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

2. 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. 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. 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. 5 Total and Formal Syntheses 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 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

6. 6 Total and Formal Syntheses 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 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

7. 7 Snider Retrosynthesis 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 A  AB  ABC approach 17 linear steps 2.6% overall yield

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

9. 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. 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. 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. 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. 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. 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. 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. 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. 17 Sorenson’s 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 A + C  AC  ABC approach

18. 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. 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. 20 Favouring Cyclobutane Cleavage Crimmins, M.T.; Mascarella, S.W. Tet. Lett. 1987, 28, 5063

21. 21 SmI 2 -Promoted Radical Ring Opening Motherwell, W.B.; Batey, R.A. Tetrahedron Letters, 1991, 32, 6649

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

23. 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. 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. 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. 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. 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. 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. 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. 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. 31 Proposed Mechanism Sorenson, E.J.; Shipe, W.D. J. Am. Chem. Soc. 2006, 128, 7025

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

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

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

35. 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. 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. 37 Comparison of Key Steps

38. 38 Acknowledgements 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

39. 39

40. 40 Investigation Non-Cyclizing Reduction  Increased dilution favours cyclization – suggests intermolecular pathway  THF-d 8 – no deuterium incorporation, no change in ratio of products  workup with D 2 O – 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

41. 41 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

42. 42 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

43. 43 Proposed Oxidation 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 Expected result: Solvolysis gives retention Thermolysis gives inversion

44. 44 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

45. 45 Torsional Steering Houk, K.N.; Danishefsky, S.J.; Cheong, P.H.; Yun, H. Org. Lett. 2006, 8, 1513

46. 46 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

47. 47 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

48. 48 Competing Heterolytic Cleavage Danishefsky, S.J.; Mandal, M.; Yun, H.; Dudley, G.B.; Lin, S.; Tan, D.S. J. Org. Chem. 2005, 70, 10619

49. 49 SmI 2 -Promoted Regioselective Radical Ring-Opening Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963

50. 50 SmI 2 -Promoted Regioselective Radical Ring-Opening Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa, H. Tet. Lett. 2003, 44, 1963