1. Cationic Olefin Polyannulations: History and Application to Steroid and Other Fused Polycycle Syntheses
David A. Nicewicz

2. Squalene Enzymatic Cyclizations

3. Oxidosqualene Enzymatic Cyclizations

4. Mechanism for Squalene Enzymatic Cyclization

5. Mechanism for Oxidosqualene Enzymatic Cyclization

6. Acid-Catalyzed Cyclization of 1,5-Dienes
J. W. Cook and C. L. Hewett, J. Chem. Soc., 1934, 365.
P. G. Stevens and S. C. Spalding, Jr., J. Am. Chem. Soc., 1949, 71, 1687.

7. Stork-Eschenmoser Postulate
-Trans olefins lead to trans ring fusions
-Cis olefins lead to cis ring fusions
Stork G.; Burgstahler, A. W., J. Am. Chem. Soc., 1955, 77, 5068.
Stadler, P. A.; Eschenmoser, A.; Schinz, H.; Stork, G., Helv. Chim. Acta, 1957, 40, 2191.

8. Farnesic Acid Cyclizations
Stork G.; Burgstahler, A. W., J. Am. Chem. Soc., 1955, 77, 5068.
Stadler, P. A.; Eschenmoser, A.; Schinz, H.; Stork, G., Helv. Chim. Acta, 1957, 40, 2191.

9. Farnesylacetic Acid and Monocyclofarnesylacetic Acid Cyclizations
Stork G.; Burgstahler, A. W., J. Am. Chem. Soc., 1955, 77, 5068.

10. Annulation of Decadienyl Nosylates
First supporting evidence for Stork-Eschenmoser postulate
Johnson, W. S.; Bailey, D. M.; Owyang, R.; Bell, R. A.; Jacques, B.; Crandall, J. K., J. Am. Chem. Soc., 1964, 86, 1959.

11. First Biomimetic Olefin Polycyclization in Steroid Synthesis
dl-16,17-dehydroprogesterone
Johnson, W. S.; Semmelhack, M. F.; Sultanbawa, M. U. S.; Dolak, L. A., J. Am. Chem. Soc., 1968, 90, 2994.

12. First Biomimetic Olefin Polycyclization in Steroid Synthesis
dl-16,17-dehydroprogesterone
W. S. Johnson, M. F. Semmelhack, M. U. S. Sultanbawa, L. A. Dolak, J. Am. Chem. Soc., 1968, 90, 2994.
W. S. Johnson, T. –t. Li, C. A. Harbert, W. R. Bartlett, T. R. Herrin, B. Staskun, D. H. Rich, J. Am. Chem. Soc., 1970, 92, 4461.

13. Aromatic Polyolefin Cyclization
Bartlett, P. A.; Johnson, W. S., J. Am. Chem. Soc., 1973, 95, 7501.

14. Acylimmonium Polycyclizations

15. Acylimmonium Polycyclizations
Dijkink, J.; Speckamp, W. N., Tet. Lett., 1977, 11, 935.

16. Acylimmonium Polycyclizations
Dijkink, J.; Speckamp, W. N., Tet. Lett., 1977, 11, 935.

17. Acylimmonium Polycyclizations Used in Azasteroid Synthesis
Romero, A. G.; Leiby; Mizsak, S. A., J. Org. Chem., 1996, 61, 6974.

18. Johnson Model for 2,3 Oxidosqualene Cyclases
Johnson, W. S.; Lindell, S. D.; Steele, J., J. Am. Chem. Soc., 1987, 109, 5852.

19. Cation-Stabilizing Auxiliaries

20. Cation Stabilizing Auxiliaries: Isobutenyl
Johnson, W. S.; Telfer, S. J.; Cheng, S.; Schubert, U., J. Am. Chem. Soc., 1987, 109, 2517.
Johnson, W. S.; Wiedhaup, K.; Brady, S. F.; Olson, G. L., J. Am. Chem. Soc., 1968, 90, 5277.

