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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
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
Part 1: Background One-Pot, Four-Component n+4 Annulations Posner, G.H.  et. al.   J. Am. Chem. Soc.   1988 ,  110 , 4754.
Background Tin Mediated n+3 Ring Expansions Posner, G.H.  et. al.   Tetrahedron Lett.   2000 ,  41 , 9655. ,[object Object],[object Object],[object Object]
Medium Sized Natural Products
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.
Hemiketal X-Ray Structure
Background: Oxidative Cleavage (1) Suárez, E.;  et. al. Tetrahedron Lett .  1986 ,  27 , 383.  (2) Yamamoto, H.;  et. al. J. Org. Chem .  1990 ,  55 , 5814.
Lactone X-Ray Structure
Mechanistic Explanation Lusztyk, J.  et. al.  Tetrahedron Lett.   1994 ,  35 , 1003.
Proposed Mechanism Kochi, J.K.  et. al.   J. Am. Chem. Soc.   1972 ,  94 , 8065.
Ring Expansions of Cyclohexenone  ,[object Object],[object Object]
Ring Expansions of Cycloalkenones
Tin vs. Silicon Methodology ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
HMPA-Free n+3 Ring Expansions ,[object Object],[object Object],[object Object],[object Object],Fleming, I.  et. al . J. Chem. Soc. Perkin Trans. 1. 1981, 2520.
Introduction: n+3+p Expansions
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.
n+3+p Translactonization Results Posner, G.H.; Hatcher, M.; Maio, W.M.  Org.  Lett. ,  2005 , 7, 4301.
Alkyl-Assisted n+3+p Reactions Posner, G.H.; Hatcher, M.; Maio, W.M.  Org.  Lett. ,  2005 , 7, 4301.
Alkyl-Assisted n+3+p Reactions Posner, G.H.; Hatcher, M.; Maio, W.M.  Org.  Lett. ,  2005 , 7, 4301.
Benzyl-Ether Translactonization ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Posner, G.H.; Hatcher, M.; Maio, W.M.  Org.  Lett. ,  2005 , 7, 4301.
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.
n+3+p  Lactam ization Results
Introduction: Ring Contractions (1)  Holmes, A.B.;  et. al.   Tetrahedron Lett .  2000 ,  41 , 117.  (2)  Suárez, E.;  et. al. Tetrahedron Lett .  1986 ,  27 , 383.
Formation of Iodolactones Maio, W.A.; Sinishtaj, S.; Posner, G.H.  Org.  Lett. ,  2007 , 9, 2673.
Lactone - Lactam Ring Contraction Maio, W.A.; Sinishtaj, S.; Posner, G.H.  Org.  Lett. ,  2007 , 9, 2673.
Lactam X-Ray Structures Maio, W.A.; Sinishtaj, S.; Posner, G.H.  Org.  Lett. ,  2007 , 9, 2673.
Sedum Alkaloids ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Bates, R.W.  et. al. Tetrahedron   2002 ,  58 , 5957.
Lactam to Piperidine Reduction Maio, W.A.; Sinishtaj, S.; Posner, G.H.  Org.  Lett. ,  2007 , 9, 2673.
 -Lactam Formation Maio, W.A.; Sinishtaj, S.; Posner, G.H.  Org.  Lett. ,  2007 , 9, 2673.
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
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.
Distribution of Malaria as of 2006 World Health Organization (WHO) Website
Antimalarial Chemotherapeutics
Pitfall of Semi-Synthetic Drugs Posner, G.H.  et. al. J. Med. Chem .  2003 ,  46 , 1060.
Synthesis of Fluoroartemisinin Posner, G.H.; Maio, W.A.; Kalinda, A.S.  Biorg.  Med. Chem.  2008 , 16 , 5247 .
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 .
Bonnet-Delpon Trifluoromethyl  Bonnet-Delpon, D.;  et al. Chem MedChem.  2007 , 2 , 608 .
Synthesis of Fluoroartesunate and Biological   Data Posner, G.H.; Maio, W.A.; Kalinda, A.S.  Biorg.  Med. Chem.  2008 , 16 , 5247 .
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
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

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Thesis Defense, 2008

  • 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.
  • 4.
  • 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.
  • 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.
  • 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.
  • 12.
  • 13. Ring Expansions of Cycloalkenones
  • 14.
  • 15.
  • 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.
  • 21.
  • 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.
  • 28.
  • 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
  • 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