The Solid-State and Solution-State Reassigned Structures of Tagitinin A, a 3,10-Epoxy- Germacrolide from Tithonia diversifolia, and the Interconversion of 3,10-Epoxy-Germacrolide Conformational Families via a Ring-Atom Flip Mechanism


  • Robert Glaser Ben-Gurion University of the Negev
  • Abraham García Universidad Nacional Autónoma de México
  • María Isabel Chávez Universidad Nacional Autónoma de México
  • Guillermo Delgado Universidad Nacional Autónoma de México


Tagitinin A, Horeau’s rule, conformational interconversion, molecular modeling


Abstract. Tagitinin A (2), a known 3,10-epoxy-germacrolide-6,7-trans-lactone isolated from Tithonia diversifolia, was investigated by single crystal X-ray diffraction analysis. It was found to have a 1β,4α,6α,7β,8β relative configuration which differed at C(1) from the 1α-orientation originally reported in the literature which was determined by Horeau’s Rule. Analysis of the 1H NMR spectrum of 2 shows the molecule to maintain its crystallographically observed twist-chair-boat (TCB) ninemembered ring conformation in acetone-d6 solution. The twist-chair-boat/skew-chair-boat type 3 conformations of saturated/unsaturated nine-membered rings within 3,10-epoxy-germacrolides can be interconverted to the skew-chair-chair (SCC) conformation by means of a C(9) ring atom flip mechanism. As a result of this conformational change, the orientation of the C(1) atom and the C(8)-oxycarbonyl moiety are transformed from diequatorial to diaxial. The reported stereochemistry of 3,10-epoxy-germacrolide lactone structures, and the DFT B3LYP/6-31g(d) modeling findings in this work indicate that tetrahedral C(1) atoms stabilize the TCB/SCB type 3 conformations, while their trigonal counterparts stabilize the SCC conformation .


