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[2+2] Photocycloaddition/ Fragmentation in the Synthesis of Guanacastepenes A and E

[2+2] Photocycloaddition/ Fragmentation in the Synthesis of Guanacastepenes A and E. Jennifer Chaytor November 2, 2006 University of Ottawa. Guanacastepene A. Isolated in 2000 Produced by the endophytic fungus CR115

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[2+2] Photocycloaddition/ Fragmentation in the Synthesis of Guanacastepenes A and E

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  1. [2+2] Photocycloaddition/Fragmentation in the Synthesis of Guanacastepenes A and E Jennifer Chaytor November 2, 2006 University of Ottawa

  2. Guanacastepene A • Isolated in 2000 • Produced by the endophytic fungus CR115 • Fungus isolated from the branch of a Daphnopsis americana tree from the Guanacaste Conservation Area in Costa Rica • Structure determined by NMR and X-ray crystallography • Mixture of two slowly interconverting conformers Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116 Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900

  3. Five Guanacastepene Ring Systems • CR115 produces a family of related but structurally diverse metabolites • 15 different guanacastepenes comprise five ring systems • All contain the 5-7-6 tricyclic guanacastepene skeleton Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116 Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900

  4. Potential New Antibiotics? • Guanacastepene A showed antibiotic activity against drug-resistant strains of Staphylococcus aureus and Enterococcus faecalis • Guanacastepene I showed antibacterial activity towards S. aureus • C-15 aldehyde or masked aldehyde appears to be necessary for activity • Guanacastepene A also displays nonselective hemolytic activity against human blood cells • Suggests nonspecific membrane lysis is the mode of action Clardy, J.; Brady, S.F.; Singh, M.P.; Janso, J.E. J. Am. Chem. Soc. 2000, 122, 2116 Clardy, J.; Brady, S.F.; Bondi, S.M. J. Am. Chem. Soc. 2001, 123, 9900 Clardy, J.; Singh, M.P.; Janso, J.E.; Luckman, S.W.; Brady, S.F.; Greenstein, M.; Maiese, W.M. J. Antibiot. 2002, 53, 256

  5. Total and Formal Syntheses Hanna et al., Org. Lett. 2004, 6, 1817 Mehta et al., Chem. Comm. 2005, 4456 Sorenson et al., J. Am. Chem. Soc. 2006, 128, 7025 Overman et al., J. Am. Chem. Soc. 2006, ASAP Danishefsky et. al, Angew. Chem. Int. Ed. 2002, 41, 2185 Danishefsky et al., Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefksy et al., J. Org. Chem. 2005, 70, 10619 Snider et al., J. Org. Chem. 2003, 68, 1030

  6. Total and Formal Syntheses Hanna et al., Org. Lett. 2004, 6, 1817 Mehta et al., Chem. Comm. 2005, 4456 Sorenson et al., J. Am. Chem. Soc. 2006, 128, 7025 Overman et al., J. Am. Chem. Soc. 2006, ASAP Danishefsky et. al, Angew. Chem. Int. Ed. 2002, 41, 2185 Danishefsky et al., Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefksy et al., J. Org. Chem. 2005, 70, 10619 Snider et al., J. Org. Chem. 2003, 68, 1030

  7. Snider Retrosynthesis A  AB  ABC approach 17 linear steps 2.6% overall yield Snider, B.B.; Hawryluk, N.A. Org. Lett. 2001, 3, 569 Snider, B.B.; Shi, B. Tet. Lett. 2001, 42, 9123 Snider, B.B.; Hawryluk, N.A.; Shi, B. J. Org. Chem. 2003, 68, 1030

  8. Hanna Retrosynthesis A  ABC approach 17 linear steps <1.8% overall yield Hanna, I.; Boyer, F-D.; Ricard, L. Org. Lett. 2004, 6, 1817

  9. Danishefsky’s Approach A  AB  ABC approach Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399 Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  10. Synthesis of Hydroazulene Core Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399 Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  11. Successive Dialkylation Strategy Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  12. Hydroboration and Oxidations Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  13. Epoxide-Opening β-Elimination/Knoevenagel Cyclization Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  14. Final Steps to Guanacastepene A Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  15. Final Steps to Guanacastepene A Danishefsky, S.J.; Tan, D.S.; Dudley, G.B. Angew. Chem. Int. Ed.2002, 41, 2185 Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  16. Danishefsky’s Total Synthesis: Summary • 17 steps to key intermediate (5.3% overall yield) • 20 steps to Guanacastepene A (3.0% overall yield) • Key step: tandem epoxide-opening β-elimination/Knoevenagel cyclization

