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Sesquiterpene cyclizations catalysed inside the resorcinarene capsule and application in the short synthesis of isolongifolene and isolongifolenone

Nature Catalysis volume 1, pages 609–615 (2018)Cite this article

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Abstract

Terpenes constitute the largest class of natural products and serve as an important source for medicinal treatments. Despite constant progress in chemical synthesis, the construction of complex polycyclic sesqui- and diterpene scaffolds remains challenging. However, natural cyclase enzymes are able to form the whole variety of terpene structures from just a handful of linear precursors. Man-made catalysts able to mimic such natural enzymes are lacking. Here, we describe examples of sesquiterpene cyclizations inside an enzyme-mimicking supramolecular catalyst. This strategy allowed the formation of the tricyclic sesquiterpene isolongifolene in only four steps. The mechanism of the catalysed cyclization reaction was elucidated using 13C-labelling studies and density functional theory calculations.

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Fig. 1: Comparison of the total synthesis and biosynthesis6 of isolongifolene3,4 and longifolene5.
Fig. 2: Selective cyclization of the monoterpene geranyl acetate catalysed by the resorcinarene capsule.
Fig. 3: Product analysis of the capsule-catalysed cyclization reactions of farnesyl substrates.
Fig. 4: Product analysis of the capsule-catalysed cyclization reactions of cyclofarnesyl substrates.
Fig. 5: Computed energy profile for the formation of protonated isolongifolene 19.
Fig. 6: Short synthesis of isolongifolene and isolongifolenone.

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Acknowledgements

This work was supported by funding from the European Research Council Horizon 2020 Programme (ERC Starting Grant 714620-TERPENECAT), Swiss National Science Foundation (as part of the NCCR Molecular Systems Engineering) and Bayerische Akademie der Wissenschaften (Junges Kolleg). We thank the computing center of the University of Cologne (RRZK) for providing CPU time on the DFG-funded supercomputer CHEOPS.

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Authors and Affiliations

  1. Department of Chemistry, University of Basel, Basel, Switzerland

    Qi Zhang & Konrad Tiefenbacher

  2. Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Bonn, Germany

    Jan Rinkel & Jeroen S. Dickschat

  3. Institut für Organische Chemie, Universität zu Köln, Cologne, Germany

    Bernd Goldfuss

  4. Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland

    Konrad Tiefenbacher

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  1. Qi Zhang
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Contributions

K.T. conceived and supervised the project. K.T. and Q.Z. planned the project. Q.Z. carried out all the experiments except the synthesis of 13C-labelled substrates, which were synthesized by J.R. J.S.D. conceived the investigations concerning the 13C-labelled substrates. The 13C-labelled products were analysed by J.S.D. and J.R., who elucidated the proposed mechanism for the formation of isolongifolene. B.G. performed the DFT calculations. Q.Z. and K.T. compiled the first draft of the manuscript. All authors contributed to the final version of the manuscript.

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Correspondence to Konrad Tiefenbacher.

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Supplementary Information

Supplementary Methods, Supplementary Discussion, Supplementary Figures 1–31, Supplementary Tables 1–10, Supplementary References

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Cartesian Coordinates of the optimized intermediates and transition states

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Zhang, Q., Rinkel, J., Goldfuss, B. et al. Sesquiterpene cyclizations catalysed inside the resorcinarene capsule and application in the short synthesis of isolongifolene and isolongifolenone. Nat Catal 1, 609–615 (2018). https://doi.org/10.1038/s41929-018-0115-4

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