This is a copy of my thesis defense from 2008. I received my PhD in organic chemistry under the direction of Professor Gary H. Posner.

1. Inventing New Synthetic Ring Enlargement Methods and Exploring the Use of Novel Trioxanes for the Treatment of Malaria William Maio The Johns Hopkins University Advisor: Professor Gary H. Posner

2. Outline: Part I: Inventing New Synthetic Methodology -Background -Tin-mediated n+3 reactions -Silicon-mediated n+3 reactions -Ring Enlargements -Ring Contractions Part II: Exploring the Use of Trioxanes for the Treatment of Malaria -Background -Fluoroartemisinin and derivatives -Biological Data

3. Part 1: Background One-Pot, Four-Component n+4 Annulations Posner, G.H. et. al. J. Am. Chem. Soc. 1988 , 110 , 4754.

5. Medium Sized Natural Products

6. Background: Epoxide Opening Silicon Mediated n+3 Ring Expansions (1) Still, W.C. J. Org. Chem. 1976 , 41 , 3063. (2) Hatcher, M.; Borstnik, K.; Posner G.H. Tetrahedron Lett. 2003 , 44 , 5407.

7. Hemiketal X-Ray Structure

8. Background: Oxidative Cleavage (1) Suárez, E.; et. al. Tetrahedron Lett . 1986 , 27 , 383. (2) Yamamoto, H.; et. al. J. Org. Chem . 1990 , 55 , 5814.

9. Lactone X-Ray Structure

10. Mechanistic Explanation Lusztyk, J. et. al. Tetrahedron Lett. 1994 , 35 , 1003.

11. Proposed Mechanism Kochi, J.K. et. al. J. Am. Chem. Soc. 1972 , 94 , 8065.

13. Ring Expansions of Cycloalkenones

16. Introduction: n+3+p Expansions

17. Introduction: n+3+p Expansions (1) Holmes, A.B. et. al. J. Am. Chem. Soc . 1993 , 115 , 5815. (2) Holmes, A.B. et. al. J. Am. Chem. Soc . 2004 , 126 , 2194.

18. n+3+p Translactonization Results Posner, G.H.; Hatcher, M.; Maio, W.M. Org. Lett. , 2005 , 7, 4301.

19. Alkyl-Assisted n+3+p Reactions Posner, G.H.; Hatcher, M.; Maio, W.M. Org. Lett. , 2005 , 7, 4301.

20. Alkyl-Assisted n+3+p Reactions Posner, G.H.; Hatcher, M.; Maio, W.M. Org. Lett. , 2005 , 7, 4301.

22. Introduction: n+3+p Expansions (1) Holmes, A.B. et. al. Tetrahedron Lett . 2000 , 41 , 117. (2) Kume, M.; et. al . J. Org. Chem . 2002 , 67 , 9146.

23. n+3+p Lactam ization Results

24. Introduction: Ring Contractions (1) Holmes, A.B.; et. al. Tetrahedron Lett . 2000 , 41 , 117. (2) Suárez, E.; et. al. Tetrahedron Lett . 1986 , 27 , 383.

25. Formation of Iodolactones Maio, W.A.; Sinishtaj, S.; Posner, G.H. Org. Lett. , 2007 , 9, 2673.

26. Lactone - Lactam Ring Contraction Maio, W.A.; Sinishtaj, S.; Posner, G.H. Org. Lett. , 2007 , 9, 2673.

27. Lactam X-Ray Structures Maio, W.A.; Sinishtaj, S.; Posner, G.H. Org. Lett. , 2007 , 9, 2673.

29. Lactam to Piperidine Reduction Maio, W.A.; Sinishtaj, S.; Posner, G.H. Org. Lett. , 2007 , 9, 2673.

30.  -Lactam Formation Maio, W.A.; Sinishtaj, S.; Posner, G.H. Org. Lett. , 2007 , 9, 2673.

31. Part I: Conclusions Many new epoxide examples added synthetic value to the methodology Removal of HMPA allows for a more environmentally-friendly procedure Reduction/deprotection of the certain functionality on the side-chains of the lactones can lead to further ring enlarged systems Lactone to lactam ring contraction provides novel access to the sedum alkaloid family of natural products

32. Part II: Malaria Introduction One of the most deadly vector-born diseases known Complex lifecycle that involves two hosts: human and mosquito On average causes the deaths of about 2 million people each year Highest transmission is in tropical and subtropical areas Parasite resistance to current chemotherapies are emerging Mlambo, G. et. al. Am. J. Trop. Med. Hyg . 2008 , 78 , 114.

33. Distribution of Malaria as of 2006 World Health Organization (WHO) Website

34. Antimalarial Chemotherapeutics

35. Pitfall of Semi-Synthetic Drugs Posner, G.H. et. al. J. Med. Chem . 2003 , 46 , 1060.

36. Synthesis of Fluoroartemisinin Posner, G.H.; Maio, W.A.; Kalinda, A.S. Biorg. Med. Chem. 2008 , 16 , 5247 .

37. Competition Experiment 1 eq of DHA, 1 eq F-DHA, ½ eq MeOH, cat. TsOH After 30 min, all the MeOH was consumed and no F-Artemether had formed by NMR or by TLC Qualitatively speaking, the presence of the Fluorine atom Significantly retards the rate of acid-catalyzed etherification Relative to DHA Posner, G.H.; Maio, W.A.; Kalinda, A.S. Biorg. Med. Chem. 2008 , 16 , 5247 .

38. Bonnet-Delpon Trifluoromethyl Bonnet-Delpon, D.; et al. Chem MedChem. 2007 , 2 , 608 .

39. Synthesis of Fluoroartesunate and Biological Data Posner, G.H.; Maio, W.A.; Kalinda, A.S. Biorg. Med. Chem. 2008 , 16 , 5247 .

40. Part II. Conclusions The presence of a fluorine atom alpha to C10 significantly retards the acid- catalyzed hydrolysis of ether and ester derivatives The compounds were submitted for biological evaluation: unfortunately no new antimalarial was discovered This lack of antimalarial activity may be due to changes in lipophilicity, transport, and/or metabolism rather than to only the increased hydrolytic stability of these fluoro analogs

41. Acknowledgements Professors: Gary H. Posner Thomas Lectka John D. Tovar Lawrence Principe Tamara Hendrickson Craig Townsend Group Members: Dr. Mehmet Kharaman Dr. Mark A. Hatcher Dr. Sandra Sinishtaj Dr. Wonsuk Chang Dr. Jamie Singleton Alvin S. Kalinda Lectka Group Members: Dr. Ciby Abraham Data Analysis: Dr. Amy Sarjeant Dr. Phil Mortimer Dr. Charles Long Fordham Professors: Dr. James A. Ciaccio Dr. Moses Kalustian Family and Friends: Mom & Dad Grandma Rita Leah