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Group Meeting Montreal, February 22, 2012 Sonia Diab

Group Meeting Montreal, February 22, 2012 Sonia Diab. CONSTANTINE. CAEN (Basse-Normandie. ROUEN (Haute-Normandie). SYNTHESIS OF DIFLUOROPHOSPHONATES BY CARBANIONIC AND RADICAL PROCESS FOR THE PREPARATION OF THYMIDINE PHOSPHORYLASE INHIBITORS. Sonia DIAB Montreal, February 22, 2012.

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Group Meeting Montreal, February 22, 2012 Sonia Diab

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  1. Group MeetingMontreal, February 22, 2012Sonia Diab

  2. CONSTANTINE

  3. CAEN (Basse-Normandie

  4. ROUEN (Haute-Normandie)

  5. SYNTHESIS OF DIFLUOROPHOSPHONATES BY CARBANIONIC AND RADICAL PROCESS FOR THE PREPARATION OF THYMIDINE PHOSPHORYLASE INHIBITORS Sonia DIAB Montreal, February 22, 2012 PhD Supervisor: Pr. Thierry. LEQUEUX Laboratoire de Chimie Moléculaire et Thio-organique. UMR-CNRS 6507 6 Boulevard du Maréchal Juin 14050 CAEN, France

  6. Introduction • Tumoral Angiogenesis PD-ECGF::Platelet-derived endothelial cell growth factor • Protein involved in angiogenesis of cancerous cells. • Identified as Human Thymidine Phosphorylase (HTP) (a) Folkman J and al. J Biol Chem1992 ; 267 : 10931-10934, (b) Ishikawa, F. and al. Nature 1989, 338, 557-562. • Propperties of Human Thymidine Phosphorylase Inhibitor of TP (a) Walter, M. R. And al. J. Biol. Chem. 1990, 265, 14016-14022. (b) Norman, R. A. And al. Structure2004, 12, 75-84.

  7. Inhibitors of Thymidine phosphorylase • Multisubstrats Inhibitors • Very few TP inhibitors described • Phosphonate as mimics of the phosphate • function Blazarini, J. and al. J. Med. Chem.2000, 43, 971-984. • Analogie phosphate / phosphonate / fluorophosphonate • Difluorophosphonates best isopolar and isosteric phosphate analogue Blackburn, M. G. ; England, D. A. ; Kolkmann, F. J. Chem. Soc. Chem. Comm. 1981, 930-392 • No fluorinates TP inhibitors described to date Synthesis of new fluorinated inhibitors of TP

  8. Choice of structures to synthesize

  9. Choice of structures to synthesize

  10. Les Families of TP Inhibitors • Family I : Linear Inhibitors • Family II : Conformationally constrained Inhibitors How to introduce the difluoromethylphosphonate function

  11. General methods for the synthesis of fluorophosphonates (a) Burton, D. J. et al. Chem. Rev. 1996, 96, 1641-1715. (b) Matulic-Adamic, J. et al. J. Org. Chem. 1995, 60, 2563-2569. (a) Li, A.-R. ; Chen, Q.-Y. Synthesis1996, 606-608. (b) Yokomatsu, T. et al. J. Org. Chem. 1996, 61, 7207-7211. Herpin, T. F.  Et al. Chem. Commun. 1996, 613-614. (a) Blades, K. et al. Chem. Commun. 1996, 1457-1458. (b) Xu, Y. et al. Org. Lett. 2002, 4, 4021-4024. (a) Solas, D. et al. J. Org. Chem. 1996, 61, 1537-1539. (b) Lequeux, T. et al. Org. Lett.2001, 3, 185-188

  12. Limits: based on the use of HCFC or CFC (a) McCulloch, A. J. Fluorine Chem.1999, 100, 163-173. (b) Obayashi, M. ; Ito, E. ; Kondo, K. Tetrahedron Lett.1982, 23, 2323-2326. (c) Burton, D. J. et al. Chem. Lett.1982, 755-758. (d) Burton, D. J. ; Takei, R. ; Seiji, S. J. Fluorine Chem. 1981, 18, 197-202. • Halons and freons: regulated and prohibited for use since the Kyoto and Montreal protocole Need to find other methods that avoid the use of ecotoxic materials.

