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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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Cationic Olefin Polyannulations: History and Application to Steroid and Other Fused Polycycle Syntheses

David A. Nicewicz

acid catalyzed cyclization of 1 5 dienes
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.

stork eschenmoser postulate
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.

farnesic acid cyclizations
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.

farnesylacetic acid and monocyclofarnesylacetic acid cyclizations
Farnesylacetic Acid and Monocyclofarnesylacetic Acid Cyclizations

Stork G.; Burgstahler, A. W., J. Am. Chem. Soc., 1955, 77, 5068.

annulation of decadienyl nosylates
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.

first biomimetic olefin polycyclization in steroid synthesis
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.

first biomimetic olefin polycyclization in steroid synthesis1
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.

aromatic polyolefin cyclization
Aromatic Polyolefin Cyclization

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

acylimmonium polycyclizations1
Acylimmonium Polycyclizations

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

acylimmonium polycyclizations2
Acylimmonium Polycyclizations

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

acylimmonium polycyclizations used in azasteroid synthesis
Acylimmonium Polycyclizations Used in Azasteroid Synthesis

Romero, A. G.; Leiby; Mizsak, S. A., J. Org. Chem., 1996, 61, 6974.

johnson model for 2 3 oxidosqualene cyclases
Johnson Model for 2,3 Oxidosqualene Cyclases

Johnson, W. S.; Lindell, S. D.; Steele, J., J. Am. Chem. Soc., 1987, 109, 5852.

cation stabilizing auxiliaries isobutenyl
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.

cation stabilizing auxiliaries fluoride
Cation-Stabilizing Auxiliaries: Fluoride

Johnson, W. S.; Chenera, B.; Tham, F. S.; Kullnig, R. K., J. Am. Chem. Soc., 1993, 115, 493.

cation stabilizing auxiliaries fluoride1
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.

defluoronation using ohsawa oishi reagent
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.

retrosynthesis of amyrin
Retrosynthesis of β-Amyrin

Johnson, W. S.; Plummer, M.S.; Reddy, S. P.; Bartlett, W. R., J. Am. Chem. Soc., 1993, 115, 515.

synthesis of amyrin
Synthesis of β-Amyrin

Johnson, W. S.; Plummer, M.S.; Reddy, S. P.; Bartlett, W. R., J. Am. Chem. Soc., 1993, 115, 515.

cation stabilizing auxiliaries silyl
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.

cation stabilizing auxiliaries silyl1
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.

concerted vs stepwise cyclization
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.

concerted vs stepwise cyclization1
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.

mimic of chair boat chair oxidosqualene enzymatic cyclization
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
mimic of chair boat chair oxidosqualene enzymatic cyclization1
Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization

Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

mimic of chair boat chair oxidosqualene enzymatic cyclization2
Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization

Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

mimic of chair boat chair oxidosqualene enzymatic cyclization3
Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization

Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

mimic of chair boat chair oxidosqualene enzymatic cyclization4
Mimic of Chair-Boat-Chair Oxidosqualene Enzymatic Cyclization

Wood, Jr., H. B.; Corey, E. J., J. Am. Chem. Soc., 1996, 118, 11982.

mimic of sterol folding in onocerin synthesis
Mimic of Sterol Folding in Onocerin Synthesis

Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124, 11290.

mimic of sterol folding in onocerin synthesis1
Mimic of Sterol Folding in Onocerin Synthesis

Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124, 11290.

mimic of sterol folding in onocerin synthesis2
Mimic of Sterol Folding in Onocerin Synthesis

Yuan, M.; Schreiber, J. V.; Corey, E. J., J. Am. Chem. Soc., 2002, 124, 11290.

nazarov initiated polyannulation
Nazarov-Initiated Polyannulation

4π conrotatory

electrocyclization

nazarov initiated polyannulation1
Nazarov-Initiated Polyannulation

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

nazarov initiated polyannulation2
Nazarov-Initiated Polyannulation

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

nazarov initiated polyannulation3
Nazarov-Initiated Polyannulation

Bender, J. A.; Arif, A. M.; West, F. G., J. Am. Chem. Soc., 1999, 121, 7443.

nazarov initiated polyannulation4
Nazarov-Initiated Polyannulation

Bender, J. A.; Arif, A. M.; West, F. G., J. Am. Chem. Soc., 1999, 121, 7443.

conclusions
Conclusions

- Cationic olefin polyannulations are efficient methods for the stereoselective generation of fused ring systems.

- Stork-Eschenmoser postulate is valid for most systems.

conclusions1
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.

acknowledgements
Acknowledgements
  • Dr. Jeff Johnson
  • Johnson Group
  • UNC-CH