Abstract
The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs to probe these features typically requires toxic, radioactive gases such as [14C]CO and [14C]CO2. Here we describe an approach to directly carbon-label carboxylic-acid-containing pharmaceuticals via a metal-catalysed functional group exchange reaction, forming 14C-labelled carboxylic-acid-containing drugs without radioactive gases, in one pot, using an easily available and handled carboxylic acid 14C source. To enable this process, a functional group metathesis of carbon–carbon covalent bonds in acid chloride functionalities is developed, exploiting the ability of nickel catalysts to both reversibly activate carbon–chloride bonds and exchange functionalities between organic molecules. The drug development applicability is illustrated by the direct incorporation of the 14C label or 13C label into an array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or a special apparatus, at ambient conditions and without loss of the radiolabel.
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Data availability
Detailed experimental procedures and characterization of all compounds can be found in the Supplementary Information, and original NMR and gas chromatography data can be found on figshare (https://doi.org/10.6084/m9.figshare.19929908). Crystallographic data for L1Ni(CO)3 has been deposited at the Cambridge Crystallographic Data Centre (CCDC) as 2157554 and can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/getstructures.
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Acknowledgements
We thank Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, for financial support. We thank the National Science and Engineering Research Council of Canada (NSERC) and the Fonds de Recherche du Québec – Nature et Technologie (FRQNT) supported Centre for Green Chemistry and Catalysis (CGCC) for funding this research. J.Z. thanks FRQNT (318000 – B2X) for providing funding for doctoral studies. P.-L.L.-T. thanks NSERC (PGSD2 – 534186 – 2019) and FRQNT (272570 – B2X) for providing funding for doctoral studies. C.Z. thanks FRQNT (336031– B2X) for providing funding for doctoral studies. We thank N. Saadé and A. Wahba for assistance with HRMS analysis, R. Stein for assistance with NMR analysis and H. Titi for assistance with X-ray diffraction characterization.
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B.A.A. and D.R.G. conceived and directed the project. R.G.K. helped conceive the idea and conducted the early development, which was fully developed by the research of J.Z., P.-L.L.-T. and C.Z. and the carbon-14 labelling done by H.Y. and J.L. All authors were involved in preparing the manuscript.
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Nature Chemistry thanks Dieter Muri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Information
Supplementary Figs. 1–5, Tables 1–5, considerations, discussion, protocols, methods, data and additional experiments.
Supplementary Data 1
Crystallographic data for L1Ni(CO)3; CCDC reference 2157554.
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Kinney, R.G., Zgheib, J., Lagueux-Tremblay, PL. et al. A metal-catalysed functional group metathesis approach to the carbon isotope labelling of carboxylic acids. Nat. Chem. 16, 556–563 (2024). https://doi.org/10.1038/s41557-024-01447-7
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DOI: https://doi.org/10.1038/s41557-024-01447-7
