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Aldehyde-catalysed carboxylate exchange in α-amino acids with isotopically labelled CO2

Nature Chemistry volume 14, pages 1367–1374 (2022)Cite this article

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Abstract

The isotopic labelling of small molecules is integral to drug development and for understanding biochemical processes. The preparation of carbon-labelled α-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labelled products and presents a major challenge in 11C applications (11C t1/2 = 20 min). Here we report that aldehydes catalyse the isotopic carboxylate exchange of native α-amino acids with *CO2 (* = 14, 13, 11). Proteinogenic α-amino acids and many non-natural variants containing diverse functional groups undergo labelling. The reaction probably proceeds via the trapping of *CO2 by imine-carboxylate intermediates to generate iminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage 11C-radiolabelling of α-amino acids in the presence of [11C]CO2.

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Fig. 1: Isotopic labelling of α-amino acids.
Fig. 2: Optimization experiments.
Fig. 3: Aldehyde-catalysed carboxylate exchange of α-amino acids with [11C]CO2.
Fig. 4: Mechanistic studies probing the nature of isotopic carboxylate exchange.
Fig. 5: Simplified potential mechanism of the aldehyde-catalysed isotopic carboxylate exchange of α-amino acids.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

Support was provided by NSERC Canada (RGPIN-2019-06050 and RGPAS-2019-00051 to R.J.L., RGPIN-2017-06167 to B.H.R., CGS-D fellowship to M.G.J.D., PGS-D fellowship to B.A.M., PGS-D fellowship to C.J.C.C.), the Canadian Foundation for Innovation (IOF 32691 to R.J.L., JELF 36848 to B.H.R.), the Province of Alberta (AGES fellowship to O.B., AGES fellowship to M.G.J.D., AGES fellowship to C.J.C.C.), the Province of Ontario (ER17-13-119 to B.H.R.), and the University of Ottawa Heart Institute (Endowed Fellowship to M.M.). We thank Marcelo Muñoz for HPLC recommendations as well as Béla Reiz and Angelina Morales-Izquierdo for assistance with mass spectrometry studies.

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Author notes

  1. These authors contributed equally: Odey Bsharat, Michael G. J. Doyle.

Authors and Affiliations

  1. Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada

    Odey Bsharat, Michael G. J. Doyle, Christopher J. C. Cooze, Duanyang Kong & Rylan J. Lundgren

  2. Department of Biochemistry, Microbiology and Immunology and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada

    Maxime Munch, Braeden A. Mair & Benjamin H. Rotstein

  3. University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    Maxime Munch, Braeden A. Mair & Benjamin H. Rotstein

  4. Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery, Isotope Chemistry, Industriepark Höchst, Frankfurt, Germany

    Volker Derdau & Armin Bauer

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Contributions

O.B., M.G.J.D. and C.J.C.C. designed and performed experiments and analysed data related to studies involving 13C. D.K. conducted the selected 13C scope studies. M.M. and B.A.M. designed and performed experiments and analysed data related to studies involving 11C. A.B. and V.D. designed and performed experiments and analysed data related to studies involving 14C. R.J.L. and B.H.R. directed the research, R.J.L. conceived the project and prepared the manuscript, all authors contributed to discussion.

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Correspondence to Benjamin H. Rotstein or Rylan J. Lundgren.

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V.D. and A.B. are employees of Sanofi and may hold shares or options of the company. The remaining authors declare no competing interests.

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Nature Chemistry thanks Chad Elmore, Da-Gang Yu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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General considerations, procedures, additional scope and mechanistic information, compound characterization and data.

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Bsharat, O., Doyle, M.G.J., Munch, M. et al. Aldehyde-catalysed carboxylate exchange in α-amino acids with isotopically labelled CO2. Nat. Chem. 14, 1367–1374 (2022). https://doi.org/10.1038/s41557-022-01074-0

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