21. Cation-Stabilizing Auxiliaries: Fluoride
Johnson, W. S.; Chenera, B.; Tham, F. S.; Kullnig, R. K., J. Am. Chem. Soc., 1993, 115, 493.

22. Cation-Stabilizing Auxiliaries: Fluoride
Johnson, W. S.; Fletcher, V. R.; Chenera, B.; Bartlett, W. R.; Tham, F. S.; Kullnig, R. K., J. Am. Chem. Soc., 1993, 115, 497.

23. Defluoronation Using Ohsawa-Oishi Reagent
Johnson, W. S.; Fletcher, V. R.; Chenera, B.; Bartlett, W. R.; Tham, F. S.; Kullnig, R. K., J. Am. Chem. Soc., 1993, 115, 497.

24. Retrosynthesis of β-Amyrin
Johnson, W. S.; Plummer, M.S.; Reddy, S. P.; Bartlett, W. R., J. Am. Chem. Soc., 1993, 115, 515.

25. Synthesis of β-Amyrin
Johnson, W. S.; Plummer, M.S.; Reddy, S. P.; Bartlett, W. R., J. Am. Chem. Soc., 1993, 115, 515.

26. Cation Stabilizing Auxiliaries: β-Silyl
Burke, S. D.; Kort, M. E.; Strickland, S. M. S.; Organ, H. M., Silks, III, L. A., Tet. Lett., 1994, 10, 1503.

27. Cation Stabilizing Auxiliaries: β-Silyl
Burke, S. D.; Kort, M. E.; Strickland, S. M. S.; Organ, H. M., Silks, III, L. A., Tet. Lett., 1994, 10, 1503.

28. Concerted vs. Stepwise Cyclization
ΔHo = - 20 kcal/mol
ΔSo = - 21 eu (-6.25 kcal/mol at 298 K)
ΔGo = - 14 kcal/mol at 298 K
Bartlett, P. A., In Asymmetric Synthesis.; Morrison, J. D., Ed; Academic Press: New York, 1984, Vol. 3, pp

29. Concerted vs. Stepwise Cyclization
π-complex
Sutherland, J. K., In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;Permagon Press:
Oxford, 1991; Vol. 3, p.341.
Bartlett, P. A., In Asymmetric Synthesis.; Morrison, J. D., Ed; Academic Press: New York, 1984, Vol. 3, pp

30. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization
Enzymatic cyclization to the protolanolsterol cation has never been emulated
in a non-enzymatic system
-Chair-boat-chair transition state several kcal/mol less stable than all chair
conformation

31. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization
Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118,

32. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization
Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118,

33. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization
Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118,

34. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization
Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118,

35. Mimic of Sterol Folding in Onocerin Synthesis
Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124,

36. Mimic of Sterol Folding in Onocerin Synthesis
Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124,

37. Mimic of Sterol Folding in Onocerin Synthesis
Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124,

38. Nazarov-Initiated Polyannulation
4π conrotatory
electrocyclization

39. Nazarov-Initiated Polyannulation
Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G., J. Am. Chem. Soc., 1998, 63, 2430.

40. Nazarov-Initiated Polyannulation
Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G., J. Am. Chem. Soc., 1998, 63, 2430.

41. Nazarov-Initiated Polyannulation
Bender, J. A.; Arif, A. M.; West, F. G., J. Am. Chem. Soc., 1999, 121, 7443.

42. Nazarov-Initiated Polyannulation
Bender, J. A.; Arif, A. M.; West, F. G., J. Am. Chem. Soc., 1999, 121, 7443.

43. Conclusions
- Cationic olefin polyannulations are efficient methods for the stereoselective generation of fused ring systems.
- Stork-Eschenmoser postulate is valid for most systems.

44. Conclusions
- Cation-stabilizing auxiliaries can enhance cyclization yields.
- Cyclizations can be initiated by a number of different transient cations.
- Cationic olefin polyannulations can be stepwise and concerted, although concerted pathway is
not plausible past second ring formation.

45. Acknowledgements
Dr. Jeff Johnson
Johnson Group
UNC-CH