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

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,
Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1994, 116,
Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett. 2003, 44,
Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto, Y. Org. Lett. 2002, 4,

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,
Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett. 2003, 44,

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,
Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett. 2003, 44,

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

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

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

14. Overman’s Retrosynthesis
Biginelli Condensation

15. Synthesis of the Iodide
Weber, B.; Seebach, D. Tetrahedron 1994, 50,

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

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,
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 ,

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. Tetrahedron 1993, 49,
Kappe, C. O. J. Org. Chem. 1997, 62,

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

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

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

24. Synthesis

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

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,
Coffey, D. S.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc. 2000, 122,

28. Retrosynthesis
Biginelli Condensation

29. Synthesis

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

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,

35. Crambidine Retrosynthesis

36. Crambidine Synthesis

37. Crambidine Synthesis

38. Conclusion