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New Synthesis Methodologies of α-Fluorocarbonylated Building-Blocks Gérald Lemonnier Supervisor : Dr. P. Jubault UMR6014 - COBRA - IRCOF - INSA Rouen LHO.

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Presentation on theme: "New Synthesis Methodologies of α-Fluorocarbonylated Building-Blocks Gérald Lemonnier Supervisor : Dr. P. Jubault UMR6014 - COBRA - IRCOF - INSA Rouen LHO."— Presentation transcript:

1 New Synthesis Methodologies of α-Fluorocarbonylated Building-Blocks Gérald Lemonnier Supervisor : Dr. P. Jubault UMR COBRA - IRCOF - INSA Rouen LHO – Pr. J. C. Quirion Université de Montréal - April 21 st, 2009

2 Outline Introduction Organofluorinated Chemistry historical background fluorine properties previous results Synthesis of α-Fluoroacrylates Literature overview results mecanistic study Synthesis of Fluorinated Epoxides Literature overview results mecanistic study Conclusion

3 Fluorine : significant dates 1886 Isolated by Henry Moissan (Nobel 1906) 1928 Freon® 12 (CF 2 Cl 2 ) 1938 Teflon® (PTFE) discovery of fluoropolymers 1954 Fried synthesise the 9-α-fluorohydrocortison fluorinated medicinal chemistry 1973 Discovery of ozon depletion by CFCs Rowland and Molina (Nobel 1995) 1987 Monteal Protocol Interdiction of synthesis and use of CFCs 1940s Development of fluorination methods

4 Current Situation. only 13 fluorinated natural molecules. large industrial (thermoplastic, elastomers, liquid crystal, fire extinction…) and medical applications (anesthesiology, artificial veins, …). exponential increase of publication number. 20 to 25 % of compounds developed in medicinal chemistry contains at least one fluorine atom Fluoxetine 2 (PROZAC ® ) O H N F 3 C Ciprofloxacine 3 (CIPRO ® ) NN F O CO 2 H HN N H N F F MeO 2 C N N CO 2 MeHO H OCOMe Vinflumine 4 (Pierre Fabre)

5 Physico-Chemical Properties Fluorine element R VDW = 1,47 Ǻ (third smaller) low polarisability 2, cm 3 (Br : 6,03) most electronegative (Pauling) 4,0 non negligeable mesomer effect C-F bond short, L = 1,38 Ǻ high polarity E bonding = 485 Kj.mol -1 (E C-C = 348 ; E C-H = 416) Chemical stability, mecanic and thermic resistance FC FC stabilisation  -cation

6 Physico-Chemical Properties Modification Physico-Chemical Properties Modification pKa  acidity of proximal function (carboxylic acids, alcohols, amines,…) C-H ↔ carbanion stability Lipophily effect hard to predict  lipophily except on saturated alkyl chains CF C F CC F CC F - répulsion n  destabilisation carbanion   fluoré hyperconjugaison carbanion  fluoré

7 Non-covalent Interactions F  H bond? low energy bond (low polarisability) needs very acidic H, C(F) sp 3 rare exemples Electrostatic Interactions C-F polarity ↔ high dipolar moment fluorinated aromatic rings : new interactions sites interactions in biological recognition sites :  receptors affinity Barbarich, T. J. ; Rithner, C. D. ; Miller, S. M. ; Anderson, O. P. ; Strauss, S. H. J. Am. Chem. Soc. 1999, 121, 4280 Razgulin, A. V. ; Mecozzi, S. J. Med. Chem. 2006, 49, 7902 Medicinal chemistry : modulation of pharmacological parameters

8 Analog Development Approach Replacement of atom or atomic group C-H ↔ C-F CH 3 ↔ CF 3 C-OH ↔ C-F C=O ↔ CHF Isostere Group carbon chain modification steric and/or electronic analogs chemical and thermal stability pKa, lipophily steric interactions, conformational and electronical undesired effects O P O O OH C P O O OH F F O O O C F F O NH F C H O C FF stability towards metabolic reactions

9 Situation - Goals Fluorine : large application field Medicinal chemistry pharmacological properties modulation optimisation of non-fluorinated compounds new compounds through fluorine integration in structure-activity relationship studies Synthetic Approach electrophilic/nucleophilic fluoration (DAST, deoxofluor) use of fluorinated building-blocks ↔ Montreal protocol Goals new fluorinated building-blocks fast, simple and effective methodology

10 Previous Results Fluorine Source : CFBr 2 CO 2 Et authorised in Montreal protocol, cheap only a few publications ester function ↔ further structural modification Association with Et 2 Zn F Br Br OEt O F Br OEt OZnEt F EtZn Br OEt O Et 2 Zn 8 forme carbénoïde 8 forme énolate 7

11 Previous Results Previous Results Non-selective synthesis of fluorinated acrylates aldehydes, ketones, lactones Wittig-like olefination no selectivity use of phosphonium salt : better yield, easier work up but no selectivity L. Zoute, G. Dutheuil, J.-C. Quirion, P. Jubault, X. Pannecouke Synthesis 2006, 20, 3409 L. Zoute, C. Lacombe, J.-C. Quirion, A. B. Charette, P. Jubault Tetrahedron Letters 2006, 47, 7931 PPh 3, Et 2 Zn, RCOR' THF, rt R R' CO 2 Et F F Br Br OEt O % F Br Br OEt O 7 Et 2 Zn, RCOR' CH 2 Cl 2, rt F CO 2 EtR' R PPh 3 Ph 2 P ClO % 109

12 Previous Results Previous Results Acces to α-Bromo-α-Fluoro-β-Hydroxyesters aldehydes, ketones, lactones no selectivity F Br Br OEt O 7 R R' O OH R' R Br EtO 2 C F 11 Et 2 Zn THF, rrt, 3h 30-99%

