavy isotopes of hydrogen (deuterium and tritium) to aromoatic molecules via an ortho-directed C-H insertion process. Indeed, when employed with a broad selection of substrates including ketones, amides, esters, and N-heterocycles, these catalysts have emerged to become some of the most active species in this area of labelling chemistry on a global scale.
Following on from this, a research programme was initiated in October 2016, in collaboration with Merck (USA), with the goal of applying our developed iridium catalysts in the much rarer, and more challenging, sp3 labelling of amino acids and, in turn, peptides. As part of this research partnership, initial investigations focused on a range of NHC/phosphine catalysts in the labelling of glycine derivatives, with a board variety of N- and C-terminus protecting groups, and have provided the foundations for the research detailed as part of this programme of work.
As part of this programme the collaboration with Merck (USA) will be further extended to develop even more broadly effective methods for the labelling of amino acids and peptides. Specifically, and based on the significant understanding established through our ongoing studies, the project objectives will be to:
- Further develop the hydrogen-isotope exchange of sp3 hybridised C-H bonds in amino acids through novel catalyst design, underpinned by computational studies;
- Extend the methodology to the labelling of more complex amino acids and peptides; and
- Explore the labelling of amino acids and peptides on solid phase.
The research described in this programme of work will drive the development of an appreciable range of new stable and highly active catalysts for application within a series of novel C-H activation and deuterium/tritium isotope exchange processes of C-H sp3 bonds. Capitalising on emerging techniques from our laboratories, a series of tuned iridium-based catalyst systems will emerge to deliver access to a variety of labelled amino acids and peptides via both solution and solid phase techniques. Indeed, regarding the latter, the labelling of peptides on solid phase is an attractive proposition: it simplifies solubility issues, and allows separation of catalyst and any labelled waste from the product, when post-cleavage purification would deliver a pure labelled peptide.