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Temporary or removable directing groups enable activation of unstrained C–C bonds

Nature Reviews Chemistry volume 4, pages 600–614 (2020)Cite this article

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Abstract

Carbon–carbon (C–C) bonds make up the skeletons of most organic molecules. The selective manipulation of C–C bonds offers a direct approach to editing molecular scaffolds but remains challenging. The kinetic inertness of C–C bonds can be overcome with transition-metal catalysis, which, nevertheless, relies on a substrate being highly strained or bearing a permanent directing group (DG). The driving force for C–C activation in these cases is strain relief and the formation of a stable metallocycle, respectively. Over the past two decades, a strategy has emerged that uses temporary or removable DGs to effect C–C activation of more common and less strained compounds. A variety of C–C bonds in less strained organic molecules are converted into more reactive transition-metal–carbon (M–C) bonds, enabling downstream transformations as part of diverse synthetic methods. This Review highlights catalytic approaches using temporary or removable DGs to help activate unstrained C–C bonds. The content is organized according to the temporary or removable nature of the DGs and includes applications in the synthesis of natural products or bioactive molecules.

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Fig. 1: General strategies in C–C bond activation.
Fig. 2: Alkyl exchange by activating unstrained C–C bonds and performing olefin extrusion–insertion.
Fig. 3: Merging intramolecular arylation with activation of an unstrained C–C(O) bond.
Fig. 4: Merging C–C bond activation of ketones with Suzuki–Miyaura cross-coupling.
Fig. 5: ‘Cut-and-sew’ reactions by activating unstrained C–C bonds.
Fig. 6: Unstrained C–C bond activation enabled by 2-amino-3-picoline.
Fig. 7: Caryl–Caryl bond activation using phosphinites as removable directing groups.
Fig. 8: Activation of unstrained C–C bonds enabled by removable heterocyclic directing groups.
Fig. 9: Aromatization-promoted C–C bond activation leads to deacylative transformations of unstrained ketones.
Fig. 10: Palladium-mediated activation of unstrained Calkyl–Calkyl bonds.

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Acknowledgements

The authors thank NIGMS (2R01GM109054) for the generous support of their C–C activation projects. Y.X. acknowledges start-up funding from Sichuan University.

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  1. West China School of Public Health and West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China

    Ying Xia

  2. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Guangbin Dong

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Xia, Y., Dong, G. Temporary or removable directing groups enable activation of unstrained C–C bonds. Nat Rev Chem 4, 600–614 (2020). https://doi.org/10.1038/s41570-020-0218-8

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