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Synthesis of epothilones A and B in solid and solution phase

A Corrigendum to this article was published on 06 November 1997


Epothilones A and B, two compounds that have been recently isolated1 from myxobacterium Sorangium cellulosum strain 90, have generated intense interest2–16 among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with micro tubules and anticancer potential of these molecules. Like taxol* (refs 17, 18), they exhibit cytotoxicity against tumour cells by inducing microtubule assembly and stabilization3,4, even in taxol-resistant cell lines. Following the structural elucidation of these molecules by X-ray crystallography in 19961, several syntheses of epothilones A (refs 12–16) and B (ref. 19) have been reported, indicative of the potential importance of these molecules in the cancer field. Here we report the first solid-phase synthesis of epothilone A, the total synthesis of epothilone B, and the generation of a small epothilone library. The solid-phase synthesis applied here to epothilone A could open up new possibilities in natural-product synthesis and, together with solution-phase synthesis of other epothilones, paves the way for the generation of large combinatorial libraries of these important molecules for biological screening.

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  1. Höfle, G. et al. Epothilone A and B—novel 16-membered macrolides with cytotoxic activity: isolation, crystal structure, and conformation in solution. Angew. Chem. Int. Edn. Engl. 35, 1567–1569 (1996).

    Article  Google Scholar 

  2. Grever, M. R., Schepartz, S. A. & Chabner, B. A. The national cancer institute: cancer drug discovery and development program. Semin. Oncol. 19, 622–638 (1992).

    CAS  PubMed  Google Scholar 

  3. Bollag, D. M. et al. Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res. 55, 2325–2333 (1995).

    CAS  Google Scholar 

  4. Kowalski, R. J., Giannakakou, P. & Hamel, E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J. Biol. Chem. 272, 2534–2541 (1997).

    CAS  Article  Google Scholar 

  5. Nicolaou, K. C., He, Y., Vourloumis, D., Vallberg, H. & Yang, Z. An approach to epothilones based on olefin metathesis. Angew. Chem. Int. Edn. Engl. 35, 2399–2401 (1996).

    CAS  Article  Google Scholar 

  6. Meng, D., Sorensen, E. J., Bertinato, P. & Danishefsky, S. J. Studies toward a synthesis of epothilone A: use of hydropyran templates for the management of acyclic stereochemical relationships. J. Org. Chem. 61, 7998–7999 (1996).

    CAS  Article  Google Scholar 

  7. Bertinato, P., Sorensen, E. J., Meng, D. & Danishefsky, S. J. Studies toward a synthesis of epothilone A: stereocontrolled assembly of the acyl region and models for macrocyclization. J. Org. Chem. 61, 8000–8001 (1996).

    CAS  Article  Google Scholar 

  8. Schinzer, D., Limberg, A. & Böhm, O. M. Studies toward the total synthesis of epothilones: asymmetric synthesis of the key fragments. Chem. Eur. J. 2, 1477–1482 (1996).

    CAS  Article  Google Scholar 

  9. Mulzer, J. & Mantoulidis, A. Synthesis of the C(1)-C(9) segment of the cytotoxic macrolides epothilon A and B. Tetrahedr. Lett. 37, 9179–9182 (1996).

    CAS  Article  Google Scholar 

  10. Claus, E., Pahl, A., Jones, P. G., Meyer, H. M. & Kalesse, M. Synthesis of the C1-C9 segment of epothilons. Tetrahedr. Lett. 38, 1359–1362 (1997).

    CAS  Article  Google Scholar 

  11. Gabriel, T. & Wessjohann, L. The Chromium-Reformatsky reaction: asymmetric synthesis of the aldol fragment of the cytotoxic epothilons from 3-(2-bromoacyl)-2-oxazolidinones. Tetrahedr. Lett. 38, 1363–1366 (1997).

    CAS  Article  Google Scholar 

  12. Balog, A. et al. Total synthesis of (-)-epothilone A. Angew. Chem. Int. Edn Engl. 35, 2801–2803 (1996).

    CAS  Article  Google Scholar 

  13. Yang, Z., He, Y., Vourloumis, D., Vallberg, H. & Nicolaou, K. C. Total synthesis of epothilone A: the olefin metathesis approach. Angew. Chem. Int. Edn. Engl. 36, 166–168 (1997).