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Author Biographies

Robert Glaser, Ben-Gurion University of the Negev

Department of Chemistry

Abraham García, Universidad Nacional Autónoma de México

Instituto de Química

María Isabel Chávez, Universidad Nacional Autónoma de México

Instituto de Química

Guillermo Delgado, Universidad Nacional Autónoma de México

Instituto de Química


1. Horeau, A.; Tetrahedron Lett. 1961, 506; ibid. 1962, 965; Horeau, A.; Kagan, H. B.; Tetrahedron 1964, 20, 2431.
2. Eliel, E. L.; Wilen, S. H.; Mander, L. N.; Stereochemistry of Organic Compounds, Wiley-Interscience: New York, 1994, p. 140-142.
3. Brewster, J. H. In Elucidation of Organic Structures by Physical and Chemical Methods; Bentley, K. W.; Kirby, G. W., eds.; 2nd ed., Wiley-Interscience: New York, 1972, p. 1-249, vol. IV, Part III.
4. Horeau, A.; Stereochemistry, Fundamentals and Methods, Georg Thieme Publishers: Stuttgart, 1977, vol 3.
5. Kupchan, S. M.; Kelsey, J. E.; Sim, G. A.; Tetrahedron Lett. 1967, 2863.
6. Rogers, D.; Moss, G. P.; Neidle, S.; J. Chem. Soc. Chem. Commun. 1972, 142.
7. Romo de Vivar, A.; Guerrero, C.; Díaz, E.; Ortega, A.; Tetrahedron 1970, 26, 1657; It has been suggested that the actual natural source of Zexbrevin is Viguiera greggi: Delgado, G.; Alvarez, L.; Mata, R.; Pereda-Miranda, R.; Romo de Vivar, A.; Villaseñor, J. L.; J. Nat. Prod. 1986, 49, 1165; Romo de Vivar, A.; Delgado, G.; Bol. Soc. Chil. Quím. 1985, 30, 79.
8. Baruah, N. C.; Sharma, R. P.; Madhusudanan, K. P.; Thyagrarajan, G.; Herz. W.; Murari, R.; J. Org. Chem. 1979,
44, 1831; Sarma, J. C.; Sharma, R. P.; de Jong, R.; Stam, C. H.; Phytochemistry 1987, 26, 2406.
9. Fischer, N. H.; Oliver, E. J.; Fischer, H. D.; Prog. Chem. Org. Nat. Prod. 1979, 38, 47.
10. Soriano-García, M.; Toscano, R. A.; Acta Crystallogr. 1984, C40, 1425.
11. Fronzek, F. R.; Lee, I-Y.; Fischer, N. H.; J. Nat. Prod. 1983, 46, 104.
12. Rodríguez-Hahn, L.; Jiménez, M.; Saucedo, R.; Soriano-García, M.; Toscano, R. A.; Díaz, E.; Tetrahedron 1983, 39, 3909.
13. Soriano-García, M.; Toscano, R. A.; Díaz, E.; Rodríguez-Hahn, L.; Rev. Latinoamer. Quím. 1985, 16, 112.
14. Pal, R.; Kulshreshta, D. K.; Rastogi, R. P.; Indian J. Chem. 1976, 14B, 77 and 259; ibid. 1977, 15B, 208 and 533. For additional studies on Tithonia diversifolia, see: Pereira, P. S.; Dias, D. A.; Vichnewski, W.; Turco Tussi Nasi, A. M.; Herz, W.; Phytochemistry 1997, 45, 1445; Kuo, Y.-H.; Chen, Ch.-H.; J. Nat. Prod. 1998, 61, 827; Gu, J.-Q.; Gills, J.J.; Park, E. J.; Mata-Greenwood, E.; Hawthorne, M. E.; Axelrod, F.;
Chavez, P. I.; Fong, H. H. S.; Mehta, R. G.; Pezzuto, J. M.; Kinghorn, A. D.; J. Nat. Prod. 2002, 65, 532.
15. Glaser, R.; Shiftan, D.; Levi-Roso, G.; Ergaz, I.; Geresh, S.; J. Org. Chem. 2002, 67, 5486.
16. Heinrich, M.; Robles, M.; West, J. A.; Ortíz de Montellano, B. R.; Rodríguez, E.; Annu. Rev. Pharmacol. Toxicol. 1998, 38, 539.
17. Bijvoet, J. M.; Peerdeman, A. F.; van Brommel, A. J.; Nature (London) 1951, 168, 271.
18. The authors have deposited atomic coordinates for 2 with the Cambridge Crystallographic Data Centre. The coordinates can be obtained, free of charge via (or from the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge, CB2 1EZ UK; Tel: +44 1223 336408; Fax: +44 1223 336033; or e-mail: [email protected]).
19. Müller, N.; Ball&Stick 3.8β3, Institut für Chemie, Johannes Kepler Universität: Linz, Austria, 2000.
20. Allen, F. H. ; Acta Crystallogr. 2002, B58, 380.
21. González, A. G.; Galindo, H.; Mansilla, H.; Kestermich, V. H. ; Palenzuela, J. A.; Rodríguez, M. L.; J. Nat. Prod. 1990, 53, 462.
22. Macias, F. A.; Aguilar, J. M.; Molinillo, J. M. G.; Massanet, G. M. Fronczek, F. R.; Tetrahedron 1994, 50, 5439.
23. Quijano, L.; Núñez, I. S.; Fronczek, F. R.; Fischer, N. H.; Phytochemistry 1997, 45, 769.
24. Hayashi, T.; Nakano, T.; Kozuka, M.; McPhail, D. R.; McPhail, A. T.; Lee, K. H.; J. Nat. Prod. 1999, 62, 302.
25. Sundin, A.; MacMimic 3.0, In-Star Software: Lund, Sweden, 1996 [now Department of Bioorganic Chemistry, Lund Technische Hochsuhle: Lund, Sweden].
26. Gaussian-98W, revision A-7; Gaussian Inc.: Pittsburgh, PA, 1998.
27. Herz, W.; Blount, J. F.; J. Org. Chem. 1978, 43, 1268.
28. Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M.; Macrae, C. F.; McCabe, P.; Pearson, J.; Taylor, R.; Acta Crystallogr. 2002, B58, 389.
29. CSChemDraw Ultra 5.0; CambridgeSoft: Cambridge, MA, 1999; Chem3D Pro 5.0; CambridgeSoft: Cambridge, MA, 1999.
30. Anet, F. A. L.; Tetrahedron Lett. 1990, 31, 2125.
31. Dale, J.; Stereochemistry and Conformational Analysis, Universitetsforlaget/Verlag Chemie: Oslo/New York, 1978, p. 206.
32. Herz, W.; Goedken, V. L.; J. Org. Chem. 1982, 47, 2798.
33. Le Quesne, P. W.; Menachery, M. D.; Pastore, M. P.; Kelley, C. J.; Brennan, T. F.; Onan, K. D.; Raffauf, R. F.; Weeks, C. M.; J. Org. Chem. 1982, 47, 1519.
34. Manchand, P. S.; Todaro, L. J.; Cordell, G. A.; Soejarto, D. D.; J. Org. Chem. 1983, 48, 4388.
35. Lee, I.-Y.; Fronczek, F. R.; Malcolm, A.; Fischer, N. H.; Urbatsch, L. E.; J. Nat. Prod. 1982, 45, 311.
36. Fischer, N. H.; Lee, I.-Y.; Fronczek, F. R.; Chiari, G.; Urbatsch, L. E.; J. Nat. Prod. 1984, 47, 419.
37. Castañeda-Acosta, J.; Ober, A. G.; Fronczek, F. R.; Fischer, N. H.; Chiari, G.; J. Chem. Cryst. 1997, 27, 641.
38. Herz, W.; Blount, J. F.; J. Org. Chem. 1978, 43, 4887.
39. Gershenzon, J.; Liu, Y.-L.; Mabry, T. J.; Korp, J. D.; Bernal, I.; Phytochemistry 1984, 23, 1281.
40. Rodríguez, J. D.; Perales, A.; Rodríguez-Ubis, J. C.; Vázquez, P.; Borges, J.; J. Nat. Prod. 1995, 58, 446.
41. Budzelaar, P. H. M.; Gnmr 4.1; Cherwell Scientific Ltd.: Oxford, U.K., 1999.
42. Goto, H.; Osawa, E.; J. Am. Chem. Soc. 1989, 111, 8950.
43. Hendrickson, J. B.; J. Am. Chem. Soc. 1967, 89, 7047.
44. Glaser, R.; Michel, A.; Drouin, M.; Can. J. Chem. 1990, 68, 1128.
45. Glaser, R.; Novoselsky, A.; Shiftan, D.; Drouin, M.; J. Org. Chem. 2000, 65, 6345.
46. SMART (5.625); Bruker AXS Inc.: Madison, WI, 2000.
47. Sheldrick, G. M.; SHELXTL97; An Integrated System for Solving, Refining and Displaying Crystal Structures from Diffraction Data, University of Göttingen: Germany, 1997.
48. International Tables for X-ray Crystallography, Kynoch Press: Birmingham, vol IV, 1974.






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