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  • Review Article
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Late-stage C–H functionalization offers new opportunities in drug discovery

Nature Reviews Chemistry volume 5, pages 522–545 (2021)Cite this article

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Abstract

Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest.

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Fig. 1: Opportunities for modern chemistry to enable late-stage C–H functionalization strategies in drug discovery.
Fig. 2: Directed late-stage C–H functionalization of drug-like molecules.
Fig. 3: Late-stage C–H functionalization of drugs controlled by steric and electronic effects.
Fig. 4: Late-stage C–H functionalization of drugs exploiting innate reactivity.
Fig. 5: Late-stage C–H functionalization of pharmaceuticals involving radical chemistry.
Fig. 6: Late-stage C–H functionalization of drug-like compounds and natural products involving emerging reaction manifolds.
Fig. 7: Late-stage C–H diversification in the new modalities sphere.
Fig. 8: Limitations and perspectives of late-stage C–H functionalization strategies.

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Acknowledgements

The authors thank M. A. Hayes and A. Tomberg for helpful discussions, as well as R. Sheppard and D. Antermite for valuable advice on the preparation of this manuscript. L.G. and M.J.J. acknowledge AstraZeneca and the AstraZeneca Postdoc Programme for their financial support. N.K. and L.A. are grateful to the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation), the Onassis Foundation (fellowship to N.K.) and acknowledge the Georg-August-Universität Göttingen.

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Authors and Affiliations

  1. Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Lucas Guillemard & Magnus J. Johansson

  2. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany

    Nikolaos Kaplaneris & Lutz Ackermann

  3. German Centre for Cardiovascular Research (DZHK), Berlin, Germany

    Lutz Ackermann

  4. Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

    Magnus J. Johansson

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  1. Lucas Guillemard
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  2. Nikolaos Kaplaneris
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  3. Lutz Ackermann
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  4. Magnus J. Johansson
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All authors contributed equally to the preparation of this manuscript.

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Correspondence to Lutz Ackermann or Magnus J. Johansson.

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Nature Reviews Chemistry thanks C. Kelly and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Guillemard, L., Kaplaneris, N., Ackermann, L. et al. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat Rev Chem 5, 522–545 (2021). https://doi.org/10.1038/s41570-021-00300-6

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