1. A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005

2. Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

3. Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

4. Cyclopropane Strain and Reactivity  Cyclopropane has significant ring strain.  Cyclopropanes have pi character.

5. Alkenes and Cyclopropanes  “Virtually every reaction that an alkene undergoes has its counterpart in the repertoire of transformations possible with cyclopropanes.” Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 901.

6. Alkenes and Cyclopropanes  Carreira’s approach to spirotryprostatin B  Cossy’s approach to zincophorin Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, ASAP. Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem. Int. Ed. 2002, 41, 2144.

7. Alkenes and Cyclopropanes

8. Oxocarbenium-Based Heterocycle Syntheses

9. Zimmerman-Traxler Cyclization

10. The Kulinkovich Cyclopropanation Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.

11. Cyclopropanation Yields Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337-1339.

12. Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

13. Initial Attempts at Oxepane Formation

14. Softer Lewis acids (CuSO 4, ZnCl 2, SnCl 2 ) stop at acetal

15. Mechanism of Oxepane Formation

17. Stereochemistry of Oxepane Formation

18. Zimmerman-Traxler Cyclization

19. Initial Limitations of Oxepane Formation

20. Two-Lewis Acid System No problems associated with coexistence of two Lewis acids

21. Yields and Scope of Oxepane Formation O'Neil, K. E.; Kingree, S. V.; Minbiole, K. P. C. Org. Lett. 2005, 7, 515-517.

22. Appearance of Trans Oxepane

23. Inclusion of Sidechain Functionality

24. Certain chelating groups are tolerated…

25. Inclusion of Sidechain Functionality Certain chelating groups are tolerated… but others fail to rearrange to oxepane

26. Reaction Optimization  Alternate Lewis acids Zirconium tetrachloride  Alternate drying agents Molecular sieves  Alternate solvent systems More or less polar solvents

27. Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

28. Nitrogen Analogs: Azepines  Analogous reaction in nitrogenous heterocycles?

29. Nature of Protecting Group on Nitrogen

30. Assembly of Azepine Precursor

31. Cyclization attempts

32. Cyclization Attempts with Free Amine Amino alcohol not yet isolated

33. Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

34. Radical Cyclization

35. Heterolysis is known for cyclopropanols with mild single electron oxidants (e.g., Mn 3+ and Fe 3+ ).

36. Radical Cyclization Utilizing Azide Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116, 5521-5522.

37. Radical Cyclization Towards Heterocycles

38. Radical Cyclization Towards Functionalized Heterocycle

39. Progress Towards Piperidine

40. Recourse for Piperidine

41. Towards the Pyrrolidine Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 6029-6032.

42. Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

43. Alternative Ring Size

44. Sites of Functionalization on Oxepane Ring

45. Cyclopropane Functionalization via Cyclopropene Doyle, M. P.; Protopopova, M.; Müller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, 8492. Müller, P.; Granicher, C. Helv. Chim. Acta 1995, 78, 129. Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719.

46. Natural Product Total Synthesis

47. Conclusions  Cyclopropanes can be utilized as homo-alkenes to prepare heterocycles  A facile two-step procedure has been developed to prepare oxepanes with excellent stereoselectivity  Further substitution and alternate heterocycles are being explored  Radical cyclization promises another method to deliver heterocycles from cyclopropanols

48. Epilogue on Undergraduate Teaching and Research  Quality of Life  Opportunities for Funding  Satisfaction Direction of research Students

49. The Group Kerry O’Neil, JMU ’05Seth Kingree, JMU ’06Cambria Baylor, JMU ’06 Andrew Blanchard, JMU ’07Steve Andrews, JMU ’07Erik Stang, JMU ’06

50. Where’s James Madison University?

51. Funding

52. Acknowledgements  NMR: Tom Gallaher and Jeff Molloy  Nebraska Center for Mass Spectrometry  Drs. Kevin Caran and Scott Lewis  James Madison University

54. Future Direction: Cyclopropane Functionalization

55. Other Backups: Discrete Homoenolate

56. Other Backups: Radical

57. Aza Cope Possibility

58. Modified Point of Attachment

59. Precedent For Acyliminium Formation  Hsung Precedent