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Selective and synergistic cobalt(iii)-catalysed three-component C–H bond addition to dienes and aldehydes

Nature Catalysis volume 1, pages 673–679 (2018)Cite this article

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Abstract

Two-component C–H bond additions to a large variety of coupling partners have been developed with applications towards materials, natural product and drug synthesis. Sequential three-component C–H bond addition across two different coupling partners potentially enables the convergent synthesis of complex molecular scaffolds from simple precursors. Here, we report three-component Co(iii)-catalysed C–H bond additions to dienes and aldehydes that proceed with high regio- and stereoselectivity, resulting in two new carbon–carbon σ-bonds and four to six new stereocentres. The reaction relies on the synergistic reactivity of the diene and aldehyde, with neither undergoing C–H bond addition alone. A detailed mechanism is supported by X-ray structural characterization of a Co(iii)-allyl intermediate, observed transfer of stereochemical information, and kinetic isotope studies. The applicability of the method to biologically relevant molecules is exemplified by the rapid synthesis of the western fragment of the complex ionophore antibiotic lasalocid A.

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Fig. 1: Three-component strategy for the rapid assembly of complex structures.
Fig. 2: C–H functionalization with benzamide 1a, butadiene 2a and diverse aldehydes 3.
Fig. 3: C–H functionalization with dienes and aldehydes.
Fig. 4: Mechanistic experiments.
Fig. 5: Proposed mechanism for the three-component transformation.
Fig. 6: Synthesis of the core scaffold in lasalocid A.

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Acknowledgements

This work was supported by the NIH (R35GM122473).

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Author notes

  1. These authors contributed equally to this work: Jeffrey A. Boerth, Soham Maity.

Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, CT, USA

    Jeffrey A. Boerth, Soham Maity, Sarah K. Williams, Brandon Q. Mercado & Jonathan A. Ellman

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Contributions

J.A.B. co-conceived the concept and developed the reaction conditions. J.A.B. also completed the scope with respect to C–H bond substrates, including the lasalocid A derivative, conducted the mechanistic experiments and co-prepared the manuscript. S.M. helped with the development of the reaction conditions and completed the scope with respect to both aldehyde and diene coupling partners. S.M. also helped with the preparation of the manuscript. S.K.W. helped with the completion of the scope with respect to C–H bond substrates. B.Q.M. solved the X-ray crystal structures of compounds 4b, 4ar′ and 8a. J.A.E. co-conceived the concept and co-prepared the manuscript with feedback from J.A.B. and S.M.

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Correspondence to Jonathan A. Ellman.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Figures 1–5, Supplementary Tables 1 & 2, Supplementary References

Supplementary Information

Crystallographic data for compound 4b, CCDC reference 1812525

Supplementary Information

Crystallographic data for compound 4ar’, CCDC reference 1826301

Supplementary Information

Crystallographic data for compound 8a, CCDC reference 1812526

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Boerth, J.A., Maity, S., Williams, S.K. et al. Selective and synergistic cobalt(iii)-catalysed three-component C–H bond addition to dienes and aldehydes. Nat Catal 1, 673–679 (2018). https://doi.org/10.1038/s41929-018-0123-4

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