  13. Previous work of the laboratory • New method to generate the anion • Fluorosulfide: Novel source of the anion developed in Lequeux’s Laboratory Henry-dit-Quesnel, A. ; Toupet, L. ; Pommelet, J. C. ; Lequeux, T. Org. Biomol. Chem. 2003, 1, 2486-2491 • Study of th reactivity of the anion depending on its source • E+ : TMSCl, aldehyde, ketone, CS2 The same reactivity • E+ : , , , DMF  Different reactivity Ozouf, P. ; Binot, G. ; Pommelet, J. C. ; Lequeux, T. Org Lett.2004, 6, 21, 37-47. Anion can open oxacycles to prepare corresponding alcohols.

  14. Family I: Inhibitors with a linear chain

  15. Hydroxyphosphonates: Key molecules for the synthesis of our inhibitors • Formation of hydroxydifluoromethylphosphonates with various size • Opening reations of oxacycles

  16. Preparation of b-hydroxydifluoromethylphosphonates • 1,2-cyclic sulfates opening Diab, S. A. ; Sene, A. ; Pfund, E. ; Lequeux, T. Org. Lett. 2008, 10, 3895-3898.

  17. Preparation of g-hydroxydifluoromethylphosphonates • Oxetanes opening Ozouf, P. ; Binot, G. ; Pommelet, J. C. ; Lequeux, T. Org Lett.2004, 6, 21, 37-47. Diab, S. A. ; Sene, A. ; Pfund, E. ; Lequeux, T. Org. Lett. 2008, 10, 3895-3898.

  18. Preparation of d-hydroxydifluoromethylphosphonates • THF opening Ozouf, P. ; Binot, G. ; Pommelet, J. C. ; Lequeux, T. Org Lett.2004, 6, 21, 37-47. • THP opening • No reaction • The size of oxacycles opening is limited to the THF Exploit other alternatives to increase the size of the spacer

  19. Preparation of w-hydroxydifluoromethylphosphonates • Lactones opening: e-caprolactone and z-lactone • Lactones opening leads to the formation of hydroxyketodifluoromethylphosphonates Introduction of the nucleic base

  20. Preparation of fluorinated analogues of linear acyclonucleotides • Approach 1: Mitsunobu Reaction • Direct introduction of the nucleic base by Mitsunobu reaction  Moderate yields and nonreproducible reaction • Approach 2: Activation by tosylate Conditions tested: 1/ NaH/DMF/reflux  Low yields (< 35%) 2/ K2CO3/DMF/r.t.  No reaction 3/ TMG/DMSO/r.t.  Best results Using TMG to introduce the nucleic base Diab, S. A. ; Sene, A. ; Pfund, E. ; Lequeux, T. Org. Lett. 2008, 10, 3895-3898.

  21. Preparation of fluorinated analogues of linear acyclonucleotides • Introduction of the nucleic base Diab, S. A. ; Sene, A. ; Pfund, E. ; Lequeux, T. Org. Lett. 2008, 10, 3895-3898

  22. Access to long-chain inhibitors • Synthesis according to the first strategy: ionic process • Early introduction of the difluoromethylphosphonate group • Late introduction of the nucleobase • Synthesis according to the second strategy: radical process • Late introduction and at the same time of the difluoromethylphosphonate group and the nucleobase

