Design and Development of Safe and Selective Deoxofluorinating Reagents Robyn Biggs February 17th, 2011 University of Ottawa
13 naturally occurring fluorinated organics • Majority are homologues of fluoroacetic acid
10% of launched drugs contain fluorine 5-Fluorouracil Diflucan (Fluconazole) Maraviroc Fluticasone propionate Lipitor
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.
Mechanism of Oxidation by CYP450s Active Site
Discourage oxidation by Addition of Electron Withdrawing Substituents C-H Bond Strength= 99 Kcal/mol C-F Bond Strength= 117 Kcal/mol
Fluorine Substitution Exploited in Mechanism of Action of 5-Fluorouracil 5-Fluorouracil Inhibits DNA Replication
Mechanism of Action of 5-Fluorouracil • No dTMP formed • No TTP formed • DNA replication stopped
Reactions With Elemental Fluorine Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
Elemental Fluorine Can Be Very Dangerous • High reactivity and toxicity • Lack of selectivity
Perchloryl Fluoride as Fluorinating Agent Gabbard, R. B.; Jensen, E. V. J. Org. Chem. 1958, 23, 1406.
Perchloryl Fluoride Is Explosive Explosion University of Ottawa, 1982: Glinski, M. B.; Freed, J. C.; Durst, T. J. Org. Chem. 1987, 52, 2749.
More Stable/Selective Alternatives F-F bond strength= 36.6 Kcal/mol O-F bond strength= 44 Kcal/mol
O-F Reagents as Selective Fluorinating Agents Kirk, K. L. Org. Process Res. Dev.2008, 12, 305.
Safety Still an Issue With O-F Reagents Reaction set-up: • 1985: • AcOF explosion ∨ ∨ Adam, M. J. Chem. Eng. News, 1985, 63, 2.
Safer Alternatives to O-F Reagents O-F Bond Strength= 44 Kcal/mol N-F Bond Strength= 65 Kcal/mol NFSI Selectfluor
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.
Selectfluor Best Electrophilic Reagent • Easy to handle (solid) • Selective • Stable Radwan-Olszewska, K.; Palacios, F.; Kafarski, P. J. Org. Chem. 2011, 76, 1170.
Selectively Replacing an Existing Functional Group with Fluorine Use nucleophilic reagent
SF4 Was First Nucleophilic Fluorinating Reagent Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am. Chem. Soc. 1960,82, 543.
Mechanism of SF4 Reaction • HF generated in situ catalyzes the reaction
Danger of Runaway Reaction Using SF4 Catalyzes reaction Rate increases with production
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.
Convenient Substitute for SF4 Markovskij (1973) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis, 1973, 787.
Impact Was Not Realized Until1975 Middleton, W. J. J. Org. Chem. 1975, 40, 574.
DAST Became Popular in Pharmaceutical Industry • Liquid • Thermally unstable
Preparation of DAST • Distillation step is hazardous
DAST Produces HF During Reaction • Similar to mechanism of SF4 • HF produced as byproduct
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.
β Completion of -Amino Ester Fragment
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.
Explosion Reported While Distilling DAST (1979) Explosion Cochran, J. Chem. Eng. News, 1979, 57, 43.
Stabilize With Encumbering Group Around Sulfur Recall: Detonation
Deoxo-Fluor Improves Stability • Degrades more slowly than DAST • Same decomposition temperature Lal, G. S. et. al. J. Org. Chem. 1999, 64, 7048.
Previous Fluorinating Reagents Had Many Undesired Charactaristics
Fluorinating Reagents Recently Developed Show Improvements Fluolead XtalFluor-E XtalFluor-M
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.
Improve Stability with Stronger Bond to Sulfur Recall: Detonation Disproportionation
Deoxofluorinations with Fluolead Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.