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Scalable enantioselective total synthesis of taxanes

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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.

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Figure 1: Retrosynthetic analysis of Taxol (1) and other members of the taxane family.
Figure 2: Enantioselective synthesis of key taxane 6.
Figure 3: Elaboration of (+)-taxadienone (6) to (+)-taxadiene (7) by a three-step reduction–deoxygenation sequence.
Figure 4: Initial synthetic investigations towards the synthesis of taxadienone (6).

References

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

    Google Scholar 

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

    Book  Google Scholar 

  3. Maimone, T. J. & Baran, P. S. Modern synthetic efforts toward biologically active terpenes. Nature Chem. Biol. 3, 396–407 (2007).

    Article  CAS  Google Scholar 

  4. Schiff, P. B., Fant, J. & Horwitz, S. B. Promotion of microtubule assembly in vitro by taxol. Nature 277, 665–667 (1979).

    Article  CAS  Google Scholar 

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

    Google Scholar 

  6. Itokawa, H. & Lee, K.-H. Taxus: The Genus Taxus (Taylor & Francis, 2003).

    Book  Google Scholar 

  7. Wani, M. C., Taylor, H. L., Wall, M. E., Coggon, P. & McPhail, A. T. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Holton, R. A. Method for preparation of taxol. European patent EP0400971 (A2) (1990).

  10. Ojima, I. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Masters, J. J., Link, J. T., Snyder, L. B., Young, W. B. & Danishefsky, S. J. A total synthesis of taxol. Angew. Chem. Int. Ed. 34, 1723–1726 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Shiina, I., Saitoh, K., Fréchard-Ortuno, I. & Mukaiyama, T. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009).

    Article  CAS  Google Scholar 

  24. Davis, E. M. & Croteau, R. Cyclization enzymes in the biosynthesis of monoterpenes, sesquiterpenes and diterpenes. Top. Curr. Chem. 209, 53–95 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Woods, M. C., Chiang, H.-C., Nakadaira, Y. & Nakanishi, K. Nuclear Overhauser effect, a unique method of defining the relative stereochemistry and conformation of taxane derivatives. J. Am. Chem. Soc. 90, 522–523 (1968).

    Article  CAS  Google Scholar 

  27. Hanson, J. R. Diterpenoids. Nat. Prod. Rep. 10, 159–174 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Guéritte-Voegelein, F., Guénard, D. & Potier, P. Taxol and derivatives: a biogenetic hypothesis. J. Nat. Prod. 50, 9–18 (1987).

    Article  Google Scholar 

  30. Baloglu, E. & Kingston, D. G. I. The taxane diterpenoids. J. Nat. Prod. 62, 1448–1472 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Shi, Q.-W. & Kiyota, H. New natural taxane diterpenoids from Taxus species since 1999. Chem. Biodiversity 2, 1597–1623 (2005).

    Article  CAS  Google Scholar 

  33. Ishihara, Y. & Baran, P. S. Two-phase terpene total synthesis: historical perspective and application to the Taxol® problem. Synlett 1733–1745 (2010).

  34. Koepp, A. E. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Brown, P. A. & Jenkins, P. R. 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. Rubenstein, S. M. & Williams, R. M. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Winkler, J. D., Kim, H. S. & Kim, S. A highly efficient synthesis of taxanes via the tandem Diels–Alder reaction. Tetrahedron Lett. 36, 687–690 (1995).

    Article  CAS  Google Scholar 

  40. Laurent, A. 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).

    Article  CAS  Google Scholar 

  41. Magnus, P. 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).

    Article  CAS  Google Scholar 

  42. Gaich, T. & Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem. 75, 4657–4673 (2010).

    Article  CAS  Google Scholar 

  43. Vuagnoux-d'Augustin, M. & Alexakis, A. Copper-catalyzed asymmetric conjugate addition of trialkylaluminium reagents to trisubstituted enones: construction of chiral quaternary centers. Chem. Eur. J. 13, 9647–9662 (2007).

    Article  CAS  Google Scholar 

  44. May, T. L., Brown, M. K. & Hoveyda, A. H. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Mukaiyama, T., Narasaka, K. & Banno, K. New aldol type reaction. Chem. Lett. 2, 1011–1014 (1973).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. Deshayes, H. & Pete, J.-P. 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. Cain, C. M., Cousins, R. P. C., Coumbarides, G. & Simpkins, N. S. Asymmetric deprotonation of prochiral ketones using chiral lithium amide bases. Tetrahedron 46, 523–544 (1990).

    Article  CAS  Google Scholar 

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

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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).

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Contributions

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

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Correspondence to Phil S. Baran.

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The authors declare no competing financial interests.

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Supplementary information (PDF 1248 kb)

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Supplementary information, NMR spectra (PDF 1371 kb)

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Crystallographic data for compound 6 (CIF 12 kb)

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Crystallographic data for compound S2 (CIF 15 kb)

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Mendoza, A., Ishihara, Y. & Baran, P. Scalable enantioselective total synthesis of taxanes. Nature Chem 4, 21–25 (2012). https://doi.org/10.1038/nchem.1196

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