  23. Radical reaction • Preparation of iododifluoromethylphosphonate • Chalcogen-halogen exchange  avoids the use of HCFCs Henry-dit-Quesnel, A. ; Toupet, L. ; Pommelet, J. C. ; Lequeux, T. Org. Biomol. Chem. 2003, 1, 2486-2491 • Reaction with n-octene • Three initiator systems were used • Regioselective reaction Sène, A. ; Diab, S. ; Hienzsch, A. ; Cahard, D. ; Lequeux, T. Synlett. 2009, 981-985. Functionalized alkenes

  24. Addition of the radical phosphonodifluoromethyle on the alkenes • Addition on the allylthymine • Addition on functionalized alkenes with long-chain • Reaction performed in the presence of purine and pyrimidine base

  25. Family II: Conformationally constrained Inhibitors

  26. Retrosynthsis of the structures to be synthetized • Mimic the approach of the phosphate group • Conformation frozen by a benzene ring • Conformation frozen by a triazole moiety

  27. Conformation frozen by a furan ring • Radical addition on 2,3-dihydrofuran • Differents initiators were used  The product was only observed in the presence of sodium dithionite • The trans isomer is predominant (confirmed by NMR experiments HOESY 1H{19F}) • Heterocycle to block the conformation

  28. Conformation frozen by a furan ring • Introduction of the nucleic base • Diastereoselective reaction (trans configuration) • Formation of two regioisomers N 1 and N 3

  29. Conformation frozen by a benzene ring • Preparation of 1,4-cyclic sulfate (a) Soai, K. ; Ookawa, A. J. Org. Chem. 1986, 51, 4000-4005. (b) Gao, Y. ; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-7539. • 1,4-cyclic sulfate opening • First exemple of 1,4-cyclic sulfate opening by difluoromethylphosphonate anion

  30. Conformation frozen by a triazole ring • 1,3-dipolar cycloaddition Diab, S. A. ; Hienszch, A. ; Lebargy, C. ; Pfund, E. ; Lequeux, T. Organic and Biomolecular Chemistry, 2009, 21, 4481-4490.

  31. Tests of inhibition of Thymidine phosphorylase from E.Coli

  32. In vitro inhibition of TP from E. Coli • Deprotection of the phosphonic acids McKenna, C. E. ; Higa, M. T. ; Cheung, N. H. ; McKenna, M.-C. Tetrahedron Lett. 1977, 2, 155-158. • This method was applied to all phosphonic esters synthesized (fluorinated linear acyclonucleotides analogues and conformationally constrained) • Non-fluorinated analogue Directed inhibition tests in collaboration with Dr. Murielle Muzard from the University of Reims Diab, S. A.; De Schutter, C.; Muzard, M.; Plantier-Royon, R.; Pfund, E.; Lequeux, T. J. Med. Chem. 2012, submitted.

  33. Influence of the fluorine atoms and the size of the spacer • Influence of the fluorine atom • Increased activity with the fluorine compound • CF2 > CH2 % I = 23% % I = 51% I (1 mM) • Influence of the size of the spacer % I = 68% % I = 51% • Long chain  Better activity I (1 mM) Diab, S. A.; De Schutter, C.; Muzard, M.; Plantier-Royon, R.; Pfund, E.; Lequeux, T. J. Med. Chem. 2012, submitted.

  34. Influence of the nucleobase and the iodine atom • Influence of the nature of the nucleobase % I = 61% % I = 44% % I = 74% % I = 68% • Uracil  Moderate activity • Thymine, 5-bromouracil, guanine  Good activity I (1 mM) • Influence of the iodine atom • The presence of an iodine atom increase the activity % I = 95% % I = 52% % I = 51% % I = 4% I (1 mM) I (100 mM) Diab, S. A.; De Schutter, C.; Muzard, M.; Plantier-Royon, R.; Pfund, E.; Lequeux, T. J. Med. Chem. 2012, submitted.

