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Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization

Nature Chemistry volume 4, pages 915–920 (2012)Cite this article

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Abstract

Non-stop carbocationic polycyclizations of isoprenoids have been called the most complex chemical reactions occurring in nature. We describe a strategy for the initiation of tail-to-head polycyclization that relies on the sequestration of the counteranion away from the carbocation, which allows full propagation of the cationic charge. If the anion is mobile, Coulombic forces hold this species in close proximity to the carbocation and cause preemptive termination through elimination. Anion sequestration is crucial for effecting the biomimetic synthesis of complex and unstable terpenes, including the highly strained funebrenes. This study illustrates the deleterious role of the counterion in tail-to-head carbocationic polycyclization reactions, which to the best of our knowledge has not been rigorously explored. These observations are also expected to find use in the design and control of cationic polycyclization along biosynthetic pathways that have previously been inaccessible in bulk solvent.

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Figure 1: Different branches of terpene biosynthesis.
Figure 2: Mechanistic comparisons of bulk solvent and cyclase active sites.
Figure 3: Analysis of polycyclization outcomes.
Figure 4: Proposed reaction pathway.
Figure 5: Effect of a mobile anion.
Figure 6: Biomimetic total syntheses.

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Acknowledgements

The authors thank R. Mohan of Exelixis for the very generous donation of supplies and chemicals, and C. Moore and A. Rheingold for crystal X-ray diffraction data. The authors also thank J. Sears for technical assistance. Financial support was provided by the Scripps Research Institute (Novartis ADI Grant) and Eli Lilly.

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  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA

    Sergey V. Pronin & Ryan A. Shenvi

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  1. Sergey V. Pronin
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S.V.P. and R.A.S. contributed equally to the work.

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Correspondence to Ryan A. Shenvi.

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The authors declare no competing financial interests.

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Crystallographic data for the cocrystal of compounds 12 and 13 (CIF 19 kb)

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Pronin, S., Shenvi, R. Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization. Nature Chem 4, 915–920 (2012). https://doi.org/10.1038/nchem.1458

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