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Amphidinolide A

Amphidinolide A. Isolation : 1. Kobayashi, J. et al. Tetrahedron Lett. 1986 , 27 , 5755. 2. Kobayashi, J. et al. J. Nat. Prod . 1991 , 54 , 1435. Biological Activity : L1210 murine leukemia cells human epidermoid carcinoma KB cells rabbit skeletal muscle actomysion ATPase

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Amphidinolide A

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  1. Amphidinolide A Isolation: 1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, 5755. 2. Kobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435. Biological Activity: L1210 murine leukemia cells human epidermoid carcinoma KB cells rabbit skeletal muscle actomysion ATPase Kobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435.

  2. Amphidinolide A: Pattenden’s Retrosynthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed.2002, 41, 508–511. For Stille Reaction Review See: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1–652.

  3. Amphidinolide A: Trost’s Retrosynthesis Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421.

  4. Amphidinolide A: Our Retrosynthesis Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844.

  5. Synthesis of Fragment A

  6. Synthesis of Fragment A

  7. Synthesis of Fragment C

  8. Synthesis of Fragment C

  9. Coupling of Fragments C and D For an example synthesis of Fragment D see: Thibonnet, J. et. al. Tetrahedron Lett. 1998, 39, 4277.

  10. Chelation Controlled Additions

  11. Chelation Controlled Additions

  12. Chelation Controlled Additions

  13. Elaboration of the AB Subunit

  14. Elaboration of the AB Subunit For leading Red-Sil references see: (a) Reed-Mundell, J. J.; Nadkarni, D. V.; Kunz, J. M., Jr.; Fry, C. W.; Fry, J. L. Chem. Mater. 1995, 7, 1655-1660. (b) Kini, A. D.; Nadkarni, D. V.; Fry, J. L. Tetrahedron Lett. 1994, 35, 1507-1510. (c) Fry, J. L.; Nadkarni, D. V. U. S. Patent 5,281,440, 1994.

  15. The Union

  16. The RCM Note: Employing the bis-phosphine catalysts solely affords the methyl ketone See: Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123-1125.

  17. High Yielding Highly Selective RCM is possible

  18. The Total Synthesis of Amphidinolide A?

  19. Presumed Amphidinolide A 35 steps from article of commerce with a longest linear sequence of 23 steps from L-(-)-ephedrine. Spectroscopic data inconsistent with those of the natural product! Possible Reasons for the Discrepancy: (1) We screwed up. (2) Trace contamination affecting NMR data. (3) Misidentification of natural product. Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844.

  20. Presumed Amphidinolide A 35 steps from article of commerce with a longest linear sequence of 23 steps from L-(-)-ephedrine. Spectroscopic data inconsistent with those of the natural product! Possible Reasons for the Discrepancy: (1) We screwed up. (2) Trace contamination affecting NMR data. (3) Misidentification of natural product. Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844.

  21. Amphidinolide A: Pattenden’s Retrosynthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed.2002, 41, 508–511. For Stille Reaction Review See: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1–652.

  22. Pattenden’s Epoxide Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed.2002, 41, 508–511.

  23. Pattenden’s Epoxide Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed.2002, 41, 508–511.

  24. Pattenden’s Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed.2002, 41, 508–511.

  25. Pattenden’s Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed.2002, 41, 508–511.

  26. Amphidinolide A: Trost’s Retrosynthesis 58% 46% Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421.

  27. Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421. Presumed Amphidinolide A: Trost’s Syntheses 11 isomers Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028–5029.

  28. Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421. Presumed Amphidinolide A: Trost’s Syntheses Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028–5029.

  29. Ishiyama, H.; Nakamura, Y.; Kobayashi, J. Tetrahedron 2006,62, 166–170. Trost, B. M.; et al. J. Am. Chem. Soc. 2005, 126, 13589–13610. Amphidinolide A: Another Possibility? Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844.

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