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Nineteen-step total synthesis of (+)-phorbol

Nature volume 532, pages 90–93 (2016)Cite this article

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Abstract

Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters1. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes2, germacrenes3, taxanes4,5 and ingenanes6,7,8 have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C–C bond constructions and C–H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.

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Figure 1: A two-phase approach to ingenanes and tiglianes enables a concise approach to the phorbol structure.
Figure 2: 19-step total synthesis of 1.
Figure 3: Predicting the site of C–H functionalization on intermediate 7.

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Acknowledgements

This work was supported by LEO Pharma, the Uehara Memorial Foundation (postdoctoral fellowship to S.K.) and the National Institute of General Medical Sciences Grant GM-097444. We are especially grateful to S. Natarajan of KemXtree and his team for providing ample quantities of compound 5. We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy, and A. L. Rheingold and C. E. Moore for X-ray crystallographic analysis.

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Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, 92037, California, USA

    Shuhei Kawamura, Hang Chu & Phil S. Baran

  2. Front End Innovation, LEO Pharma A/S Industriparken 55, Ballerup, 2750, Denmark

    Jakob Felding

Authors
  1. Shuhei Kawamura
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  2. Hang Chu
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  4. Phil S. Baran
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Contributions

S.K. and P.S.B. conceived this work; J.F. provided compound 5; S.K., H.C. and P.S.B. designed the experiments and analysed that data; S.K. and H.C. conducted the experiments; S.K. performed the molecular mechanics calculations; and S.K. and P.S.B. wrote the manuscript.

Corresponding author

Correspondence to Phil S. Baran.

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The authors declare no competing financial interests.

Additional information

Metrical parameters for the structures of 12 and 19 are available free of charge from the Cambridge Crystallographic Data Centre (CCDC) under reference numbers 1434376 and 1434377.

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Kawamura, S., Chu, H., Felding, J. et al. Nineteen-step total synthesis of (+)-phorbol. Nature 532, 90–93 (2016). https://doi.org/10.1038/nature17153

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