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Total synthesis of eudesmane terpenes by site-selective C–H oxidations

Nature volume 459, pages 824–828 (2009)Cite this article

Abstract

From menthol to cholesterol to Taxol, terpenes are a ubiquitous group of molecules (over 55,000 members isolated so far) that have long provided humans with flavours, fragrances, hormones, medicines and even commercial products such as rubber1. Although they possess a seemingly endless variety of architectural complexities, the biosynthesis of terpenes often occurs in a unified fashion as a ‘two-phase’ process2,3. In the first phase (the cyclase phase), simple linear hydrocarbon phosphate building blocks are stitched together by means of ‘prenyl coupling’, followed by enzymatically controlled molecular cyclizations and rearrangements. In the second phase (the oxidase phase), oxidation of alkenes and carbon–hydrogen bonds results in a large array of structural diversity. Although organic chemists have made great progress in developing the logic3,4,5 needed for the cyclase phase of terpene synthesis, particularly in the area of polyene cyclizations6, much remains to be learned if the oxidase phase is to be mimicked in the laboratory. Here we show how the logic of terpene biosynthesis has inspired the highly efficient and stereocontrolled syntheses of five oxidized members of the eudesmane family of terpenes in a modicum of steps by a series of simple carbocycle-forming reactions followed by multiple site-selective inter- and intramolecular carbon–hydrogen oxidations. This work establishes an intellectual framework in which to conceive the laboratory synthesis of other complex terpenes using a ‘two-phase’ approach.

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Figure 1: Outline of the ‘two-phase’ approach to terpene total synthesis.
Figure 2: Simple, enantioselective total synthesis of dihydrojunenol (4).
Figure 3: Total syntheses of 4-epiajanol (5) and dihydroxyeudesmane (6) through site-specific C–H oxidations of dihydrojunenol (4).
Figure 4: Total syntheses of pygmol (7) and eudesmantetraol (8) through site-specific C–H oxidations of 16.
Figure 5: Pyramid diagram for the retrosynthetic planning of terpene synthesis using a ‘two-phase’ approach.

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Acknowledgements

We are grateful to A. Eschenmoser for discussions and to Bristol-Myers Squibb for financial support. M. Morón Galán and Y. Ishihara are acknowledged for technical contributions to the early stages of this project. We are grateful to B. Shi and A. Reingold for assistance with high-performance liquid chromatography and X-ray crystallographic analyses, respectively.

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Authors and Affiliations

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

    Ke Chen & Phil S. Baran

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  1. Ke Chen
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  2. Phil S. Baran
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Correspondence to Phil S. Baran.

Additional information

The X-ray crystallographic coordinates for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 718278 (5), CCDC 719000 (6), CCDC 718279 (15), CCDC 718280 (19), CCDC 718281 (21) and CCDC 718282 (22). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre (http://www.ccdc.cam.ac.uk/data_request/cif).

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This file contains a Supplementary Discussion, Supplementary Methods, Supplementary Figures S1-S5, Supplementary References and Supplementary Data. (PDF 4149 kb)

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Chen, K., Baran, P. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009). https://doi.org/10.1038/nature08043

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