Article | Published:

Scalable enantioselective total synthesis of taxanes

Nature Chemistry volume 4, pages 2125 (2012) | Download Citation

Abstract

Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the ‘parent’ taxane—taxadiene—which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels–Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.

  • Compound C47H51NO14

    Taxol®

  • Compound C20H30O8

    2-Debenzoyl-4,10-bis(deacetyl)-baccatin III

  • Compound C20H32O7

    (1S,2S,3R,5S,7S,8S,9R,10R,13S)-1,2,5,7,9,10,13-Heptahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene

  • Compound C20H32O5

    (1R,2R,3R,5S,8R,9R,10R,13S)-2,5,9,10,13-Pentahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene

  • Compound C20H32O4

    (1R,2R,3S,5S,8S,10S,13S)-2,5,10,13-Tetrahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene

  • Compound C20H30O

    (+)-Taxa-4(5),11(12)-dien-2-one

  • Compound C20H32

    (+)-Taxa-4(5),11(12)-diene

  • Compound C6H12

    2,3-Dimethylbut-2-ene

  • Compound C8H12O2

    3-Ethoxycyclohex-2-enone

  • Compound C7H11Br

    3-Bromo-2,4-dimethylpenta-1,3-diene

  • Compound C8H10O

    3-Vinylcyclohex-2-enone

  • Compound C15H22O

    3-[4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohex-2-enone

  • Compound C32H34NO2P

    2,4,8,10-Tetramethyl-N,N-bis[(S)-1-phenylethyl]dibenzo[d,f][1,3,2]dioxaphosphepin-6-amine

  • Compound C19H34OSi

    (S)-Trimethyl{{3-methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohex-1-en-1-yl}oxy}silane

  • Compound C16H26O

    (S)-3-Methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone

  • Compound C19H28O2

    (2S,3S)-2-Acryloyl-3-methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone

  • Compound C19H28O2

    (1R,3S,8S)-8,12,15,15-Tetramethyl-tricyclo[9.3.1.03,8]pentadec-11-en-2,4-dione

  • Compound C21H30O2

    (2S,3S)-3-Methyl-2-[(R)-2,2,4-trimethyl-3-vinylcyclohex-3-enecarbonyl]-3-vinylcyclohexanone

  • Compound C19H30O2

    2,2,4-Trimethyl-3-{2-[(S)-1-methyl-3-oxocyclohexyl]ethyl}cyclohex-3-enecarbaldehyde

  • Compound C17H28O

    (2S)-2,6-Dimethyl-2-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone

  • Compound C19H26O

    1-{2-[4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]-6-methylenecyclohex-1-en-1-yl}prop-2-en-1-one

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The Chemistry of the Terpenes. (P. Blakiston's Son & Co., 1902).

  2. 2.

    Terpenes: Flavors, Fragrances, Pharmaca, Pheromones (Wiley-VCH, 2006).

  3. 3.

    & Modern synthetic efforts toward biologically active terpenes. Nature Chem. Biol. 3, 396–407 (2007).

  4. 4.

    , & Promotion of microtubule assembly in vitro by taxol. Nature 277, 665–667 (1979).

  5. 5.

    TAXOL®: Science and Applications (CRC Press, 1995).

  6. 6.

    & Taxus: The Genus Taxus (Taylor & Francis, 2003).

  7. 7.

    , , , & Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93, 2325–2327 (1971).

  8. 8.

    et al. Highly efficient, practical approach to natural taxol. J. Am. Chem. Soc. 110, 5917–5919 (1988).

  9. 9.

    Method for preparation of taxol. European patent EP0400971 (A2) (1990).

  10. 10.

    et al. New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of β-lactam synthon method. Tetrahedron 48, 6985–7012 (1992).

  11. 11.

    et al. Total synthesis of taxol. Nature 367, 630–634 (1994).

