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Bergman Cycloaromatization

Bergman Cycloaromatization. ∆. 2 [H ]. Whitney M. Erwin February 21, 2002. Outline. Background Reaction Control - Substituent Effects - Variations - Use of metals - Triggers Applications - Synthesis - Materials Science - Biology IV. Summary. Robert G. Bergman.

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Bergman Cycloaromatization

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  1. Bergman Cycloaromatization ∆ 2 [H ] Whitney M. Erwin February 21, 2002

  2. Outline • Background • Reaction Control - Substituent Effects - Variations - Use of metals - Triggers • Applications - Synthesis - Materials Science - Biology IV. Summary

  3. Robert G. Bergman • 1963 – B.S. Carleton College • 1966 – Ph.D. University of Wisconsin • 1966 - Postdoc Colombia University • 1968 - California Institute of Technology • 1977 - University of California - Berkeley

  4. Bergman Cycloaromatization 200 ºC 0.01 M 2 [H ] t1/2 = 30 s 100% 2,6,10,14-tetramethylpentadecane as solvent Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc., 1972, 94, 660. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.

  5. Alkyne Termini Separation A d B C Critical d range for spontaneous cyclization at rt = 3.4 – 2.9 Å Schreiner, P. R. Chem. Commun. 1998, 4, 483. Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184. Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866.

  6. + 2 Calculated Values Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184.

  7. Outline • Background • Reaction Control - Substituent Effects - Variations - Use of metals - Triggers • Applications - Synthesis - Materials Science - Biology IV. Summary

  8. Alkynyl Substituent Effects Monosubstituted • Strong σ–acceptors and /or π-donors lower the cyclization barrier • Ex. –F, -OH, -NH3+, -OH2+ • π-Withdrawing groups raise the cyclization barrier • Ex. -BH2, -AlH2 ∆G (kcal/mol) ∆G (kcal/mol) R = R = H H Br Disubstituted Cl Cl NO2 • Barriers depend on steric hindrance to substituents in the TSs • Planar systems follow same pattern as above Br OH NO2 NH3+ OH Reaction coordinate Reaction coordinate F F OH2+ OH2+ Prall; M.; Wittikopp, A.; Fokin, A. A.; Schreiner, P. R. J. Comp. Chem. 2001, 22, 1605.

  9. Vinylic Substituent Effects • Electron-withdrawing groups increase the cyclization barrier. • Ex. –Cl, -NO2 • σ-Donating groups decrease the cyclization barrier. • Ex. -CH3, -(CH2)3 • π-Conjugation has little effect. • Most annulations slightly raise or lower the cyclization barrier. Jones, G. B.; Warner, P. M. J. Am. Chem. Soc. 2001, 123, 2134-2145.

  10. Effect of Ring Size and Electronics 9-membered 10-membered 11-membered 10-membered dichloro t1/2 = 8h/0°C t1/2 = 60h/40°C 18h/50°C 5h/80°C t1/2 = 2h/170°C t1/2 = 24h/170°C Jones, G. B.; Plourde II, G. W. Org. Lett. 2000, 2, 1757.

  11. Benzannelation Alters the kinetically important step in the cyclization of strained cyclic enediynes. H-donor Rate-limiting Retro-cyclization barrier = 15.3 kcal/mol H abstraction barrier = 12.7 kcal/mol H-donor Rate-limiting Retro-cyclization barrier = 5.9 kcal/mol H abstraction barrier = 11.8 kcal/mol Kaneko, T.; Takahashi, M.; Hirama, M. Tet. Lett. 1999, 40, 2015. Koseki, S.; Fujimura, Y.; Hirama, M. J. Phys. Chem. A1999, 103, 7672.

  12. Aza- and Protonated Aza-Bergmans Reaction coordinate Cramer, C. J. J. Am. Chem. Soc.1998, 120, 6261.

  13. Donors ∆ RH CCl4 CH3OH Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.

  14. Mg2+-induced Cyclization MeOH, MgCl2 0°C, 8h 70% MeOH NaBH4, 5-10°C rt DMF, EDTA, CH2Cl2 40% Rawat, D. S.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 9675.

  15. Metal Coordination 194°C 116°C 152°C Benites, P. J.; Rawat, D. S.; Zaleski, J. M. J. Am. Chem. Soc. 2000, 122, 7208.

  16. CpRu as Accelerator / Inhibitor Accelerator THF, rt 0% THF, 5h, rt 71% Inhibitor 15% hν, CH3CN 0% hν, CD2Cl2 Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil, T. L. J. Am. Chem. Soc. 1996, 118, 3291. O’Connor, J. M.; Lee, L. I.; Gantzel, P. J. Am. Chem. Soc.2000, 122, 12057.

  17. Redox Control t½ = 15 h, 84°C t½ > 24 h, 120°C 82% Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038.

  18. Tautomeric Trigger Lumazine Oxo tautomer Hydroxy tautomer DMSO 165°C DMSO 165°C t1/2 = 6.1 min. t1/2 = 10.1 min. 37% 0% Choy, N.; Russell, K. C. Heterocycles1999, 51, 13.

  19. “Photo-Bergman” hν A-3 (cis) + + i-PrOH A-1 A A-2 A-3 (trans) hν i-PrOH B-1 B Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.

  20. “Photo-Bergman” hν A-3 (cis) + + i-PrOH A-1 A A-2 2 Product ratio 2 : 4 : 1 Mechanism: A-3 (trans) hν A 1[A] A-1 ISC [A] 3[A] A-2 + A-3 Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.

  21. “Photo-Bergman” hν i-PrOH B B-1 Mechanism: hν B 1[B] B-1 ISC [B] 3[B] Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.

