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Design and Development of Safe and Selective Deoxofluorinating Reagents

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  1. Design and Development of Safe and Selective Deoxofluorinating Reagents Robyn Biggs February 17th, 2011 University of Ottawa

  2. 13 naturally occurring fluorinated organics • Majority are homologues of fluoroacetic acid

  3. 10% of launched drugs contain fluorine 5-Fluorouracil Diflucan (Fluconazole) Maraviroc Fluticasone propionate Lipitor

  4. Roles of Fluorine in Medicinal Chemistry Can improve: • Metabolic stability • Binding to target • Solubility Thrombin Inhibitor Burgey, C. S. et al. J. Med. Chem. 2003, 46, 461.

  5. Oxidation of C-H Bonds by CYP450s

  6. Mechanism of Oxidation by CYP450s Active Site

  7. Discourage oxidation by Addition of Electron Withdrawing Substituents C-H Bond Strength= 99 Kcal/mol C-F Bond Strength= 117 Kcal/mol

  8. Fluorine Substitution Exploited in Mechanism of Action of 5-Fluorouracil 5-Fluorouracil Inhibits DNA Replication

  9. Uracil Can Be Converted to ThymidineTriphoshpate For DNA Replication

  10. Mechanism of Action of 5-Fluorouracil • No dTMP formed • No TTP formed • DNA replication stopped

  11. Fluorinating Reagents Over Last 130 Years

  12. Reactions With Elemental Fluorine Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.

  13. Elemental Fluorine Can Be Very Dangerous • High reactivity and toxicity • Lack of selectivity

  14. Perchloryl Fluoride as Fluorinating Agent Gabbard, R. B.; Jensen, E. V. J. Org. Chem. 1958, 23, 1406.

  15. Perchloryl Fluoride Is Explosive Explosion University of Ottawa, 1982: Glinski, M. B.; Freed, J. C.; Durst, T. J. Org. Chem. 1987, 52, 2749.

  16. More Stable/Selective Alternatives F-F bond strength= 36.6 Kcal/mol O-F bond strength= 44 Kcal/mol

  17. O-F Reagents as Selective Fluorinating Agents Kirk, K. L. Org. Process Res. Dev.2008, 12, 305.

  18. Safety Still an Issue With O-F Reagents Reaction set-up: • 1985: • AcOF explosion ∨ ∨ Adam, M. J. Chem. Eng. News, 1985, 63, 2.

  19. Safer Alternatives to O-F Reagents O-F Bond Strength= 44 Kcal/mol N-F Bond Strength= 65 Kcal/mol NFSI Selectfluor

  20. N-F Reagents in Synthesis α:β 95:5 Differding, E.; Ofner, H. Synlett, 1991, 187. Lal, G. S. J. Org. Chem.1993, 58, 2791.

  21. Selectfluor Best Electrophilic Reagent • Easy to handle (solid) • Selective • Stable Radwan-Olszewska, K.; Palacios, F.; Kafarski, P. J. Org. Chem. 2011, 76, 1170.

  22. Selectively Replacing an Existing Functional Group with Fluorine Use nucleophilic reagent

  23. Fluorinating Reagents Over Last 130 Years

  24. SF4 Was First Nucleophilic Fluorinating Reagent Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am. Chem. Soc. 1960,82, 543.

  25. Mechanism of SF4 Reaction • HF generated in situ catalyzes the reaction

  26. Danger of Runaway Reaction Using SF4 Catalyzes reaction Rate increases with production

  27. Problems with SF4 • Gas • Highly toxic and corrosive • Typically requires high temperatures (>100°C) • Low selectivity Middleton, W. J. J. Org. Chem.1975, 40, 574.

  28. Convenient Substitute for SF4 Markovskij (1973) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis, 1973, 787.

  29. Impact Was Not Realized Until1975 Middleton, W. J. J. Org. Chem. 1975, 40, 574.

  30. DAST Became Popular in Pharmaceutical Industry • Liquid • Thermally unstable

  31. Preparation of DAST • Distillation step is hazardous

  32. DAST Produces HF During Reaction • Similar to mechanism of SF4 • HF produced as byproduct

  33. DAST Used In Synthesis of Maraviroc • Used in the treatment of HIV • Blocks viral entry into the host immune system cells • DAST used in synthesis of a key fragment Åhman, J. et al. Org. Process. Res. Dev. 2008, 12, 1104.

  34. Three Key Fragments Assembled to Make Maraviroc

  35. Synthesis of TropaneFragment

  36. Synthesis of TropaneFragment

  37. DAST Step Outsourced to Specialized Facility

  38. Coupling of Fragments

  39. β Completion of -Amino Ester Fragment

  40. Final Assembly of Maraviroc

  41. DAST is Thermally Unstable Recall: DAST step outsourced to specialized fluorination facility Disproportionation Detonation Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137.

  42. Explosion Reported While Distilling DAST (1979) Explosion Cochran, J. Chem. Eng. News, 1979, 57, 43.

  43. Stabilize With Encumbering Group Around Sulfur Recall: Detonation

  44. Deoxo-Fluor Improves Stability • Degrades more slowly than DAST • Same decomposition temperature Lal, G. S. et. al. J. Org. Chem. 1999, 64, 7048.

  45. Previous Fluorinating Reagents Had Many Undesired Charactaristics

  46. Fluorinating Reagents Recently Developed Show Improvements Fluolead XtalFluor-E XtalFluor-M

  47. Fluolead • Selective deoxofluorinating reagent • Resistant to aqueous hydrolysis • Easily handled air stable solid • Thermally stable Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.

  48. Improve Stability with Stronger Bond to Sulfur Recall: Detonation Disproportionation

  49. C-S Bond Stronger Than N-S Bond

  50. Deoxofluorinations with Fluolead Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.