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Organic synthesis provides opportunities to transform drug discovery

Abstract

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C–H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C–X or C–C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

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Fig. 1: Molecule–value relationship in drug discovery and organic synthesis.
Fig. 2: Drug molecules typically feature a number of groups — often clustered — that present significant synthetic challenges.
Fig. 3: Syntheses involving nitrogen-containing compounds and late-stage functionalizations.
Fig. 4: Hypothetical transformations that would overcome some of the synthetic challenges outlined.
Fig. 5: Metal-catalysed C–C bond-forming reactions.
Fig. 6: In situ use of potentially unstable intermediates.
Fig. 7: Syntheses compatible with biomacromolecules are increasingly important.

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Acknowledgements

We thank D. Dixon (University of Oxford) and S. Marsden (University of Leeds) for commenting on the manuscript. We also thank T. McGuire and F. Goldberg (AstraZeneca), C. Johnson (Astex) and N. Fadeyi (Pfizer) for help in preparing the manuscript, and A. Davey for assistance with the graphical abstract.

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Blakemore, D.C., Castro, L., Churcher, I. et al. Organic synthesis provides opportunities to transform drug discovery. Nature Chem 10, 383–394 (2018). https://doi.org/10.1038/s41557-018-0021-z

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