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The synthesis of diverse terpene architectures from phenols

Nature Synthesis volume 1, pages 313–321 (2022)Cite this article

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Abstract

Nature has evolved exquisite synthetic pathways for terpenes by combining isoprenes into chains, folding them into carbocycles and then oxidizing and/or rearranging them into a vast range of complex molecules (>50,000 examples). Although laboratory syntheses can sometimes emulate elements of this process, additional approaches that can similarly emulate nature’s approach and lead to molecular diversity are desirable. Here we show that the synthesis of polycyclic terpene molecules can be achieved through a predictable and reliable process that starts from phenols. The synthetic route comprises three steps: prenylation, dearomatization and/or prenyl migration, and, finally, epoxidation and/or radical cyclization. Critically, the third step uses a cooperative bimetallic catalyst to mediate the cyclization of epoxy enones under hydrogenative conditions. Overall, this approach leads to the stereocontrolled formation of bicyclic-, linear-, angular-, clovane- and propellane-based terpene structures with functional groups that allow further manipulation. For example, these motifs can be repurposed for ring contractions to access additional terpene-based architectures. Of note, several natural products were prepared through a formal total synthesis using this approach; these routes are as concise as, and often shorter than, previously reported syntheses.

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Fig. 1: Development of a cohesive and unified strategy for terpene synthesis.
Fig. 2: Redox neutral and reductive dearomatizations.
Fig. 3: Scope of the epoxidation and radical cyclization cascade.
Fig. 4: Exploration of cooperative catalysis to achieve the radical cyclization.
Fig. 5: Application of the radical cyclization sequence for natural product synthesis.
Fig. 6: Further application of the radical cyclization sequence for natural product synthesis.

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Data availability

Full experimental procedures, compound characterization and spectral data for all the new materials can all be found in the Supplementary Information. Crystallographic data for the 14 structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2117563 (60), 2117564 (74), 2117565 (62), 2117566 (57), 2117567 (13), 2117568 (14), 2117569 (51), 2117570 (Supplementary54), 2117571 (38), 2117572 (66), 2117573 (11), 2117574 (84), 2117575 (12) and 2117576 (Supplementary55). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank A. Filatov, K. Jesse and S. Whitmeyer (University of Chicago) for X-ray analyses of our crystalline intermediates, and J. Kurutz and C. Jin Qin for assistance with the NMR spectroscopy and mass spectrometry, respectively (University of Chicago). This work was supported by funds from the University of Chicago and the NIH (R01-124295A).

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Farbod Salahi & Scott A. Snyder

  2. Department of Chemistry, Columbia University, New York, NY, USA

    Chengbo Yao & Jack R. Norton

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Contributions

S.A.S. and F.S. conceived the project, and S.A.S. and J.R.N. directed the research. F.S. designed, carried out and analysed all experiments described in the main article, except for those studies on the catalytic approach to the epoxy-enone cyclizations (which were performed by C.Y.). S.A.S. and F.S. composed the manuscript and the Supplementary Information; all the authors commented on the manuscript and the Supplementary Information.

Corresponding author

Correspondence to Scott A. Snyder.

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The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Peter Seavill was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary information

Supplementary Information

Supplementary Sections A–T, experimental details, Schemes 1–3, and Tables 1 and 2.

Supplementary Data 1

Crystallographic data of compound 11, CCDC 2117573.

Supplementary Data 2

Crystallographic data of compound 12, CCDC 2117575.

Supplementary Data 3

Crystallographic data of compound 13, CCDC 2117567.

Supplementary Data 4

Crystallographic data of compound 14, CCDC 2117568.

Supplementary Data 5

Crystallographic data of compound 38, CCDC 2117571.

Supplementary Data 6

Crystallographic data of compound 51, CCDC 2117569.

Supplementary Data 7

Crystallographic data of compound 57, CCDC 2117566.

Supplementary Data 8

Crystallographic data of compound 60, CCDC 2117563.

Supplementary Data 9

Crystallographic data of compound 62, CCDC 2117565.

Supplementary Data 10

Crystallographic data of compound 66, CCDC 2117572.

Supplementary Data 11

Crystallographic data of compound 74, CCDC 2117564.

Supplementary Data 12

Crystallographic data of compound 84, CCDC 2117574.

Supplementary Data 13

Crystallographic data of compound S54, CCDC 2117570

Supplementary Data 14

Crystallographic data of compound S55, CCDC 2117576.

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Salahi, F., Yao, C., Norton, J.R. et al. The synthesis of diverse terpene architectures from phenols. Nat. Synth 1, 313–321 (2022). https://doi.org/10.1038/s44160-022-00051-2

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