    CAS  Article  Google Scholar 

  14. Nicolaou, K. C., Sarabia, F., Ninkovic, S. & Yang, Z. Total synthesis of epothilone A: the macro-lactonization approach. Angew. Chem. Int. Edn. Engl. 36, 525–527 (1997).

    CAS  Article  Google Scholar 

  15. Schinzer, D., Limberg, A., Bauer, A., Böhm, O. M. & Cordes, M. Total synthesis of ( – )-epothilone A. Angew. Chem. Int. Edn Engl. 36, 523–524 (1997).

    CAS  Article  Google Scholar 

  16. Meng, D. et al. Remote effects in macrolide formation through ring-forming olefin metathesis: an application to the synthesis of fully active epothilone congeners. J. Am. Chem. Soc. 119, 2733–2734 (1997).

    CAS  Article  Google Scholar 

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

    ADS  Article  Google Scholar 

  18. Nicolaou, K. C., Dai, W.-M. & Guy, R. K. The chemistry and biology of Taxol. Angew. Chem. Int. Edn. Engl. 33, 15–44 (1994).

    Article  Google Scholar 

  19. Su, D.-S. et al. Total synthesis of ( – )-epothilone B: an extension of the Suzuki coupling method and insights into structure-activity relationships of the epothilones. Angew. Chem. Int. Edn. Engl. 36, 757–759 (1997).

    CAS  Article  Google Scholar 

  20. Grubbs, R. H., Miller, S. J. & Fu, G. C. Ring-closing metathesis and related processes in organic synthesis. Acc. Chem. Res. 28, 446–452 (1995).

    CAS  Article  Google Scholar 

  21. Miller, S. J., Blackwell, H. E. & Grubbs, R. H. Application of ring-closing metathesis to the synthesis of rigidified amino acids and peptides. J. Am. Chem. Soc. 118, 9606–9614 (1996).

    CAS  Article  Google Scholar 

  22. Xu, Z., Johannes, C. W., Salman, S. S. & Hoveyda, A. H. Enantioselective total synthesis of antifungal agent Sch 38516. J. Am. Chem. Soc. 118, 10926–10927 (1996).

    CAS  Article  Google Scholar 

  23. van Maarseveen, J. H. et al. Solid phase ring-closing metathesis: cyclization/cleavage approach towards a seven membered cycloolefin. Tetrahedr. Lett. 37, 8249–8252 (1996).

    CAS  Article  Google Scholar 

  24. Miller, J. F., Termin, A. & Piscopio, A. D. Ester enolate Claisen-ring closing metathesis route to functionalized carbocycles and heterocycles. Presented at 213th Am. Chem. Soc. Natl Meeting, San Francisco. 13–17 April (1997).

  25. Schuster, M., Pemerstorfer, J. & Blechert, S. Ruthenium-catalyzed metathesis of polymer-bound olefins. Angew. Chem. Int. Edn. Engl. 35, 1979–1980 (1996).

    CAS  Article  Google Scholar 

  26. Bernard, M. & Ford, W. T. Wittig reagents bound to cross-linked polystyrenes. J. Org. Chem. 48, 326–332 (1983).

    CAS  Article  Google Scholar 

  27. Yang, D., Wong, M.-K. & Yip, Y.-C. Epoxidation of olefins using methyl(trifluoromethyl)dioxirane generated in situ. J. Org. Chem. 60, 3887–3889 (1995).

    CAS  Article  Google Scholar 

  28. Lin, C. M. et al. A convenient tubulin-based quantitative assay for paclitaxel (Taxol) derivatives more effective in inducing assembly than the parent compound. Cancer Chetnother. Pharmacol. 38, 136–140 (1996).

    CAS  Article  Google Scholar 

  29. Giannakakou, P. et al. Paclitaxel resistant human ovarian cancer cells have mutant β-tubulins that exhibit impaired paclitaxel driven polymeriazation. J. Biol. Chem. (in the press).

  30. Rogan, A. M. et al. Reversal of adriamycin resistance by verapamil in human ovarian cancer. Science 244, 994–996 (1984).

    ADS  Article  Google Scholar 

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Nicolaou, K., Winssinger, N., Pastor, J. et al. Synthesis of epothilones A and B in solid and solution phase. Nature 387, 268–272 (1997).

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