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Biomimetic tail-to-head terpene cyclizations using the resorcin[4]arene capsule catalyst

Nature Protocols volume 19, pages 313–339 (2024)Cite this article

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Abstract

The tail-to-head terpene (THT) cyclization is a biochemical process that gives rise to many terpene natural product skeletons encountered in nature. Historically, it has been difficult to achieve THT synthetically without using an enzyme. In this protocol, a hexameric resorcin[4]arene capsule acts as an artificial enzyme mimic to carry out biomimetic THT cyclizations and related carbocationic rearrangements. The precursor molecule bears a leaving group (usually an alcohol or acetate group) and undergoes the THT reaction in the presence of the capsule catalyst and HCl as a cocatalyst. Careful control of several parameters (including water content, amount of HCl cocatalyst, temperature and solvent) is crucial to successfully carrying out the reaction. To facilitate the application of this unique capsule-catalysis methodology, we therefore developed a very detailed procedure that includes the preparation and analysis of all reaction components. In this protocol, we describe how to prepare two different terpenes: isolongifolene and presilphiperfolan-1β-ol. The two procedures differ in the water content required for efficient product formation, and thus exemplify the two common use cases of this methodology. The influence of other crucial reaction parameters and means of precisely controlling them are described. A commercially available substrate, nerol, can be used as simple test substrate to validate the reaction setup. Each synthetic procedure requires 5–7 d, including 1–5 h of hands-on time. The protocol applies to the synthesis of many complex terpene natural products that would otherwise be difficult to access in synthetically useful yields.

Key points

  • The tail-to-head terpene cyclization converts simple precursors into a wide variety of terpene structures. The enzymes used in nature are precursor specific, making it difficult to access modified terpenes.

  • A hexameric resorcin[4]arene capsule can catalyze tail-to-head terpene cyclizations for a wide variety of precursors if reaction conditions (e.g., water content and catalytic HCl concentration) are carefully optimized and controlled.

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Fig. 1: THT cyclizations.
Fig. 2: Nerol cyclization.
Fig. 3: Reaction progress for isolongifolene synthesis.
Fig. 4: Chromatogram of isolongifolene synthesis.
Fig. 5: Chromatogram of isolongifolene oxidation to isolongifolenone.
Fig. 6: Chromatograms of presilphiperfolan-1β-ol synthesis.
Fig. 7: Reaction progress for presilphiperfolan-1β-ol synthesis.

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Data availability

Relevant data for this protocol can be found in the text and Supplementary Information of this paper and/or its supporting primary research papers. Raw data for the figures have been deposited at https://zenodo.org/records/10052551.

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Acknowledgements

This publication was created as part of National Centre of Competence in Research (NCCR) Catalysis, funded by the Swiss National Science Foundation. L.-D.S. thanks the University of Basel for a Novartis Universität Basel Excellence Scholarship for Life Sciences.

Author information

Author notes

  1. These authors contributed equally: Ivan Cornu, Leonidas-Dimitrios Syntrivanis.

Authors and Affiliations

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

    Ivan Cornu, Leonidas-Dimitrios Syntrivanis & Konrad Tiefenbacher

  2. Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland

    Konrad Tiefenbacher

Authors
  1. Ivan Cornu
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  2. Leonidas-Dimitrios Syntrivanis
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  3. Konrad Tiefenbacher
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Contributions

I.C. optimized Protocol 2 and wrote a first version of this part. L.-D.S. optimized Protocol 3 and wrote a first version of this part and the introduction. K.T. supervised the project and helped write the protocols.

Corresponding author

Correspondence to Konrad Tiefenbacher.

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Competing interests

The authors declare no competing interests.

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Peer review information

Nature Protocols thanks Carmine Gaeta and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Key references using this protocol

Zhang, Q. & Tiefenbacher, K. Nat. Chem. 7, 197–202 (2015): https://doi.org/10.1038/nchem.2181

Zhang, Q. et al. Nat. Catal. 1, 609–615 (2018): https://doi.org/10.1038/s41929-018-0115-4

Syntrivanis, L.-D. et al. J. Am. Chem. Soc. 142, 5894–5900 (2020): https://doi.org/10.1021/jacs.0c01464

Key data used in this protocol

Zhang, Q. et al. Nat. Catal. 1, 609–615 (2018): https://doi.org/10.1038/s41929-018-0115-4

Syntrivanis, L.-D. et al. J. Am. Chem. Soc. 142, 5894–5900 (2020): https://doi.org/10.1021/jacs.0c01464

Extended data

Extended Data Fig. 1 HCl stock solution preparation.

Setup for the preparation of the HCl stock solution in chloroform or benzene.

Extended Data Fig. 2 HCl stock solution titration.

HCl solution titration coloration (a) before endpoint and (b) at the endpoint.

Extended Data Fig. 3 Resorcin[4]arene synthesis.

Resorcin[4]arene synthesis photos (see Procedure for corresponding letters).

Extended Data Fig. 4 Photo of the resorcin[4]arene stock solution prepared in Steps 9–17 of Procedure 2.

Resorcin[4]arene stock solution.

Extended Data Fig. 5 Dissolution of resorcin[4]arene in water-saturated chloroform.

Resorcin[4]arene catalyst in water-saturated chloroform (Procedure 3, Step 5), before (a) and after (b) complete dissolution.

Extended Data Fig. 6 Reaction setup.

Reaction setup (a) screening scale, (b) preparative scale synthesis of isolongifolene (Procedure 2) and (c) preparative scale synthesis of presilphipefolan-1β-ol (Procedure 3).

Supplementary information

Supplementary Information

Supplementary Figs. 1–10 and derivation of the equations.

Reporting Summary

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Cornu, I., Syntrivanis, LD. & Tiefenbacher, K. Biomimetic tail-to-head terpene cyclizations using the resorcin[4]arene capsule catalyst. Nat Protoc 19, 313–339 (2024). https://doi.org/10.1038/s41596-023-00919-3

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