  35. Influence of the traizole • concentration of 1 mM % I = 79% % I = 90% % I = 76% % I = 79% % I = 76% % I = 69% I (1 mM) • Concentration of 100 mM % I = 68% % I = 36% % I = 35% % I = 35% % I = 22% % I = 29% • The activity increases with the size of the spacer • Best result obtained with compound conformationally constrained I (100 mM) Diab, S. A.; De Schutter, C.; Muzard, M.; Plantier-Royon, R.; Pfund, E.; Lequeux, T. J. Med. Chem. 2012, submitted.

  36. General conclusion • Inhibitors of the family I: Linear chain • Two synthetic athways: ionic and radical

  37. General conclusion • Inhibitors with constrained conformation

  38. Conclusion and outlook • All our phosphonic acids tested are active Référence 1 Référence 2 • « click chemistry »  Inhibitors by autoselection of the enzyme • Test the other phosphonic acids. • Design of new inhibitors  long chain, fonctionnality, nucleic base

  39. Post-doc work:DEAROMATIZATION OF NITROARENES BY CYCLOADDITION Supervisor: Dr. Isabelle CHATAIGNER LFAOC-IRCOF. UMR-CNRS 6014 Faculté des Sciences et Techniques. Rue Tesnières 76821 Mont Saint Aignan, Rouen. France

  40. Dearomatization of Nitroarenes by cycloaddtion Subject I:Dearomatization of Nitroarenes with N-Benzyl Azomethine Ylide Subject II:Nitroarenes reactivity with enamines

  41. Dearomatization of Nitroarenes with N-Benzyl Azomethine Ylide • Preliminary results • Cycloaddition [3+2] Lee, S.; Chataigner, I.; Piettre, S. R. Angew. Chem. Int. Ed. 2011, 50, 472-476.

  42. Dearomatization of Nitroarenes with N-Benzyl Azomethine Ylide • 1,2-dinitrobenzene • Bicycloadduct • Regioisomer cis • 3-chloronitrobenzene • 3,4-dichloronitrobenzene • The three possible chlorinated carbon-carbon double bonds were found to be unreactive • Bicycloadduct Lee, S.; Diab, S.; Queval, P.; Chataigner, I.; Piettre, S. R. Angew. Chem. Int. Ed. 2012 (will be submitted).

  43. Dearomatization of Nitroarenes with N-Benzyl Azomethine Ylide • 3-(trifluoromethyl)nitrobenzene • 3,5-bis(trifluoromethyl)nitrobenzene Lee, S.; Diab, S.; Queval, P.; Chataigner, I.; Piettre, S. R. Angew. Chem. Int. Ed. 2012 (will be submitted).

  44. Dearomatization of Nitroarenes with N-Benzyl Azomethine Ylide • Pyridine derivative: 3,5-dinitropyridine • 5-nitro-1,10-phenanthroline • Substrats without nitro group Lee, S.; Diab, S.; Queval, P.; Chataigner, I.; Piettre, S. R. Angew. Chem. Int. Ed. 2012 (will be submitted).

  45. Dearomatization of Nitroarenes by cycloaddtion Subject I:Dearomatization of Nitroarenes with N-Benzyl Azomethine Ylide Subject II:Nitroarenes reactivity with enamines

  46. Nitroarenes reactivity with enamines • The aims of the project • Re-evaluating the synthetic potential of nitroaromatic compounds • Dearomatization • nitronate chemistry • Enamine : 4-cyclohexenylmorpholine

  47. Nitroarenes reactivity with enamines • Reaction at atmospheric pressure (unpublished) Nitroindole • Mild conditions of dearomatization • Unstable product Nitrobenzofuran • Furan ring opening • No reaction

  48. Nitroarenes reactivity with enamines • Reaction under high pressure (unpublished)

  49. Nitroarenes reactivity with enamines • Reaction under high pressure (unpublished)

  50. Nitroarenes reactivity with enamines • Reduction: Cleavage of the N-O bond (unpublished) • PtO2, H2 NO • Ni/Raney, 10 bar H2  NO • H-Cube  trace Under acidic condition

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