Original Article | Published:

Practical synthesis of the C-ring precursor of paclitaxel from 3-methoxytoluene

The Journal of Antibiotics volume 69, pages 273279 (2016) | Download Citation

Abstract

The practical synthesis of the C-ring precursor of paclitaxel starting from 3-methoxytoluene is described. Lipase-catalyzed kinetic resolution of a substituted cyclohexane-1,2-diol, derived from 3-methoxytoluene in three steps, successfully afforded a desired enantiomer with >99% ee, which was transformed to a cyclohexenone. 1,4-Addition of a vinyl metal species, followed by Mukaiyama aldol reaction with formalin in the presence of a Lewis acid provided the known C-ring precursor of paclitaxel in a 10 g scale.

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.

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

  2. 2.

    , , & Taxane anticancer agents, Vol. 583 (Americal Chemical Society, Washington, ACS Symposium Series 1994).

  3. 3.

    et al. Natural taxanes: developments since 1828. Chem. Rev. 111, 7652–7709 (2011).

  4. 4.

    Taxol, a molecule for all seasons. Chem. Commun. 37, 867–880 (2001).

  5. 5.

    , & Chemistry and biology of taxol. Angew. Chem. Int. Ed. Engl. 33, 15–44 (1994).

  6. 6.

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

  7. 7.

    et al. Total synthesis of taxol. 4. The final stages and completion of the synthesis. J. Am. Chem. Soc. 117, 653–659 (1995).

  8. 8.

    et al. Total synthesis of baccatin III and taxol. J. Am. Chem. Soc. 118, 2843–2859 (1996).

  9. 9.

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

  10. 10.

    et al. Asymmetric total synthesis of Taxol®. Chem. Eur. J. 5, 121–161 (1999).

  11. 11.

    et al. Enantioselective total synthesis of (−)-taxol. J. Am. Chem. Soc. 122, 3811–3820 (2000).

  12. 12.

    A total synthesis of taxol (PhD thesis, Harvard University, 2000).

  13. 13.

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

  14. 14.

    , , & Formal total synthesis of (−)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation. Chem. Eur. J. 21, 355–359 (2015).

  15. 15.

    et al. Synthesis of paclitaxel. 1. Synthesis of the ABC ring of paclitaxel by SmI2-mediated cyclization. Org. Lett. 17, 2570–2573 (2015).

  16. 16.

    et al. Synthesis of paclitaxel. 2. Construction of the ABCD ring and formal synthesis. Org. Lett. 17, 2574–2577 (2015).

  17. 17.

    , , , & Chiral synthesis of the CD ring unit of paclitaxel from d-glucal. Chem. Commun. 36, 2237–2238 (2000).

  18. 18.

    et al. Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors. J. Med. Chem. 57, 5714–5727 (2014).

  19. 19.

    , , , & 4-Ethylene ketal of 4,6-dioxo-heptanoic acid: an unexpected intermediate in the attempted synthesis of homoharringtonine. Acta Chimica Sinica 39, 937–939 (1981).

  20. 20.

    & Total synthesis of gibberellic acid. A simple synthesis of a key intermediate. J. Am. Chem. Soc. 104, 6129–6130 (1982).

  21. 21.

    & Chemoselective reductive cleavage of ketals and acetals. Chem. Lett. 13, 9–12 (1984).

  22. 22.

    & Lipase-mediated chiral resolution of racemates in organic solvents. Tetrahedron Asymmetry 15, 3331–3351 (2004).

  23. 23.

    , & Enantioconvergent access to the enantiomerically pure building blocks (+)- or (–)-4-hydroxy-3-methyl-2-cyclohexenone using a chemoenzymatic process. Synlett. 403–406 (2006).

  24. 24.

    & Scalable preparation of both enantiomers of 2-(1-hydroxy-2-oxocyclohexyl)acetic acid. J. Org. Chem. 73, 3938–3941 (2008).

  25. 25.

    & Enzymatic preparation of ethyl (S-3-hydroxybutanoate with a high enantiomeric excess. Agric. Biol. Chem. 53, 2009–2010 (1989).

  26. 26.

    et al. Chemoenzymatic synthesis of (2S,3S,4S-form, the physiologically active stereoisomer of dehydroxymethylepoxyquinomicin (DHMEQ), a potent inhibitor on NF-κB. Tetrahedron 66, 7083–7087 (2010).

  27. 27.

    , , , & Significant effect of acyl groups on enantioselectivity in lipase-catalyzed transesterifications. Tetrahedron Asymmetry 7, 625–628 (1996).

  28. 28.

    & Synthesis of optically active cyclohexenol derivatives via enzyme catalyzed ester hydrolysis of 4-acetoxy-3-methyl-2-cyclohexenone. Tetrahedron 47, 5883–5894 (1991).

  29. 29.

    & Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide. J. Am. Chem. Soc. 89, 5505–5507 (1967).

  30. 30.

    & Recent studies on veratrum alkaloids: a new reaction of sodium triacetoxyborohydride [NaBH(OAc)3]. Tetrahedron Lett. 24, 273–276 (1983).

  31. 31.

    & Mukaiyama aldol reactions in aqueous media. Adv. Synth. Catal. 355, 3095–3118 (2013).

  32. 32.

    Rare earth metal trifluoromethanesulfonates as water-tolerant Lewis acid catalysts in organic synthesis. Synlett 689–701 (1994).

  33. 33.

    & Lanthanide triflates as water-tolerant Lewis acids. Activation of commercial formaldehyde solution and use in the aldol reaction of silyl enol ethers with aldehydes in aqueous media. J. Org. Chem. 59, 3590–3596 (1994).

  34. 34.

    , , & Scandium trifluoromethanesulfonate (Sc(OTf)3 as a novel reusable Lewis acid catalyst in aldol and Michael reactions. Synlett 472–474 (1993).

Download references

Acknowledgements

This research was supported by the MEXT-supported Program for the Strategic Research Foundation at Private Universities, 2012–2016, from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT). Authors also acknowledge the financial support (Grant-in Aid for Scientific Research (B), 26288018) from Japan Society for the Promotion of Science (JSPS).

Author information

Affiliations

  1. Department of Applied Chemistry, Keio University, Yokohama, Japan

    • Keisuke Fukaya
    • , Yu Yamaguchi
    • , Ami Watanabe
    • , Hiroaki Yamamoto
    • , Tomoya Sugai
    • , Takaaki Sato
    •  & Noritaka Chida
  2. Department of Pharmaceutical Science, Keio University, Tokyo, Japan

    • Takeshi Sugai

Authors

  1. Search for Keisuke Fukaya in:

  2. Search for Yu Yamaguchi in:

  3. Search for Ami Watanabe in:

  4. Search for Hiroaki Yamamoto in:

  5. Search for Tomoya Sugai in:

  6. Search for Takeshi Sugai in:

  7. Search for Takaaki Sato in:

  8. Search for Noritaka Chida in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Noritaka Chida.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ja.2016.6

Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)