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Synthèse Énantiosélective Du Monate De Méthyle C Et Réaction Aldol Organocatalysée D'aldéhydes Α,Β-Insaturés

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Synthèse Énantiosélective Du Monate De Méthyle C Et Réaction Aldol Organocatalysée D'aldéhydes Α,Β-Insaturés UNIVERSITE CATHOLIQUE DE LOUVAIN Faculté des Sciences Laboratoire de Chimie Organique et Médicinale Professeur I.E. Markó Synthèse énantiosélective du Monate de méthyle C et Réaction aldol organocatalysée d’aldéhydes α,β-insaturés : application à la synthèse de dérivés de la Goniothalamine Dissertation présentée en vue de l’obtention du grade de docteur en sciences van INNIS Livia Louvain-la-Neuve 12 Octobre 2007 2 OH OH HO O O O O OH Acide Pseudomonique C O O O O O O (R)-(+)-fannythalamine(R)-(+)-goniothalamine (R)-(+)-liviathalamine Composition du Jury: Professeur C. Willis (University of Bristol, UK) Professeur W. Dumont (FUNDP) Professeur O. Riant (UCL) Professeur J. Marchand (UCL) Professeur I. E. Markό (UCL) 3 « Celui qui trouve sans chercher est celui qui a longtemps cherché sans trouver. » Gaston Bachelard « Chercher un refuge dans la sagesse seule, car s’attacher aux résultats est cause de malheur et de misère. » Beethoven 4 Remerciements Je tiens à remercier tout d’abord le professeur Markό, plus connu sous le nom de BOSS, pour m’avoir accueillie dans son laboratoire et pour m’avoir soutenue tout au long de ces 4 années de thèse. En plus du goût pour la chimie organique que vous m’avez transmise par le biais de vos cours, je vous suis reconnaissante de m’avoir apporté des connaissances en chimie et surtout de m’avoir appris à m’intéresser et à élargir ma curiosité à d’autres domaines que « ma petite chimie ». Un tout grand merci à Juliette et à Chantal pour leur aide précieuse dans les moments importants de la thèse. Je remercie spécialement mes deux grandes copines rencontrées à LLN : Céline et Julie. On a passé de supers bons moments ensembles. Je n’oublierai pas nos diverses sorties nocturnes, nos petites virées shopping ou nos repas entre filles. Ca va me manquer !!! Un gros merci à Fabio, mon collègue de labo, pour ton amitié et pour nos bonnes discussions entre deux colonnes (eh oui je parle beaucoup !!). Si le prix du « meilleur collègue de labo » existait, je n’hésiterai pas une seconde à te le donner. Où que l’on sera, toi et ta petite famille seront toujours la bienvenue chez le « galleux » et moi. Je tiens aussi à remercier tout particulièrement : - Guiz pour ton amitié et pour les sorties cinéma et musées. Au fait, j’attends toujours la saison 2 de « Prison Break ». -Nico et Steph pour leur gentillesse et leur accueil merveilleux chaque fois que l’on allait chez eux. - J.C. et Eleonora pour leur sympathie et les nombreux repas arrosés. J’attends avec hâte votre mariage en Hongrie. -Seb et Mélanie pour les moments agréables passés ensembles. Vous êtes tous les bienvenus en Suisse ou au Portugal. - Ben L. et Fred qui m’a tenu compagnie pendant presque 3 ans dans le C328b. Saiphon a big thanks for your friendship and for the good moments spent in and outside the lab. I hope I will be able to visit you in Thailand one day. Meanwhile, you are welcome in Switzerland or in Portugal. Un grand merci aux anciens du laboratoire: - Pierre W., Mickachou, Ali, Laurent, J.C., Nico, Guillaume Michaud, Seb. Lemaire et Mélanie D. pour leurs conseils en chimie et pour les bons moments partagés en dehors du labo. - J.F. Brière qui m’a appris les rudiments de la manipulation lors de mon stage chez Rhodia. - J.M. Plancher pour avoir débuté ce merveilleux travail de synthèse et pour son soutien tout au long de cette thèse. Je souhaite aussi remercier ma famille : - mes parents sans qui je ne serai pas là aujourd’hui. Papa merci pour tes conseils avisés et pour tes visites régulières en Belgique qui m’ont permis de « matar saudades » plus souvent. Maman un grand merci pour ton réconfort et ton soutien à tout moments. Tu es pour moi plus qu’une mère, tu es mon amie et ma confidente. -mon frère Lourenço et mes sœurs Mariana et Ana Luisa. 