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Multi-carbon labelling of active pharmaceutical ingredients enabled by a three-gas surrogate hydroformylation

Nature Synthesis volume 2, pages 243–250 (2023)Cite this article

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Abstract

Drug metabolism and pharmacokinetic studies play a crucial role in drug discovery and development programmes, assessing a lead drug candidate’s efficacy and safety profile. Quantitative bioanalytical assessment of analytes with mass spectrometry requires the use of stable carbon-13-labelled compounds with a molecular mass difference of ≥3 daltons. The incorporation of three or more carbon isotopes into drug candidates is not trivial, often requiring lengthy and costly syntheses. Here we report a dual catalytic strategy for the synthesis of multi-carbon-labelled isotopologues of active pharmaceutical ingredients. This approach uses isotopically labelled gas surrogates in a three-chamber reactor for sequential release of alkenes, carbon monoxide and hydrogen followed by low-pressure hydroformylation to generate multi-labelled alkyl aldehydes. The method’s utility has been demonstrated through the synthesis of multiple labelled N-alkyl bioactive compounds, site-selective carbon-13 and deuterium introduction and for triple-carbon labelling of small molecules combined with α-functionalization.

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Fig. 1: Multi-carbon labelling via three-gas surrogate hydroformylation.
Fig. 2: Development of the three-gas surrogate hydroformylation.
Fig. 3: Scope of the multi-carbon labelling strategy.
Fig. 4: Further utilization of the multi-carbon labelling strategy.
Fig. 5: Adaptation of the hydroformylation approach for deuterium labelling with D2O.

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The data in support and related to this study are available within the paper and the Supplementary Information.

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Acknowledgements

We thank the following funding agencies for supporting this research: The Danish National Research Foundation (grant no. DNRF118), NordForsk (grant no. 85378), European Union’s Horizon 2020 research and innovation programme under grant agreement 862179 and Marie Skłodowska-Curie grant agreement 859910. Furthermore, we thank K. Baldvinsson for his generous donation of Citanest. This publication reflects the views only of the authors, and the European Commission cannot be held responsible for any use which may be made of the information contained therein.

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Authors and Affiliations

  1. Carbon Dioxide Activation Center (CADIAC), Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Aarhus, Denmark

    Hans Christian D. Hammershøj, Haraldur G. Gudmundsson, Samuel Kjærsgaard, Jonas Bønnelykke, Julia Kolodiazhnaia & Troels Skrydstrup

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Contributions

H.G.G. and T.S. devised the original idea. H.C.D.H., S.K., H.G.G. and T.S. conceptualized the strategy. H.C.D.H., S.K., H.G.G. and T.S. designed the experiments. H.C.D.H., S.K., H.G.G., J.B. and J.K. performed the experiments. H.G.G. and T.S. wrote the manuscript.

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Correspondence to Haraldur G. Gudmundsson or Troels Skrydstrup.

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Competing interests

T.S. is co-owner of SyTracks A/S, which commercializes silacarboxylic acid 2. All remaining authors have no competing interests.

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Supplementary Information

Supplementary Figs. 1–5, general experimental details and procedures, Discussion, Tables 1 and 2, NMR spectra and references.

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Hammershøj, H.C.D., Gudmundsson, H.G., Kjærsgaard, S. et al. Multi-carbon labelling of active pharmaceutical ingredients enabled by a three-gas surrogate hydroformylation. Nat. Synth 2, 243–250 (2023). https://doi.org/10.1038/s44160-022-00223-0

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