  17. Sorenson’s Approach A + C  AC  ABC approach Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  18. Reductive Opening of Cyclopropyl Ketones Shoulders, B.A.; Kwie, W.W.; Klyne, W.; Gardner, P.D. Tetrahedron, 1965, 21, 2973 Dauben, W.G.; Deviny, E.J. J. Am. Chem. Soc. 1966, 31, 3794

  19. Reductive Opening of Cyclopropyl Ketones Breakage of 1,6 bond: -more stable 2º carbanion Breakage of 1,7 bond: -Less stable 3º carbanion -Overlap with π system Dauben, W.G.; Deviny, E.J. J. Am. Chem. Soc. 1966, 31, 3794

  20. Favouring Cyclobutane Cleavage Crimmins, M.T.; Mascarella, S.W. Tet. Lett. 1987, 28, 5063

  21. SmI2-Promoted Radical Ring Opening Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649

  22. Trapping of Samarium Enolates with Electrophiles Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649

  23. Synthesis of Ring A Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  24. Synthesis of Stille Coupling Partner (Ring A) Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  25. Synthesis of Ring C Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  26. Synthesis of Ring C Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  27. Resolution of C-Ring Fragment Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  28. Stille Cross-Coupling Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025 Corey, E.J.; Han, X.; Stoltz, B.M. J. Am. Chem. Soc. 1991, 121, 7600

  29. Proposed Catalytic Cycle for CuCl-Accelerated Stille Coupling Corey, E.J.; Han, X.; Stoltz, B.M. J. Am. Chem. Soc. 1991, 121, 7600

  30. Formation of Ring B Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  31. Proposed Mechanism Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  32. Confirmation of Stereochemistry Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  33. Synthesis of Guanacastepene E Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  34. Synthesis of Guanacastepene E Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  35. Completion of Formal Synthesis of Guanacastepene A Sorenson, E.J.; Shipe, W.D. Org. Lett. 2002, 4, 2063 Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

  36. Sorenson’s Formal Synthesis: Summary • 1.2% overall yield of Guanacastepene E • 1.2% overall yield of Danishefsky’s key intermediate to Guanacastepene A • 24 steps (longest linear sequence is 17 steps) • Key steps: π-allyl Stille cross-coupling followed by a [2+2] photocycloaddition/reductive fragmentation

  37. Comparison of Key Steps

  38. Dr. Robert Ben Nick Afagh Paul Czechura Rachelle Denis Elena Dimitrijevic Hasan Khan Caroline Proulx Tahir Rana Roger Tam John Trant Elisabeth von Moos Former Ben Lab members Acknowledgements

  39. Investigation Non-Cyclizing Reduction • Increased dilution favours cyclization – suggests intermolecular pathway • THF-d8 – no deuterium incorporation, no change in ratio of products • workup with D2O – no exchange of I for D  no remaining vinyllithium • Is enolizable cyclopentanone serving as a proton source? Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399 Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  40. Isotope Labelling • Using dideutero-cyclopropanone increased the ratio from 78:22 to 91:9 Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399 Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  41. Investigation Mechanism and Proton Source • Two proton sources: 1) enolizable cyclopentanone, 2) iodobutane via E2 elimination Danishefsky, S.J.; Dudley, G.B. Org. Lett. 2001, 3, 2399 Danishefsky, S.J.; Mandal, M. Tet. Lett. 2004, 45, 3827 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  42. Proposed Oxidation Expected result: Solvolysis gives retention Thermolysis gives inversion Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  43. Studies on Oxidation • Solvolysis goes with retention • Epoxidation must occur from β-face Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  44. Torsional Steering Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513

  45. Stereoselective Epoxidation Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619 Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513

  46. Studies on Oxidation • Thermolysis lacks stereoselectivity • Why? Danishefsky, S.J.; Lin, S.; Dudley, G.B.; Tan, D.S. Angew. Chem. Int. Ed. 2002, 41, 2188 Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  47. Competing Heterolytic Cleavage Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

  48. SmI2-Promoted Regioselective Radical Ring-Opening Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963

  49. SmI2-Promoted Regioselective Radical Ring-Opening Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963

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