Highly Efficient Iridium(I) NHC/Phosphine Complexes for Hydrogen Isotope Exchange
One of the biggest challenges facing the pharmaceutical industry is the high attrition rate of drug candidates at the pre-clinical trial stage. In order to address this issue, early metabolism studies are crucial in assessing the properties of a drug candidate. An important method in this area is labelling by hydrogen isotope exchange, which allows the biological fate of a potential drug molecule to be carefully monitored. In recent years, iridium complexes have garnered considerable attention within the field of transition metal-catalysed hydrogen-isotope exchange.[i] The key to their applicability in this area lies in the ability of such complexes to selectively target unactivated C-H bonds, whilst simultaneously allowing convenient isotope incorporation with the use of practically convenient deuterium or tritium gas.
Indeed, a series of detailed studies within our laboratories has revealed a family of novel iridium complexes, possessing N-heterocyclic carbene (NHC) units alongside bulky phosphine ligands, to be stable yet active catalysts capable of incorporating deuterium to particularly high levels across a range of substrates at desirably low catalyst loadings.[ii] First of all and importantly in a practical sense, a robust and readily utilisable route to these extremely stable complexes has been evolved. Furthermore, this has allowed expedient access to a range of novel iridium complexes of this type, many of which were, seemingly, inaccessible by previously employed pathways. Moreover, when employed with a broad selection of substrates, these catalysts have emerged to become some of the most active complexes in this area of labelling chemistry.
The three most effective iridium complexes from our first generation of catalysts are now commercialised by Strem Chemicals and are available now.
These catalysts are capable of efficiently mediating a range of labelling processes, with as low as 0.5 mol% loading in many cases.
Labelling of aromatic systems is directed by a broad range of functional groups, including ketones, amides (via both 5- and 6-membered metallacyclic intermediates, termed 5-mmi and 6-mmi), esters, nitroarenes, and an array of N-heterocycles, all with high levels of D-incorporation under mild conditions.2,[iii] Furthermore, we have recently extended this work to include the labelling of non-aromatic unsaturated systems.[iv]
These catalysts also excel in the labelling of complex, polyfunctional systems, such as those found in pharmaceuticals. For example, the deuterium labelling of the drug nilutamide[v] has been reported to proceed under mild reaction conditions in only one hour.
[i]. For selected reviews in ortho-directed deuterium- and tritium labeling, see: (a) G. N. Nilsson and W. J. Kerr, J. Labelled Compd. Radiopharm. 2010, 53, 662; (b) R. Salter, J. Labelled Compd. Radiopharm. 2010, 53, 645; (c) J. Atzrodt, V. Derdau, T. Fey and J. Zimmermann, Angew. Chem. Int. Ed. 2007, 46, 7744; (d) J. R. Heys, J. Labelled Compd. Radiopharm. 2007, 50, 770.
[ii]. (a) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson and G. N. Nilsson, Chem. Commun., 2008, 1115; (b) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson and G. Nilsson, J. Labelled Compd. Radiopharm., 2008, 51, 257; (c) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson and G. Nilsson, J. Labelled Compd. Radiopharm., 2009, 52, 210; (d) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson and G. Nilsson, J. Labelled Compd. Radiopharm., 2009, 52, 259; (e) W. J. Kerr, S. Irvine, J. A. Brown, S. Andersson and G. N. Nilsson, Abstracts of Papers of the American Chemical Society, 2007, 234, 79-ORGN.
[iii]. (a) J. A. Brown, A. R. Cochrane, S. Irvine, W. J. Kerr, B. Mondal, J. A. Parkinson, L. C. Paterson, M. Reid, T. Tuttle, S. Andersson and G. N. Nilsson, Adv. Synth. Catal., 2014, 356, 3551; (b) J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, P. Rojahn and R. Weck, Tetrahedron, 2015, 71, 1924; (c) J. Devlin, W. J. Kerr, D. M. Lindsay, T. J. D. McCabe, M. Reid and T. Tuttle, Molecules, 2015, 20, 11676; (d) A. R. Cochrane, C. Idziak, W. J. Kerr, B. Mondal, L. C. Paterson, T. Tuttle, S. Andersson and G. N. Nilsson, Org. Biomol. Chem., 2014, 12, 3598; (e) A. R. Kennedy, W. J. Kerr, R. Moir and M. Reid, Org. Biomol. Chem., 2014, 12, 7927; (f) A. R. Cochrane, S. Irvine, W. J. Kerr, M. Reid, S. Andersson and G. N. Nilsson, J. Labelled Compd. Radiopharm., 2013, 56, 451.