Total Synthesis of ( - )-Epothlone B: An Extension of the Suzuki Coupling Method and Insights into Structure - Activity Relationships of the Epothilones

Angewandte Chemie (International Edition in English)

Volumn 36, Issue 7, 1997, Pages 757-759

  Su, Dai Shi ^a   Meng, Dongfang ^a,c   Bertinato, Peter ^a   Balog, Aaron ^a   Sorensen, Erik J ^a   Danishefsky, Samuel J ^a,c   Zheng, Yu Huang ^d   Chou, Ting Chao ^d   He, Lifeng ^b   Horwitz, Susan B ^b  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^c Havemeyer Hall ^*  (United States)

^d NONE

Author keywords

Antitumor agents; Epothilone; Natural products; Total synthesis

Indexed keywords

EID: 0030792331     PISSN: 05700833     EISSN: None     Source Type: Journal    
DOI: 10.1002/anie.199707571     Document Type: Article

References (35)

1. D. Meng, E. J. Sorensen, P. Bertinato, S. J. Danishefsky, J. Org. Chem. 1996, 61, 7998.
2. P. Bertinato, E. J. Sorensen, D. Meng, S. J. Danishefsky, J. Org. Chem. 1996, 61, 8000.
3. A. Balog, D. Meng, T. Kamenecka, P. Bertinato, D.-S. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801.
4. A. Balog, D. Meng, T. Kamenecka, P. Bertinato, D.-S. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801.
5. D. Meng, D.-S. Su, A. Balog, P. Bertinato, E. J. Sorensen, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B. Horwitz, J. Am. Chem. Soc., in press.
6. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
7. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
8. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
9. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
10. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
11. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
12. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
13. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
14. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
15. For a subsequent total synthesis of epothilone A, see Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem., 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36, 166; K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, ibid, 1997, 109, 593 and 1997, 36, 525; D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes, ibid. 1997, 109, 543 and 1997, 36, 523. For other synthetic studies directed towards epothilone A. see a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vollberg, Z. Yang, ibid. 1996, 108, 2554 and 1996, 35, 2399; b) D. Schinzer, A. Limberg, O. M. Böhm, Chem. Eur. J. 1996, 2, 1477; J. Mulzer, A. Mantoulidis. Tetrahedron Lett, 1996, 37, 9179.
16. G. Höfle, N. Bedorf, H. Steinmetz, D. Schomberg, K. Gerth, H. Reichenbach, Angew. Chem. 1996, 108, 1671; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567.
17. G. Höfle, N. Bedorf, H. Steinmetz, D. Schomberg, K. Gerth, H. Reichenbach, Angew. Chem. 1996, 108, 1671; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567.
18. D. M. Bollag, P. A. McQueney, J. Zhu. O. Hensens, L. Koupal, J. Liesch, M. Goetz, E. Lazarides, C. M. Woods, Cancer Res. 1995, 55, 2325.
19. N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishi-Kawa, M. Satoh, A. Suzuki, J. Am. Chem. Soc. 1989, 111, 314.
20. For an excellent review, see N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
21. For some close analogies that differ in important details from the work shown here, see a) N. Miyaura, H. Suginome, A. Suzuki, Bull. Chem. Soc. Jpn. 1982. 55, 2221; b) M. Ohba, N. Kawase, T. Fujii, K. Aoe, K. Okamura, R. Fathi Afshar, T. M. Alien, Tetrahedron Lett. 1995, 36, 6101; C. R. Johnson, M. P. Braun. J. Am. Chem. Soc. 1993, 115, 11014.
22. For some close analogies that differ in important details from the work shown here, see a) N. Miyaura, H. Suginome, A. Suzuki, Bull. Chem. Soc. Jpn. 1982. 55, 2221; b) M. Ohba, N. Kawase, T. Fujii, K. Aoe, K. Okamura, R. Fathi Afshar, T. M. Alien, Tetrahedron Lett. 1995, 36, 6101; C. R. Johnson, M. P. Braun. J. Am. Chem. Soc. 1993, 115, 11014.
23. For some close analogies that differ in important details from the work shown here, see a) N. Miyaura, H. Suginome, A. Suzuki, Bull. Chem. Soc. Jpn. 1982. 55, 2221; b) M. Ohba, N. Kawase, T. Fujii, K. Aoe, K. Okamura, R. Fathi Afshar, T. M. Alien, Tetrahedron Lett. 1995, 36, 6101; C. R. Johnson, M. P. Braun. J. Am. Chem. Soc. 1993, 115, 11014.
24. G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc. 1993, 115, 8467.
25. J. Chen, T. Wang, K. Zhao, Tetrahedron Lett. 1994, 35, 2827.
26. The stereochemically controlled aldol condensation giving a product with the natural 35 configuration as previously described in the epothilone A series [3] was accomplished. However, the overall yield for reaching the 35 epimer is better with the protocol described here.
27. Although precise comparisons are not available, the epoxidation of 2 appears to be more rapid and regioselective than that of 4 [3].
28. To the best of our knowledge, this is the first successful Suzuki coupling between a B-alkyl system and an unconjugated, trisubstituted alkene.
29. Compound 18 was prepared by a stweorandom olefin metathesis route which also led to 2. These geometric isomers could be separated only with great difficulty. Details of the nonstereoselective route will be provided in a subsequent fuller disclosure.
30. 2 1 mM GTP, and 3 M gtycerol, pH 6.6. The concentration of tubulin in MTP was estimated to be about 85%. Assembly was followed spectrophotometrically at 350 nm. 35°C for 40 min, by monitoring changes in turbidity as u measure of polymer mass [22]. Drugs were tested at a concentration of 10 μM in the absence of GTP. Microtubule formation was verified by electron microscopy. To determine the stability of microtubules assembled in the presence of GTP or drug, turbidity was monitored for 40 min after the reaction temperature was shifted to 4°C.
31. D. A. Scudiero, R. H. Shoemaker, D. K. Paul, A. Monks, S. Teiney, T. H. Hafziget, J. J. Currens, D. Sheriff, M. R. Boyd. Cancer Res. 1988, 48, 4827.
32. T.-C. Chou, D. Rideout. Synergism and Antagonism in Chemotherapy. Academic Press, New York, 1991. pp. 61-102.
33. J. Chou, T-C. Chou, IBM-PC software and manual, Biosoft, Cambridge, UK. 1987.
34. R. C. Weisenberg, Science 1972, 177, 1104.
35. F. Gaskin, C. R. Cantor, M. L. Shelanski, J. Mol. Biol. 1974, 89, 737.