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E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis

Nature Chemistry volume 11, pages 478–487 (2019)Cite this article

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Abstract

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologically active compounds.

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Fig. 1: Biologically active compounds with an alkenyl nitrile or a related moiety.
Fig. 2: Challenges in designing reactions that deliver stereodefined alkenyl nitriles.
Fig. 3: A broadly applicable approach to Z-di-substituted alkenyl nitriles.
Fig. 4: E-di-substituted alkenyl nitriles.
Fig. 5: E- and Z-tri-substituted alkenyl nitriles.
Fig. 6: Utility of the method in chemical synthesis.

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Data availability

X-ray crystallographic data for compound 9a, are freely available from the Cambridge Crystallographic Data Centre (CCDC 1861573). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data in support of the findings of this study are available within the Article and its Supplementary Information or from the corresponding author upon reasonable request.

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Acknowledgements

This research was supported by a grant from the National Institutes of Health (GM-59426). T.T.N. was supported as a John LaMattina Graduate Fellow in Chemical Synthesis. The authors thank S. Torker for helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA

    Yucheng Mu, Thach T. Nguyen, Ming Joo Koh & Amir H. Hoveyda

  2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Richard R. Schrock

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Contributions

Y.M., T.T.N. and M.J.K. identified the optimal catalyst and conditions, developed the method and performed the experiments to demonstrate utility. The Mo complexes used in this study were designed and developed as part of a long-standing collaboration between the research groups of R.R.S. and A.H.H. A.H.H. directed the investigations and composed the manuscript with revisions provided by the other authors.

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Correspondence to Amir H. Hoveyda.

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Supplementary Information

All experimental and analytical data for the compounds used and generated in the study.

Crystallographic data

CIF for compound 9a; CCDC reference: 1861573

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Mu, Y., Nguyen, T.T., Koh, M.J. et al. E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis. Nat. Chem. 11, 478–487 (2019). https://doi.org/10.1038/s41557-019-0233-x

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