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David A. Nicewicz

Cationic Olefin Polyannulations: History and Application to Steroid and Other Fused Polycycle Syntheses. David A. Nicewicz. Squalene Enzymatic Cyclizations. Oxidosqualene Enzymatic Cyclizations. Mechanism for Squalene Enzymatic Cyclization. Mechanism for Oxidosqualene Enzymatic Cyclization.

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David A. Nicewicz

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  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. 341-409.

  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. 341-409.

  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, 11982.

  32. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

  33. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

  34. Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

  35. Mimic of Sterol Folding in Onocerin Synthesis Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124, 11290.

  36. Mimic of Sterol Folding in Onocerin Synthesis Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124, 11290.

  37. Mimic of Sterol Folding in Onocerin Synthesis Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124, 11290.

  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

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