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E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing

Nature Chemistry volume 14, pages 640–649 (2022)Cite this article

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Abstract

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

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Fig. 1: Unresolved problems and challenges in MRCM.
Fig. 2: Challenges associated with designing a stereoretentive MRCM that affords a trisubstituted alkene.
Fig. 3: Unexpected complications and mechanism-guided solutions.
Fig. 4: Reversing substrate-controlled selectivity and late-stage stereoretentive MRCM in total synthesis of dolabelide C.

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Data availability

All data in support of the findings of this study are available within the Article and its Supplementary Information.

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Acknowledgements

Financial support was provided by the National Institutes of Health (GM-130395). F.W.W.H. was supported as a Deutsche Forschungsgemeinschaft postdoctoral fellow. K.E.L. was supported by a Complex Systems Chemistry (CSC) graduate fellowship funded by the French National Research Agency (CSC-IGS ANR-17-EURE-0016). We thank T. Koengeter, C. Qin and S. Xu for helpful discussions and suggestions.

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Authors and Affiliations

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

    Yucheng Mu, Felix W. W. Hartrampf, Elsie C. Yu, Filippo Romiti & Amir H. Hoveyda

  2. Supramolecular Science and Engineering Institute, University of Strasbourg and CNRS, Strasbourg, France

    Katherine E. Lounsbury, Filippo Romiti & Amir H. Hoveyda

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

    Richard R. Schrock

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Contributions

Y.M., F.W.W.H., F.R. and E.C.Y. developed the method and performed the dolabelide C total synthesis. Y.M., F.R. and K.E.L. carried out the total synthesis of the E-alkene isomer related to fluvirucin B1. The molybdenum complexes used in this study were designed and developed as part of an ongoing collaboration between the research groups of A.H.H. and R.R.S. The approach was conceived by A.H.H. and F.R. The investigations were directed by A.H.H. and A.H.H. composed the manuscript with the other authors suggesting revisions.

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Correspondence to Filippo Romiti or Amir H. Hoveyda.

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Nature Chemistry thanks N. Lemcoff, Damian Young and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

The file contains an extended bibliography regarding preparation of trisubstituted macrocyclic natural products. It also contains the experimental procedures for preparation of organometallic complexes, substrates, reagents and products and all the corresponding analytical/characterization data (tabulated and reproductions of 1H and 13C NMR spectra).

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Mu, Y., Hartrampf, F.W.W., Yu, E.C. et al. E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing. Nat. Chem. 14, 640–649 (2022). https://doi.org/10.1038/s41557-022-00935-y

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