Enantioselective total synthesis of ecteinascidin 743

Journal of the American Chemical Society

Volumn 118, Issue 38, 1996, Pages 9202-9203

  Corey, E J ^a   Gin, David Y ^a   Kania, Robert S ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; ECTEINASCIDIN; UNCLASSIFIED DRUG;

ARTICLE; CHIRALITY; DRUG SYNTHESIS; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 0029805757     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja962480t     Document Type: Article

References (18)

1. The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K. K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989; pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L, H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gäde, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
2. The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K. K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989; pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L, H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gäde, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
3. The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K. K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989; pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L, H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gäde, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
4. The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K. K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989; pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L, H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gäde, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
5. The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K. K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989; pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L, H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gäde, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
6. The pioneering research in this area is due to Prof. Kenneth L. Rinehart and his group, see: (a) Rinehart, K. L.; Shield, L. S. In Topics in Pharmaceutical Sciences; Breimer, D. D., Crommelin, D. J. A., Midha, K. K., Eds.; Amsterdam Medical Press: Noordwijk, The Netherlands, 1989; pp 613. (b) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G. R.; Perun, T. J., Jr.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.; Seigler, D. S.; Li, L, H.; Martin, D. G.; Grimmelikhuijzen, C. J. P.; Gäde, G. J. Nat. Prod. 1990, 53, 771. (c) Rinehart, K. L.; Sakai, R.; Holt, T. G.; Fregeau, N. L.; Perun, T. J., Jr.; Seigler, D. S.; Wilson, G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277. (d) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin, D. G. J. Org. Chem. 1990, 55, 4512. (e) Wright, A. E.; Forleo, D. A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. J. Org. Chem. 1990, 55, 4508. (f) Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, H.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11456.
7. Science 1994, 266, 1324.
8. The current clinical plan calls for the administration of three 0.5 mg doses of 1 per patient; personal communication from Dr. Glynn Faircloth, PharmaMar USA, Cambridge, MA.
9. 2 at 0 °C; (4) treatment of the resulting 3-methyl-4,5-(methylenedioxy)salicylaldehyde with 1.5 equiv of NaH in DMF at 0 °C for 5 min and 2 equiv of benzyl bromide at 23 °C for 40 min (86% overall). (b) Prepared from the monoallyl ester of malonic acid by conversion to the mixed anhydride with BOP chloride (Aldrich) and reaction with 2,2-dimethoxyethanol.
10. This step, which involves isomerization possibly of the intermediate isocyanate, represents a generally useful process for the stereospecific synthesis of such compounds.
11. Koenig, K. E. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press, Inc.: Orlando, FL, 1985; Vol. 5, p 71.
12. The conversion 4 → 5 demonstrates a method for control of stereochemistry in the tetrahydroisoquinoline series.
13. (a) This step converts the tertiary hydroxyl group of 13 to the O-dimethylsulfonium derivative. The use of oxalyl chloride-DMSO as reagent is unsatisfactory due to interference by chloride in the subsequent steps of quinone methide formation and addition. (b) This step generates the quinone methide probably by cycloelimination of the Swern type oxosulfonium ylide intermediate.
14. Barton, D. H. R.; Elliott, J. D.; Géro, S. D. J. Chem. Soc., Perkin Trans, I 1982, 2085.
15. Obtained from Prof. K. L. Rinehart and PharmaMar USA.
16. For previous work on the synthesis of the saframycins, see: (a) Fukuyama, T.; Sachleben, R. A. J. Am. Chem. Soc. 1982, 104, 4957. (b) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J. Am. Chem. Soc. 1990, 112, 3712. (c) Saito, N.; Yamauchi, R.; Nishioka, H.; Ida, S.; Kubo, A. J. Org. Chem. 1989, 54, 5391.
17. For previous work on the synthesis of the saframycins, see: (a) Fukuyama, T.; Sachleben, R. A. J. Am. Chem. Soc. 1982, 104, 4957. (b) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J. Am. Chem. Soc. 1990, 112, 3712. (c) Saito, N.; Yamauchi, R.; Nishioka, H.; Ida, S.; Kubo, A. J. Org. Chem. 1989, 54, 5391.
18. For previous work on the synthesis of the saframycins, see: (a) Fukuyama, T.; Sachleben, R. A. J. Am. Chem. Soc. 1982, 104, 4957. (b) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J. Am. Chem. Soc. 1990, 112, 3712. (c) Saito, N.; Yamauchi, R.; Nishioka, H.; Ida, S.; Kubo, A. J. Org. Chem. 1989, 54, 5391.