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Total synthesis of nine longiborneol sesquiterpenoids using a functionalized camphor strategy

Nature Chemistry volume 14, pages 450–456 (2022)Cite this article

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Abstract

Natural product total synthesis inspires the development of synthesis strategies to access important classes of molecules. In the 1960s, Corey and coworkers demonstrated a visionary preparation of the terpenoid longifolene, using ‘strategic bond analysis’ to craft a synthesis route. This approach proposes that efficient synthesis routes to bridged, polycyclic structures should be formulated to introduce the bulk of the target’s topological complexity at a late stage. Subsequently, similar strategies have proved general for the syntheses of a wide variety of bridged, polycyclic molecules. Here, we demonstrate that an orthogonal strategy where topological complexity is introduced at the outset leads to the short synthesis of the longifolene-related terpenoid longiborneol. To implement this strategy, we access a bicyclo[2.2.1] starting material through scaffold remodelling of readily available (S)-carvone. We also employ a variety of late-stage C–H functionalization tactics in divergent syntheses of many longiborneol congeners. Our strategy may prove effective for the preparation of other topologically complex natural products that contain the bicyclo[2.2.1] framework.

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Fig. 1: Retrosynthetic approaches to longifolene and longiborneol.
Fig. 2: Structurally similar natural products and retrosynthesis of longiborneol.
Fig. 3: Total synthesis of longiborneol.
Fig. 4: Syntheses of oxygenated longiborneol congeners.
Fig. 5: Camphor derivatives accessible by scaffold remodelling of (S)-carvone.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2060682 (11) and 2060683 (10). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The experimental procedures and characterization of all compounds are provided in the Supplementary Information.

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Acknowledgements

We are grateful to the National Institutes of Health (NIGMS MIRA R35 GM130345) for grant support as well as the Molecular Scaffold Design Collective (agreement no. HR00111890024) of the Defense Advanced Research Projects Agency for partial support of this work. R.F.L. is grateful for fellowship support from the National Science Foundation Graduate Research Fellowships Program (DGE 1752814). G.S. thanks the Uehara Memorial Foundation for a postdoctoral fellowship. We thank H. Celik and University of California, Berkeley’s NMR facility in the College of Chemistry (CoC-NMR) for spectroscopic assistance. Instruments in the CoC-NMR are supported in part by National Institutes of Health S10OD024998. We thank N. Settineri (University of California, Berkeley) for single-crystal X-ray diffraction studies.

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Author notes

  1. These authors contributed equally: Robert F. Lusi, Goh Sennari.

Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, CA, USA

    Robert F. Lusi, Goh Sennari & Richmond Sarpong

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Contributions

The overall design for this project was conceptualized by G.S. with input from R.F.L. and R.S.; R.F.L. and G.S. conducted the chemical reactions. G.S. and R.F.L. developed the synthesis of 15 and 3, and G.S. optimized the route. Syntheses of 5 and 10–14 were achieved by R.F.L., who also designed the C–H functionalization sequences with input from G.S. and R.S. Rearrangement of 3 to 1 as well as preparation of 38 and 41 were discovered by G.S. The manuscript was written and edited jointly by R.F.L., G.S. and R.S.

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Correspondence to Goh Sennari or Richmond Sarpong.

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Nature Chemistry thanks Kiyosei Takasu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–8, Tables 1–8, experimental procedures, NMR data and crystallographic data.

Supplementary Data 1

Crystallographic data for compound 10; CCDC reference 2060683.

Supplementary Data 2

Crystallographic data for compound 11; CCDC reference 2060682.

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Lusi, R.F., Sennari, G. & Sarpong, R. Total synthesis of nine longiborneol sesquiterpenoids using a functionalized camphor strategy. Nat. Chem. 14, 450–456 (2022). https://doi.org/10.1038/s41557-021-00870-4

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