  12. 12.

    et al. First total synthesis of taxol. 1. Functionalization of the B ring. J. Am. Chem. Soc. 116, 1597–1598 (1994).

  13. 13.

    et al. First total synthesis of taxol. 2. Completion of the C and D rings. J. Am. Chem. Soc. 116, 1599–1600 (1994).

  14. 14.

    , , , & A total synthesis of taxol. Angew. Chem. Int. Ed. 34, 1723–1726 (1995).

  15. 15.

    et al. The pinene path to taxanes. 5. Stereocontrolled synthesis of a versatile taxane precursor. J. Am. Chem. Soc. 119, 2755–2756 (1997).

  16. 16.

    et al. The pinene path to taxanes. 6. A concise stereocontrolled synthesis of taxol. J. Am. Chem. Soc. 119, 2757–2758 (1997).

  17. 17.

    , , & Total asymmetric synthesis of taxol by dehydration condensation between 7-TES baccatin III and protected N-benzoylphenylisoserines prepared by enantioselective aldol reaction. Chem. Lett. 27, 3–4 (1998).

  18. 18.

    et al. Enantioselective total synthesis of taxol. J. Am. Chem. Soc. 120, 12980–12981 (1998).

  19. 19.

    A Total Synthesis of Taxol. PhD thesis, Harvard University (2000).

  20. 20.

    et al. A formal total synthesis of taxol aided by an automated synthesizer. Chem. Asian J. 1, 370–383 (2006).

  21. 21.

    & The Way of Synthesis: Evolution of Design and Methods for Natural Products 1st edn, 165 (Wiley-VCH, 2007).

  22. 22.

    et al. Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science 330, 70–74 (2010).

  23. 23.

    & Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009).

  24. 24.

    & Cyclization enzymes in the biosynthesis of monoterpenes, sesquiterpenes and diterpenes. Top. Curr. Chem. 209, 53–95 (2000).

  25. 25.

    et al. Taxanes from the seeds of Taxus baccata. J. Nat. Prod. 56, 514–520 (1993).

  26. 26.

    , , & Nuclear Overhauser effect, a unique method of defining the relative stereochemistry and conformation of taxane derivatives. J. Am. Chem. Soc. 90, 522–523 (1968).

  27. 27.

    Diterpenoids. Nat. Prod. Rep. 10, 159–174 (1993).

  28. 28.

    A brief survey of Taxus alkaloids and other taxane derivatives. J. Nat. Prod. 43, 425–437 (1980).

  29. 29.

    , & Taxol and derivatives: a biogenetic hypothesis. J. Nat. Prod. 50, 9–18 (1987).

  30. 30.

    & The taxane diterpenoids. J. Nat. Prod. 62, 1448–1472 (1999).

  31. 31.

    & Biological activity and chemistry of taxoids from the Japanese yew, Taxus cuspidata. J. Nat. Prod. 67, 245–256 (2004).

  32. 32.

    & New natural taxane diterpenoids from Taxus species since 1999. Chem. Biodiversity 2, 1597–1623 (2005).

  33. 33.

    & Two-phase terpene total synthesis: historical perspective and application to the Taxol® problem. Synlett 1733–1745 (2010).

  34. 34.

    et al. Cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene is the committed step of taxol biosynthesis in pacific yew. J. Biol. Chem. 270, 8686–8690 (1995).

  35. 35.

    & Synthesis of a C-1 epi taxinine intermediate using the type 2 intramolecular Diels–Alder approach. Tetrahedron Lett. 35, 1317–1320 (1994).

  36. 36.

    & Synthesis of the taxane ring system using an intramolecular Diels–Alder reaction of a 2-substituted diene. J. Chem. Soc. Perkin Trans. I 1303–1309 (1986).

  37. 37.

    & Studies on the biosynthesis of taxol: total synthesis of taxa-4(20),11(12)-diene and taxa-4(5),11(12)-diene. The first committed biosynthetic intermediate. J. Org. Chem. 60, 7215–7223 (1995).

