Cobalt-catalysed C–H methylation for late-stage drug diversification

Abstract

The magic methyl effect is well acknowledged in medicinal chemistry, but despite its significance, accessing such analogues via derivatization at a late stage remains a pivotal challenge. In an effort to mitigate this major limitation, we here present a strategy for the cobalt-catalysed late-stage C–H methylation of structurally complex drug molecules. Enabling broad applicability, the transformation relies on a boron-based methyl source and takes advantage of inherently present functional groups to guide the C–H activation. The relative reactivity observed for distinct classes of functionalities were determined and the sensitivity of the transformation towards a panel of common functional motifs was tested under various reaction conditions. Without the need for prefunctionalization or postdeprotection, a diverse array of marketed drug molecules and natural products could be methylated in a predictable manner. Subsequent physicochemical and biological testing confirmed the magnitude with which this seemingly minor structural change can affect important drug properties.

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Fig. 1: Realizing a C–H activation–methylation protocol for LSF.
Fig. 2: Competition experiment that ranked different common functional groups as directing groups for the cobalt-catalysed C–H methylation with trimethylboroxine.
Fig. 3: Effect exerted by additives on the C–H methylation reaction under various conditions.
Fig. 4: Application of cobalt-mediated C–H methylation for LSF of biologically active substrates.
Fig. 5: Modulation of pharmaceutically relevant properties on C–H methylation.

Data availability

Data, which include experimental procedures, references that support Fig. 1b, physicochemical, DMPK and pharmacological activity data for selected compounds, de novo synthesis strategies and NMR spectra, are available in the Supplementary Information.

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Acknowledgements

The authors thank R. Sheppard and M. A. Hayes for valuable insight on biological testing, M. Härslätt and A. Ristinmaa for purification support, and M. A. Hayes and M. Lemurell for advice on the preparation of this manuscript. S.D.F. and M.J.J. acknowledge AstraZeneca and the AstraZeneca PostDoc program for their financial support. L.A. acknowledges the Georg-August-Universität Göttingen.

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S.D.F., M.J.J. and L.A. conceived the project and designed the experiments. M.J.J. and L.A. directed the project. S.D.F performed and analysed the experiments. S.D.F., M.J.J. and L.A. prepared the manuscript.

Corresponding authors

Correspondence to Magnus J. Johansson or Lutz Ackermann.

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Supplementary information

Supplementary Information

Experimental protocols and characterization for compounds mentioned in this work, references supporting Fig. 1b, overview of reaction optimization, description of competition experiments and compatibility screening, de novo synthesis strategies, PhysChem-, DMPK- and pharmacological activity data for selected compound and NMR spectra..

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Friis, S.D., Johansson, M.J. & Ackermann, L. Cobalt-catalysed C–H methylation for late-stage drug diversification. Nat. Chem. 12, 511–519 (2020). https://doi.org/10.1038/s41557-020-0475-7

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