  22. Other Triggering Methods • Release of ring strain • Acid and base-induction • Enzymatic protecting group cleavage Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866-4868. Nicolaou, K. C.; Dai, W.-M. Angew. Chem. Int. Ed. Engl. 1991, 30, 1387-1530. 16. Hay, M. P.; Wilson, W. R.; Denny, W. A. Bioorg. Med. Chem. Lett. 1999, 9, 3417-3422.

  23. Outline • Background • Reaction Control - Substituent Effects - Variations - Use of metals - Triggers • Applications - Synthesis - Materials Science - Biology IV. Summary

  24. Tandem Ring Annulation PhCl, 210°C 19-24 h n=1 72% n=2 53% If n = 1 and R = -CH2OTBS, yield = 58% 42% Grissom, J. W.; Calkins, T. L. Tet. Lett. 1992, 33, 2315.

  25. Double Aromatization 170-190°C < 0.005M 10% Bharucha, K. N.; Marsh, R. M.; Minto, R. E.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 3120.

  26. Radical Cascade Path A H H Path B Bu3SnH / AIBN PhH, 80°C 36% Chow, S.-Y.; Palmer, G. J.; Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 961. Bowles, D. M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony, J. E. Tetrahedron 2001, 57, 3753.

  27. Picenoporphyrins Aihara, H.; Jaquinod, L.; Nurco, D. J.; Smith, K. M. Angew. Chem. Int. Ed. 2001, 40, 3439.

  28. Morphine Synthesis • Consumption of morphine in the U.S. is approaching 100 metric tons annually. • Produced by commercial processing of raw opium from Papaver somniferium • Most efficient synthesis by Rice and coworkers gives 29% yield. • Skeleton of morphine can be used to make other related molecules such as codeine Morphine Codeine Heroin Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis1998, Sup. 1, 665.

  29. Morphine Route ∆ [O] H+ < 225°C Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis1998, Sup. 1, 665.

  30. Diasteroselective Radical Combination PhCl 230°C 55% Xu, J.; Egger, A.; Bernet, B.; Vasella, A. Helv. Chim. Acta1996, 79, 2004. Vasella, A. Pure Appl. Chem. 1998, 70, 425.

  31. Fullerenes from Cyclic Polyynes Retro [2+2] Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.

  32. Fullerenes from Cyclic Polyynes n = 48 C60 fullerene n = # of carbons in polyyne chain n-1 n = 58 C70 fullerene n n = 60 C76 fullerene n-5 n = 62 C78 fullerene Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.

  33. Fullerenes from Cyclic Polyynes Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.

  34. Thin-film Lithography Conventional Lithographic Process SMIP Process Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson; C. Macromolecules 2001, 34, 4104.

  35. 3,4-Bis(phenylethynyl)styrene Polymerization n n initiator 50°C 250°C m = 7-8 Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson; C. Macromolecules 2001, 34, 4104.

  36. Enediyne Antibiotics Esperimicin A1 Calicheamicin gI1 Dynemicin A Neocarzinostatin chromophore

  37. Calicheamicin Bound to DNA http://www.scripps.edu/chem/nicolaou/respages/bio20b.htm

  38. Calicheamicin γ1I Triggering device – initiates cyclization when the molecule reaches the target “Warhead” – enediyne capable of forming damaging 1,4-diradical Delivery system – targets molecule to DNA Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464. Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3466.

  39. Calicheamicin Mechanism d = 3.16Å d = 3.35Å t1/2 at 37°C = 4.5 ± 1.5 s DNA cleavage Nicolaou, K. C.; Dai, W.-M. Angew. Chem. Int. Ed. Eng. 1991, 30, 1387. Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866.

  40. DNA Cleavage [Ar ] 1. O2 2. [H ] ArH Red. De Voss, J. J.; Townsend, C. A.; Ding, W.-D.; Morton, G. O.; Ellestad, G. A.; Zein, N.; Tabor, A. B.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 9669.

  41. Mylotarg™ Gemtuzumab ozogamicin Recombinant antibody conjugated with Calicheamicin antibody - a protein molecule produced by vertebrates that binds with high specificity to a "foreign" entity (antigen) that has entered the system by one means or another http://www.fda.gov/cder/foi/label/2000/21174lbl.pdf

  42. Catalytic Antibody catalytic antibody (“abzyme”)- an antibody capable of catalyzing specific chemical reactions Process of generating a catalytic antibody • Design and synthesize a molecule whose charge and shape closely resemble those of the transition state of the reaction to be catalyzed. • Attach the molecule to a larger molecule and provoke an immune response to the complex in a living system. • Isolate the resultant antibodies for catalytic activity of the type desired.

  43. Antibody Catalysis Transition-state hapten analog 2 H O2 Jones, L. H.; Harwig, C. W.; Wentworth, Jr., P.; Simeonov, A.; Wentworth, A. D.; Py, S.; Ashley, J. A.; Lerner, R. A.; Janda, K. D. J. Am. Chem. Soc. 2001, 123, 3607.

  44. Targeted Protein Degradation = a member of a library of estrogenic probes Receptor cleavage Receptor recognition element Target receptor Jones, G. B.; Wright, J. M.; Hynd, G.; Wyatt, J. K.; Yancisin, M.; Brown, M. A. Org. Lett. 2000, 2, 1863.

  45. Summary • Bergman cycloaromatization can be tuned by: • Sterics • Electronics • Metals • Triggering devices (eg. tautomerization, release of ring strain) • Varied applications • Formation of polycyclic systems • Biological (eg. antibiotics, protein degradation) • Materials Science

  46. Acknowledgements Professor Charles T. Lauhon Konstantin Levitsky Jen Slaughter Jason Pontrello Lisa Jungbauer Margaret Biddle Wendy Deprophetis John Herbert Susie Martins Scott Petersen

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