  38. 38.

    Synthesis of antitumour agents. Pure Appl. Chem. 65, 1349–1356 (1993).

  39. 39.

    , & A highly efficient synthesis of taxanes via the tandem Diels–Alder reaction. Tetrahedron Lett. 36, 687–690 (1995).

  40. 40.

    et al. Part 1: Efficient strategies for the construction of variably substituted bicyclo[5.3.1]undecenones (AB taxane ring systems). Can. J. Chem. 82, 215–226 (2004).

  41. 41.

    et al. Taxane diterpenes 5: synthesis of the A- and C-rings: an unusual rearrangement of an N-hydroxyimino lactone. Tetrahedron 55, 6435–6452 (1999).

  42. 42.

    & Aiming for the ideal synthesis. J. Org. Chem. 75, 4657–4673 (2010).

  43. 43.

    & Copper-catalyzed asymmetric conjugate addition of trialkylaluminium reagents to trisubstituted enones: construction of chiral quaternary centers. Chem. Eur. J. 13, 9647–9662 (2007).

  44. 44.

    , & Enantioselective synthesis of all-carbon quaternary stereogenic centres by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring β-substituted cyclic enones. Angew. Chem. Int. Ed. 47, 7358–7362 (2008).

  45. 45.

    et al. Unexpected regiospecific reactivity of a substituted phthalic anhydride. Tetrahedron 63, 1395–1401 (2007).

  46. 46.

    , & New aldol type reaction. Chem. Lett. 2, 1011–1014 (1973).

  47. 47.

    , & Repeated use of the catalyst in Ln(OTf)3-catalyzed aldol and allylation reactions. Bull. Chem. Soc. Jpn 67, 2342–2344 (1994).

  48. 48.

    & Reduction of alkyl esters to alkanes by sodium in hexamethylphosphoric triamide. A new method for the deoxygenation of alcohols. J. Chem. Soc. Chem. Commun. 567–568 (1978).

  49. 49.

    , , & Asymmetric deprotonation of prochiral ketones using chiral lithium amide bases. Tetrahedron 46, 523–544 (1990).

  50. 50.

    & On the practical limits of determining isolated product yields and ratios of stereoisomers: reflections, analysis, and redemption. Synlett 2701–2707 (2010).

Download references

Acknowledgements

The authors dedicate this manuscript to K.C. Nicolaou on the occasion of his 65th birthday. The authors thank D-H. Huang and L. Pasternack for NMR spectroscopic assistance, A. Rheingold for X-ray crystallographic analysis and M. Wasa for chiral HPLC assistance. N. Wilde is thanked for valuable technical assistance. Special thanks go to G. Stephanopoulos for providing a bioengineered sample of taxadiene. Financial support for this work was provided by the National Institutes of Health/National Institute of General Medical Sciences (GM-097444), Ministerio de Educación y Ciencia-Fulbright programme (postdoctoral fellowship for A. M.), Natural Sciences and Engineering Research Council of Canada (doctoral fellowship for Y. I.) and Bristol-Myers Squibb (unrestricted research support).

Author information

Author notes

    • Abraham Mendoza
    •  & Yoshihiro Ishihara

    These authors contributed equally to this manuscript

Affiliations

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

    • Abraham Mendoza
    • , Yoshihiro Ishihara
    •  & Phil S. Baran

Authors

  1. Search for Abraham Mendoza in:

  2. Search for Yoshihiro Ishihara in:

  3. Search for Phil S. Baran in:

Contributions

A.M., Y.I. and P.S.B. conceived the synthetic route, conducted the experimental work, analysed the results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Phil S. Baran.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

  2. 2.

    Supplementary information

    Supplementary information, NMR spectra

Crystallographic information files

  1. 1.

    Supplementary information

    Crystallographic data for compound 6

  2. 2.

    Supplementary information

    Crystallographic data for compound S2

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.1196

Further reading