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Total Synthesis of (+)- Cortistatin A

Malcolm P. Huestis Supervisor: Keith Fagnou. Total Synthesis of (+)- Cortistatin A. Marine Sponge Corticium simplex (22 mg from 1.5 kg organism). -Selectively inhibits angiogenesis. -IC 50 = 1.8 nM.

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Total Synthesis of (+)- Cortistatin A

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  1. Malcolm P. Huestis Supervisor: Keith Fagnou Total Synthesis of (+)-Cortistatin A

  2. Marine Sponge Corticium simplex (22 mg from 1.5 kg organism) -Selectively inhibits angiogenesis. -IC50 = 1.8 nM -Anti-angiogenetic substances inhibit the formation of new capillary blood vessels. -Cancer, diabetic eye disease, rheumatoid arthritis Isolation and structure elucidation: Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148-3149.

  3. Ongoing Synthetic efforts Total Synthesis: Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S.J. Am. Chem. Soc. 2008,130, 7241-7243. Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K.Angew. Chem. Int. Ed. 2008, 47, 7310-7313. Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D.J. Am. Chem. Soc. 2008,130, 16864-16866. Partial Syntheses (all from 2008): Danishefsky – Sloan-Kettering Institute and Columbia University Corey – Harvard University Yamashita and Hirama– Tohoku University Sarpong– University of California (Berkeley) Gung – Miami University Kobayashi – Osaka University Highlight: Nising, C. F.; Bräse, S. Angew. Chem. Int. Ed. 2008, 47, 9389-9391.

  4. This seminar – completed syntheses 1) May 14th, 2008 - Phil Baran – Highly chemoselective semi-synthetic strategy 2) August 14th, 2008 - K.C. Nicolaou and David Chen – From the Hajos-Parrish bicyclicketone 3) November 19th, 2008- Matthew Shair’skey step - An efficient aza-prinscyclization Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243. Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313. Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008,130, 16864-16866.

  5. Focusing on methods Phil Baran – -Radical ring expansion reaction -Co(III)-catalyzed alkene hydration -Alcohol-directed dibromination reaction -Chemo- and stereoselective double bond reduction K.C. Nicolaou and David Chen – -A single cascade reaction to fuse the entire oxabicycle -Mild aldehydealkynylation -IBX deprotectsdithiane-protected carbonyl -IBX-mediated enone synthesis Matthew Shair’skey step – -Late-stage aza-prinscyclization Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243. Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313. Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008,130, 16864-16866.

  6. BaranRetrosynthesis Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  7. BaranRetrosynthesis Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  8. Elaboration of The Steroid Core Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  9. Elaboration of The Steroid Core II Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  10. Elaboration of The Steroid Core II Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  11. Elaboration of The Steroid Core II Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  12. Elaboration of The Steroid Core III Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  13. Isayama, S.; Mukaiyama, T. Chem. Lett.1989, 1071-1074. Takahiro, T.; Kunikawa, S.; Masuyama, A.; Nojima, M. Org. Lett. 2002, 4, 3595-3598.

  14. Elaboration of The Steroid Core III Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  15. Construction of the Oxabicyclic ring Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  16. Key Step # 1 Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  17. Key Step # 1 Čeković, Ž. Tetrahedron 2003, 59, 8073-8090

  18. Construction of the Oxabicyclic ring Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  19. KEY Step # 2 Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  20. Construction of the Oxabicyclic ring Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  21. KEY Step # 3 Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  22. Construction of the Oxabicyclic ring Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  23. Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  24. Final Steps Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476. Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.

  25. Key Step #4 Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,130, 7241-7243.

  26. Final Steps Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476. Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.

  27. Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476.

  28. Final Steps Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476. Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.

  29. Nicolaou/Chen Retrosynthesis Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.

  30. Starting material was not commercially available Isaacs, R. C. A.; Di Grandi, M. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 3938-3941. Hajos, Z. G.; Parrish, D. R. Org. Synth. 1990,Coll. Vol. 7, 363-368; 1985, 63, 26-36. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496-497.

  31. The Hajos-Parrish Reaction Clemente, F. R.; Houk, K. N. Angew. Chem. Int. Ed. 2004, 43, 5766-5768. Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632-1633. Hajos, Z. G.; Parrish, D. R. Org. Synth. 1990,Coll. Vol. 7, 363-368; 1985, 63, 26-36. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.

  32. Synthesis of the Key Sonogashira fragment I VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,17, 1973-1976. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982. Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318-3326.

  33. Synthesis of the Key Sonogashira fragment II Dess, D. B.; Martin, J. C. J. Org. Chem. 1983,48, 4155-4156. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991,113, 7277-7287. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507. Ohira, S. Synth. Commun. 1989, 19, 561-564. Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.

  34. Parikh-Doering Oxidation Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.

  35. Synthesis of the Key Sonogashira fragment II Dess, D. B.; Martin, J. C. J. Org. Chem. 1983,48, 4155-4156. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991,113, 7277-7287. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507. Ohira, S. Synth. Commun. 1989, 19, 561-564. Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.

  36. Roth, G. J.; Liepold, B.; Müller, S. G.; Bestmann, H. J. Synlett 2004, 59-62.

  37. Ohira-Bestmann homologation Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.

  38. Installation of The A ring Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467-4470. Nicolaou; K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192-5201.

  39. Nicolaou; K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192-5201.

  40. Installation of The A ring Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467-4470. Nicolaou; K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192-5201.

  41. Key Step – 1,4 addition, aldol, dehydration cascade Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313. Same product was independently isolated: Yamashita, S.; Iso, K.; Hirama, M. Org. Lett.2008, 10, 3413-3415.

  42. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.

  43. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358.

  44. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.

  45. Final Steps Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.

  46. IBX as an alternative to the Saegusa oxidation Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc.2002,124, 2245-2258. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 993-996. Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.

  47. Final Steps Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.

  48. Final Steps Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.

  49. Final Steps Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.

  50. ShairRetrosynthesis Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008,130, 16864-16866.

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