5 Remerciements En dernier lieu mais occupant la première place dans mon cœur, je remercie Christophe. Merci pour ton soutien et ton affection. C’est grâce à tes bons conseils et à ta motivation que j’ai pu réaliser un grand nombre de projets. A mon tour, je te dédie cet ouvrage 6 Liste des abréviations et des symboles LISTE DES ABREVIATIONS ET DES SYMBOLES Ac acétyle AE acétate d’éthyle AIBN azo-bis-isobutyronitrile A.L acide de Lewis APCI ionisation chimique à pression atmosphérique APTS acide para-tolènesulfonique ARNt acide ribonucléique de transfert Ax axial Binol 1,1’-binaphtol Bn benzyle Bu butyle n-BuLi n-butyllithium Bz benzoyle °C degré Celsius CAN Cérium Ammonium Nitrate cat. catalytique CI ionisation chimique Cp Cyclopentényle C.P.G. chromatographie en phase gazeuese c.f. confer conv. conversion δ déplacement chimique en R.M.N. DBU 1,8-diazabicyclo[5-4-0]undéc-7-ène d.e. excès diastéréoisomérique d.r. rapport diastéréoisomérique DCI diisopropylcarbodiimide DCM dichlorométhane DIBAL-H hydrure de diisobutylaluminium DMAP 4-diméthylaminopyridine DMF diméthylformamide DMSO diméthylsulfoxyde e.e. excès énantiomérique env. environ Et éthyle EP éther de pétrole eq. équatorial ou équivalent et al. et altera F.I.D. flame ionisation detector g gramme h heure HRMS masse haute résolution H.P.L.C. chromatographie liquide haute pression Hz Hertz HOMO orbitale moléculaire la plus haute occupée (Highest Occupied Molecular Orbital) I.M.S.C. Intramolecular Sakurai Cyclisation i-Pr iso-propyle 7 Liste des abréviations et des symboles I.R. infrarouge J constante de couplage KHMDS bis(triméthylsilyl)amidure de potassium LDA N,N’-diisopropylamidure de lithium LUMO orbitale moléculaire la plus basse vacante (Lowest Unoccupied Molecular Orbital) mCPBA acide méta-chloroperbenzoique Me méthyle MHz mégahertz M.P.L.C. chromatographie liquide sous pression moyenne M.S. spectrométrie de masse min. minute ml mililitre MS tamis moléculaire MsCl chlorure de mésyle MM masse molaire mmol milimole MTBE tert-butylméthyléther NMO oxide de N-méthyl morpholine Nu nucléophile PCC pyridinium chlorochromate Ph phényle R.M.N résonance magnétique nucléaire R.N. registry number Rdt.. rendement ref. référence TBAF fluorure de tétra-butylammonium TBS diméthyl-tert-butylsilyle TEA triéthylamine TES triéthylsilyle Tf triflate THF tétrahydrofurane TMEDA tétraméthyléthylènediamine TMS triméthylsilyle TPAP tétrapropylammonium perruthénate U.V. ultraviolet vs versus 8 Résumé Résumé Partie A : Synthèse énantiosélective du Monate de méthyle C L’acide pseudomonique C (Schéma 1) appartient à la famille des C-glycopyrannosides. Il est produit par Pseudomonas Fluorescens, organisme aérobique qui colonise les sols et la surface des plantes. Le jus issu de la fermentation de cette levure possède des propriétés antibactériennes intéressantes envers les bactéries Gram-positives et en particulier contre les souches multirésistantes de Staphilococcus Aureus. OH OH HO O O O O OH Acide pseudomonique C Schéma 1 Le Monate de méthyle C 5.16, l’ester méthylique dérivé de l’acide pseudomonique C, constitue un très bon modèle pour l’utilisation d’une nouvelle stratégie tandem ène-I.M.S.C. développée dans notre laboratoire. En effet, le cœur du Monate de méthyle C 3.85 est obtenu, en une seule étape et avec la bonne stéréochimie relative, à partir des fragments 3.29 et 2.33E. O O OH OH Métathèse Allylation de HO Croisée TBSO Tsuji-Trost TBSO 4.94 O O O OTES 3.85 Monate de méthyle C 5.16 O O O O 4.111 O O I.M.S.C. O OH OMe TMS 2.33E 3.29 OTBS MeO OMe Schéma 2 Notre analyse rétrosynthétique est décrite dans le Schéma 2. La première disconnection située au niveau de l’oléfine en C10-C11 fournit deux fragments : le pyranne 4.94 et la chaîne latérale 9 Résumé fonctionnalisée 4.111. Une retro-allylation de Tsuji-Trost suivie d’un ajustement des fonctionnalités autour du noyau hétérocycle conduit à l’ester 3.85 Ce dernier, proviendrait de l’union entre l’alcool optiquement pur 3.29 et l’acétal 2.33E. La création d’un centre chiral sur le fragment 3.29 via une séquence oxydation-réduction asymétrique permet le contrôle de la stéréochimie absolue lors de la réaction d’annélation. Un seul énantiomère du pyranne intermédiaire 3.85 est obtenu (Schéma 3). L’addition de mCPBA sur le composé 3.85 permet l’oxydation chémosélective des deux oléfines riches en électrons. Le bis époxyde résultant est clivé par de l’acide periodique pour fournir le céto-aldéhyde intermédiaire qui est directement décarbonylé en présence du catalyseur de Wilkinson. La cétone 3.90 optiquement active est donc obtenue en 3 étapes avec un rendement de 53%. O OH TMS OTBS 3 étapes 2.1 O O TMS ee = 95% TBSO TBSO IMSC 2 étapes H 3.29 OTBS O O O 3.85 3.90 OMe O OMe O OMe 2.33E ee = 96% MeO OMe Schéma 3 La chaîne latérale droite est introduite via une réaction d’allylation de Tsuji-Trost asymétrique avec le chloroformate d’allyle. L’utilisation de (S)-SYNPHOS, comme ligand chiral, permet d’obtenir une sélectivité de 5/1 en faveur de l’isomère axial (Schéma 4). O O O O O TBSO O TBSO TBSO Cl O O Chloroformate O Allylation de O 3.90 d'allyle 4.93 Tsuji-Trost 4.94 O O ax/eq= 5/1 O O O O Schéma 4 Finalement, une métathèse croisée sélective permet la construction de l’entièreté de la chaîne latérale droite (Schéma 5). La réduction de la cétone en présence de borohydrure de sodium dans le méthanol conduit exclusivement à l’alcool axial désiré. Une dernière étape de déprotection fourni le Monate de méthyle C optiquement actif.
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