13 Outline Introduction Organofluorinated Chemistry historical background fluorine properties previous results Synthesis of α-Fluoroacrylates Literature overview results mecanistic study Synthesis of Fluorinated Epoxides Literature overview results mecanistic study Conclusion

14 Fluoroacrylates Intermediate in the synthesis of bioactive compounds enzymes inhibitor modified nucleosides (antiviral activity) anti thrombic compounds fluoroolefines : bio-isostere of amide bond

15 Synthesis Methodology Partially Z-selectives Julia olefination Peterson olefination Wittig Horner-Wadsworth-Emmons Chevrie, D. ; Lequeux, T. ; Pommelet, J.-C. Org. Lett. 1999, 1, 1539 Pfund, E. ; Lebargy, C. ; Rouden, J. ; Lequeux, T. J. Org. Chem. 2007, 72, 7871 Lin, J. ; Welsh, J. T. Tetrahedron Lett. 1998, 39, 9613 Suzuki, Y. ; Sato, M. Tetrahedron Lett. 2004, 45, 1679 Sano, S. ; Teranishi, R. ; Nagao, Y. Tetrahedron Lett. 2002, 43, 9183 selectivity yield aromatic aldehydes multi-step synthesis/cost of fluorinated reagent

16 Synthesis Methodology Synthesis Methodology Z-selectives Mioskowski – Falck : chromium salt Kitazume Barma, D. K. ; Kundu, A. ; Zhang, H. ; Mioskowski, C. ; Falck, J. R. J. Am. Chem. Soc. 2003, 125, 3218 Kawasaki, T. ; Ichige, T. ; Kitazume, T. J. Org. Chem. 1998, 63, 7525 yield commercial starting material only 2 exemples chromium toxicity R = alkyl, aryll yield (R = alkyl) precursor synthesis yield (R = aryl) cost of fluorinated reagent (49 €/g) F CO 2 R' RRCHOF 3 CCO 2 Et CrCl 2 THF, rt CO 2 Me F R RR' O NaCF(CO 2 Me) 2 THF

17 New Z-olefination Method First observation Optimisation solvent : dichloromethane quench : NH 4 Cl separation of Z-olefine and syn-fluorobromohydrine

18 Results Aldehydes

19 Results Aldehydes

20 Results Aldehydes Z-olefin average yield : 42%

21 Mecanism Mioskowski-Falck : Concellon : bimetalic enolate intermediate Barma, D. K. ; Kundu, A. ; Zhang, H. ; Mioskowski, C. ; Falck, J. R. J. Am. Chem. Soc. 2003, 125, 3218 Concellon, J. M. ; Pérez-Andrés, J. A. ; Rodriguez-Solla, H. Angew. Chem. Int. Ed. 2000, 39, 2773

22 Mecanism Our method :

23 Results Ketones

24 Mecanism acetophenone olefination : syn isomere consumed faster constant E/Z ratio common reaction intermediate

25 Mecanism Concellon model : origin of selectivity

26 Mecanism Concellon model : DFT calculation

27 Mecanism Concellon model : metalation step

28 Olefination : conclusion fluoroacrylates from commercially available and cheap compounds aldehydes : aromatiques, aliphatiques Z-selectivity E2 mecanism ketones : aromatiques, aliphatiques E1cb mecanism

29 Outline Introduction Organofluorinated Chemistry historical background fluorine properties previous results Synthesis of α-Fluoroacrylates Literature overview results mecanistic study Synthesis of Fluorinated Epoxides Literature overview results mecanistic study Conclusion

30 Introduction Epoxides use reactive intermediate C-C and C-heteroatom bond formation Usual synthesis methods

31 Literature Overview enantioselective method fluorinated glycidic esters tetrasubstituted fluorinated epoxides Bortoloni, O. ; Fogagnolo, M. ; Fantin, G. ; Maietti, S. ; Medici, A. Tetrahedron : Asymmetry 2001, 12, 1113 Elkik, E. ; LeBlanc, M. Bull. Soc. Chim. Fr.1971, 870 Shimizu, M. ; Hata, T. ; Hiyama, T. Tetrahedron Lett. 1997, 38, 4591

32 Results PPh 3 mediated epoxidation PPh 3 elimination degradation on silica gel

33 Results asymmetric attempt Use of N-dimethylethanolamine Kloetzing, R. J. ; Thaler, T. ; Knochel P. Org. Lett. 2006, 8, 1125

34 Results - simplified work-up - epoxides characterised (NMR, MS) - unstable in pure form - stable in solution

35 Mecanism Origin of diastereoselectivity halogen-metal exchange/complexe [DMEA-ZnEt] role

36 Proposed Mecanism

37 Reactivity epoxide opening analyses (NMR, MS) : 2 possibilities

38 Reactivity Reactivity Grignard addition Saponification / Reduction 1 H, 19 F NMR :addition on ester

39 Epoxidation : conclusion Epoxidation : conclusion trialkyl α-fluorinated glycidic esters only method fast and effective commercial reagents unstability extension to aldehydes, imines

40 Outcome CFBr 2 CO 2 Et Et 2 Zn CO 2 EtEtZn FBr OEt OZnEt F Br CO 2 Et F R 1 R 2 7 exemples d.r. = 70:30-100: % R 1 COR 2 Et 2 Zn (4 éq.) O R 2 R 1 CO 2 Et F R 1 COR 2 Et 2 Zn (4 éq.) DMEA 6 exemples d.r. = 52:48-91: %

41 Aknowledgment Jean-Charles Quirion Philippe Jubault Ludivine Zoute Elisabeth Roger Laëtitia Bailly

42

43 UNESCO World Heritage

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