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Research summary - 2011 updated

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Research summary - 2011 updated

  1. 1. Julien BarbionDocteur en Chimie - Ingénieur Chimiste R&D<br /><ul><li>33 ans • PACSé• 1 enfant
  2. 2. Domicilié à Sannois (95 - Val d’Oise)
  3. 3. DEA - Université Cergy-Pontoise (Prof. J. Ardisson/DR A. Pancrazi)</li></ul> “Contribution à la Synthèse Totale du (+)-Discodermolide”<br /><ul><li>Doctorat - RWTH Aachen (Prof. D. Enders)</li></ul> “Synthèse Totale du (+)-Altholactone”<br /><ul><li>Ingénieur R&D - Faculté de Pharmacie Paris V (Prof. J. Ardisson)</li></ul> “Contribution à la Synthèse Totale du Salinosporamide A, Nouvel<br /> Inhibiteur nM du Protéasome” (Programme ANR)<br /><ul><li>Ingénieur R&D - BayerCropScience Lyon (Dr. J.-P. Vors)</li></ul> “Synthèse d’Hétérocycles Trifluorométhoxylés”<br />
  4. 4. StudiesTowards the Total Syntheses<br />of Bioactive Products<br />Research Summary (last update 2011)<br /> I - (+)-Discodermolide<br /> II - (+)-Altholactone<br /> III - Salinosporamide A<br /> IV - OCF3-Heterocycles<br />
  5. 5. (+)-Discodermolide(DEA, 2002-2003)Synthesis, 2004, 3017-3022.Angew. Chem., Int. Ed.2007, 46, 1917-1921.Chem. Eur. J. 2008, 14,11092-11112.<br />
  6. 6. (+)-Discodermolide<br /><ul><li>Isolatedfrom a marine sponge</li></ul> (Discodermiadissoluta)<br /> Low extraction yield (0.002%)<br /><ul><li>Biologicalactivity</li></ul>Cytotoxic IC50 = 2.5 nM<br /> Microtubule stabilisation<br /> Target = tubuline active in vivo<br /><ul><li> Structural features</li></ul>Polypropionate<br /> 13 chiral centres<br /> 3 double bonds (Z)<br />
  7. 7. (+)-Discodermolide - Retrosynthesis<br />
  8. 8. (+)-Discodermolide - Strategies<br />
  9. 9. (+)-Altholactone(PhD, 2003-2006)defended in Aachen, the 10/27/2006 Chem. Eur. J. 2008, 14, 2842-2849.<br />
  10. 10. (+)-Altholactone<br /><ul><li>Isolatedfromthe stark oflittletrees</li></ul>(Goniothalamusgiganteus)<br />Goniothalamusisknownas a sourceofnaturalproductspresentingbiologicalactivities<br /> (5-hydroxy-5,6-dihydro-2H-pyran-2-one)<br /><ul><li>Biological activity</li></ul>Cytotoxic IC50 = 0.7 µM<br />Antitumoralandantibacterialproperties<br /><ul><li>Structural features</li></ul> 4 chiral centres in a row<br />Bicycliccis-junction<br /> Cycle 1: 5-hydroxy-5,6-dihydro-2H-pyran-2-one<br /> Cycle 2: disubstitutedtetrahydrofurane<br />
  11. 11. (+)-Altholactone - Retrosynthesis<br />
  12. 12. (+)-Altholactone - Synthesis (1/2)ChiralityIntroduction<br />
  13. 13. (+)-Altholactone - Synthesis (2/2)(18 steps, 13.7% overallyield)<br />
  14. 14. Salinosporamide A(Research Scientist, 2006-2008)ANR Programʺstill underinvestigationʺ<br />
  15. 15. Salinosporamide A<br /><ul><li>Isolatedfrom a novelmicrobialsource (2003)</li></ul> (marine bacteriumofthenewgenusSalinospora)<br /><ul><li>Biological activity</li></ul> IC50 = 10 nM (in vitro) - Human coloncarcinoma<br /> Inhibition ofthe 20S proteasome<br /><ul><li>Structural features</li></ul> 5 chiral centres in a row<br /> cis-fusedc-lactam-b-lactone bicyclic ring structure<br /> 2 sidechains: cyclohexenylcarbinol and chloroethylchains<br />
  16. 16. Salinosporamide A - SAR<br />The b-lactone isrecognized as a keypharmacophor<br />(itsforms a covalent adductwith the N-terminal Thr<br />on proteasome 20S)<br />
  17. 17. Salinosporamide A - Retrosynthesis<br />
  18. 18. Salinosporamide ASynthesis ofthe Methyl Ketone<br />TRIS = Tris(hydroxymethyl)aminomethane 99+%, 43€/500g (ACROS Organics)<br />
  19. 19. Salinosporamide ASynthesis ofthe II-Carbamate<br />Overallyield = 88% (over 4 steps) - Racemicversion of the II-carbamate<br />
  20. 20. Salinosporamide AHoppe‘sAllylationwith a II-Carbamate (1/2)<br />
  21. 21. Salinosporamide AHoppe‘sAllylationwith a II-Carbamate (2/2)<br />
  22. 22. Salinosporamide AAttempts on Assymetricmethylation (1/2)<br />
  23. 23. Salinosporamide AAttempts on Assymetricmethylation (2/2)<br />
  24. 24. OCF3-Heterocycles(Research Scientist, 2009-2010)BayerCropScience, Lyonʺstill underinvestigationʺ(BCS-Patent in press)<br />
  25. 25. Trifluoromethoxy Group<br />- OCF3group is more & more important in agrochemical and pharmaceutical industries because of its unique properties.<br />- OCF3isreferred as "pseudo- or super-halogen" (close to F or Cl):highlyelectron-withdrawing by induction (=3.7) slightlypositive mesomericeffect +M and hydrophobic R=+1.04compared to R(CF3)=+0.88 and R(OMe)=-0.02<br /><ul><li>Few methods are described in literature
  26. 26. Use of quitedrastic conditions and/or large excess of reagents
  27. 27. limitedtoaromaticsubstrates or simple aliphaticones</li></li></ul><li>TFMT as OCF3 Generator<br />TFMT (trifluoromethyltriflate) isknownsince 1965.<br />Differentsynthesis have been reported(for a reviewsee Taylor, Martin, J.Org.Chem.1987, 52, 4147-4156 )<br />Nowcommerciallyavailablefrom ABCR.<br />Reactivity of TFMT:<br />Contrary to alkyltriflates, which are powerfulalkylatingagents, TFMT is a CF3O-generator (and not a CF3+)<br />
  28. 28. TrifluoromethoxylationReaction<br />AgOCF3is an efficientreagentfor trifluoromethoxylation of primarybromides and iodides but alsosecondaryreactivebromides and tolerates a lot of functional groups.<br /> Access to OCF3-Heterocycles (patent in preparation)<br />Marrec, O.; Billard, B.; Vors, J.-P.; Pazenok, S.; Langlois, B.R. J. Fluorine Chem.2010, 131, 200-207.<br />
  29. 29. Julien Barbion - Conclusion<br /><ul><li>Solidknowledge in multi-stepssynthesis of naturalproducts
  30. 30. Real autonomy in work
  31. 31. Good capacity of communication (in 3 differentlanguages)
  32. 32. Team-worker and team leader (organisation)
  33. 33. Almostalways in a good mood</li>

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