Sébastien Goudreau

1. Total synthesis of crambescidin 800, crambescidin 359, 13,14,15-isocrambescidin 800 and crambidine. Sébastien Goudreau Literature meeting : 24-01-2006

2. Natural compound • Members of the crambescidin family. • Contain structurally unique pentacyclic guanidinium moieties having two distinctive spiroaminal units. • Cytotoxicity toward several cancer cell lines, antifungal activity, antiviral activities toward herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus (HIV), inhibition of HIV-1 envelope-mediated cell fusion, induction of differentiation of chronic mylogenous leukemia cells and inhibition of the binding of various proteins to HIV-1 Nef.

3. Overview Isolation : 1989 Model studies : Snider JOC 1992, Overman JOC 1993, Snider JACS 1994, Murphy JCS Chem. Comm. 1994, Weinreb JOC 1996 Total synthesis : Overman, JACS 1995 Isolation : 1991 Total synthesis :Overman JACS 2000 Isolation : 1993 Total synthesis : Overman JACS 1999 Overman JACS 2000 Isolation : 2000 Total synthesis : Nagasawa Org. Lett. 2002 Murphy Tet. Lett. 2003 Isolation : 1993 Total synthesis : Overman JACS 2005

4. Crambescidin 800 Synthesis • Isolated from Crambe crambe, a bright red conspicuous species of sponge found at the shallow depths along the rocky coast of the Mediterranean. • First and only total synthesis : Overman’s group. • 3% overall yield, 16 isolated and purified intermediates. • Synthesis of the guanidinium unit : Snider, Murphy, Nagasawa. Coffey, D. S.; McDonald, A. I.; Overman, L.E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc.2000, 122, 4893-4903. Snider, B. B.; Shi, Z. J. Am. Chem. Soc.1994, 116, 549-557. Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett.2003, 44, 251-254. Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto, Y. Org. Lett.2002, 4, 177-180.

5. Crambescidin 359 Synthesis • Isolated from the marine sponge of the genus Monanchora. • First total synthesis : Nagasawa’s group. • Other synthesis : Murphy’s group. Braekman, J. C.; Daloze, D.; Tavares, R.; Hajdu, E.; Van Soest, R. W. M. J. Nat. Prod.2000, 63, 193. Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto, Y. Org. Lett.2002, 4, 177-180. Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett.2003, 44, 251-254.

6. Nagasawa’s retrosynthesis

7. Nagasawa’s synthesis

8. Nagasawa’s synthesis (7:1 ds)

9. Nagasawa’s synthesis

10. Biomimetic approach Snider, B. B.; Shi, Z. J. Am. Chem. Soc.1994, 116, 549-557. Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett.2003, 44, 251-254.

11. Snider’s Synthesis Snider, B. B.; Shi, Z. J. Am. Chem. Soc.1994, 116, 549-557.

12. Snider’s Synthesis Knoevanagel Condensation Jones, G. Org. React.1967, 15, 204. Snider, B. B.; Shi, Z. J. Am. Chem. Soc.1994, 116, 549-557.

13. Snider’s Synthesis 4:1 1:1 1:1 1.3:1 Snider, B. B.; Shi, Z. J. Am. Chem. Soc.1994, 116, 549-557.

14. Overman’s Retrosynthesis Biginelli Condensation

15. Synthesis of the Iodide Weber, B.; Seebach, D. Tetrahedron1994, 50, 7473-7484.

16. Synthesis of the Weinreb Amide Taber, D. F.; Silverberg, L. J. Tetrahedron Lett.1991, 32, 4227-4230. Noyori, R.; Takaya, H. Acc. Chem. Res.1990, 23, 345-350.

17. Synthesis of the Urea

18. Synthesis of the b-Ketoester Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc.1995, 117, 2657-2658. Taber, D. F.; Amedio, J. C., Jr.; Patel, Y. K. J. Org. Chem.1985, 50, 3618. Kitumura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth., Coll. Vol. 91998, 589-595.

19. Synthesis of the pyrolidine unit Note : Knoevenagel conditions : MeOH, piperidine and acetic acid. Jones, G. Org. React.1967, 15, 204.

20. Biginelli Condensation Pietro Biginelli, 1893 dihydropyrimidinone N-acyliminium Kappe, C. O. Tetrahedron1993, 49, 6937-6963. Kappe, C. O. J. Org. Chem.1997, 62, 7201-7204.

21. Biginelli Condensation late transition state Weakly electron-withdrawing amidine group 16 = Ethyl acetoacetate cis trans McDonald, A. I.; Overman, L. E. J. Org. Chem.1999, 64, 1520-1528

22. Synthesis (1 product) Spiroaminal center : stereoelectronic effect. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: London, 1983; Chapter 1. Overman, L. E.; Rabinowitz, M. H. J. Org. Chem.1993, 58, 3235-3237.

23. Kinetic protonation Kinetic protonation Coffey, D. S.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc.2000, 122, 4904-4914. Coffey, D. S.; McDonald, A. I.; Overman, L.E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 2000, 122, 4893-4903. Overman, L. E.; Rabinowitz, M. H. J. Org. Chem.1993, 58, 3235-3237.

24. Synthesis

25. Synthesis of Spermidin unit Coffey, D. S.; McDonald, A. I.; Overman, L. E. J. Org. Chem.1999, 64, 8741-8742.

26. Synthesis of Crambescidin 800

27. 13,14,15-isocrambescidin 800 Synthesis • Isolated from Crambe crambe, a bright red marine sponge that is the most widespread species of littoral sponge found in the Northwestern Mediterranean. • First and only total synthesis : Overman’s group. • 3% overall yield, 14 isolated and purified intermediates. Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc.1999, 121, 6944-6945. Coffey, D. S.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc.2000, 122, 4904-4914.

28. Retrosynthesis Biginelli Condensation

29. Synthesis

30. Biginelli Condensation late transition state Weakly electron-withdrawing amidine group 16 = Ethyl acetoacetate cis trans McDonald, A. I.; Overman, L. E. J. Org. Chem.1999, 64, 1520-1528

31. Formation of the pentacycle • Spiroaminal center : stereoelectronic effect. • Steric interactions between the ester and the tetrahydropyran ring in the major compound.

32. Synthesis

33. Synthesis

34. Crambidin Synthesis • Isolated from Crambe crambe, a bright red marine sponge. • First and only total synthesis : Overman’s group. Overman, L.E.; Rhee, Y. H. J. Am. Chem. Soc.2005, 127, 15652-15658.

35. Crambidine Retrosynthesis

36. Crambidine Synthesis

37. Crambidine Synthesis

38. Conclusion