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Thesis Reference Thesis Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions LINDER, David Abstract La combinaison du précatalyseur stable à l'air [CpRu(η⁶-C₁₀H₈)] [PF₆] avec des ligands de type pyridine-monooxazoline a permis de développer une nouvelle stratégie pour effectuer des réactions de substitution allyliques avec des conditions expérimentales simples. Cette famille de ligands est apparue particulièrement appropriée pour effectuer l'étude de réactions du type réarrangement de Carroll. Le mécanisme de cette réaction a été étudié et un cycle catalytique raisonnable en a découlé. Une stratégie de double activation par co-catalyse a donc été développée: l'utilisation synergique de sels de magnésium a permis d'effectuer ces réactions à température ambiante et donc de manière plus sélective. Reference LINDER, David. Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions. Thèse de doctorat : Univ. Genève, 2008, no. Sc. 4033 URN : urn:nbn:ch:unige-14791 DOI : 10.13097/archive-ouverte/unige:1479 Available at: http://archive-ouverte.unige.ch/unige:1479 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES Section de Chimie et Biochimie Département de chimie organique Professeur J. Lacour Enantioselective CpRu-Catalyzed Decarboxylative C-C Bond Forming Reactions THÈSE présentée à la Faculté des sciences de l'Université de Genève pour obtenir le grade de Docteur ès sciences, mention chimie par David LINDER de Copenhague (Danemark) Thèse N° 4033 GENÈVE Atelier d'impression ReproMail 2008 Dedicated to Dr. Pierre Mangeney. On the occasion of his retirement. We want the observed facts to follow logically from our concept of reality. Without the belief that it is possible to grasp the reality with our theoretical constructions, without the belief in the inner harmony of our world, there could be no science. This belief is and always will remain the fundamental motive for all scientific creation. Throughout all our efforts, in every dramatic struggle between old and new views, we recognize the eternal longing for understanding, […] continually strengthened by the increasing obstacles to comprehension. Albert Einstein (1879-1955), Leopold Infeld (1898-1968) The Evolution of Physics, 1938 , Cambridge University Press Remerciements You can get much farther with a kind word and a gun than you can with a kind word alone. Al Capone (1899-1947) Les résultats rapportés dans ce manuscrit ont été obtenus dans le cadre d’un travail de thèse réalisé au sein du laboratoire du Professeur Jérôme Lacour, dans le département de chimie organique de l’Université de Genève, du 01 octobre 2004 au 31 octobre 2008. Je voudrais d’abord exprimer toute ma gratitude au Professeur Jérôme Lacour, pour m’avoir donné l’opportunité de réaliser ce travail de thèse dans son laboratoire, pour la confiance et l’autonomie qu’il m’a accordées ainsi que pour sa patience pendant toutes ces années. Je désire ensuite remercier le Professeur Antonio Togni (Eidgenössische Technische Hochschule Zürich) et le Docteur Clément Mazet (Université de Genève) pour avoir eu l’amabilité de bien vouloir juger les travaux de thèse rapportés ci-après. J’exprime aussi toute ma gratitude aux équipes de service d’analyse : RMN (Dr. Damien Jeannerat, André Pinto and Bruno Vitorge), SM (Philippe Perottet and Eliane Sandmeier) et SM-HR (Prof. Gérard Hopfgardner and Nathalie Oudry) pour leur indispensable contribution. Je voudrais chaleureusement saluer mes collègues, passés et présents, et de tout le département participation active et leur alcophilie partagée. Dans un ordre parfaitement chaotique, j’exprime ma gratitude à Richard, Sam-arche, Benoit, Jej and Simone pour de si nombreuses raisons que je ne peux les détailler ici. Un grand merci à Cédric (a.k.a. Boubou) et à Michael pour leur participation efficace à ces travaux. Le « réfugié politique » remercie Reno, Chloé, Stéphane (x2), Fran et les autres pour leur accueil. Un grand, grand merci à Phan (je suis pas encore devenu comme Niko Brevic…) et à la bande de gros lourds pour les gaming-sessions interminables et les sessions pizza sponsorisées par Feldschlösschen. “Gracie mille ” pour “little V” et à l’autre petite terroriste pour tout et plus encore. Il me reste à remercier Ankit Sharma, Andrei Badoiù et le Dr. Chloé Bournaud pour leur participation active à la correction de ce manuscrit. Finalement je tiens à remercier chaleureusement Pierre et Manu qui m’ont tout deux transmis leur enthousiasme pour la recherche et leur saine vision du milieu… - i - Abbreviations, Symbols and Units Abbreviations Cp*: pentamethyl cyclopentadienyl br(s): broad (singlet) Cp’: substituted cyclopentadienyl s: singlet phen: 2,2’-phenantroline d: doublet bpy: 2,2’-bipyridine dd: doublet of doublet cod: 1,4-cyclooctadiene t: triplet BSA: N,O-bis(trimethylsilyl)amide dt: doublet of triplet Tol.: toluene q: quartet TMS: trimethyl silyl sept: septet TBDMS: tert -butyl dimethyl silyl m: multiplet TIPS: triisopropyl silyl TLC: Thin layer chromatography n-Pr: propyl Rf: retardation factor i-Pr: iso -propyl cat.: catalytic amount t-Bu: tert -butyl equiv.: equivalent BDU: Diaza(1,3)bicyclo[5.4.0]undecane conv.: conversion Ts: Tosyl C: concentration Symbols litt.: literature δ: chemical shift ref.: reference λ: wave length maj.: major J: coupling constant min.: minor l: length M.p.: melting point tR: retention time ppm: part per million T: temperature rac : racemic Units ent : opposite enantiomer of °C: degree Celsius Y.: yield K: Kelvin ee : enantiomeric excess g: gram dr.: diastereomeric ratio mg: miligram R.T.: room temperature µl: microliter b: branched regioisomer mL: milliliter l: linear regioisomer mmol: millimole Ar: aryl M: molarity napht: naphthalene min: minute Cp: cyclopentadienyl h: hour - ii - Résumé en français Formation énantiosélective de liaisons C-C par décarboxylation catalysée par des complexes CpRu L’objectif des travaux de cette thèse est de développer une version asymétrique du réarrangement de Carroll, une réaction qui peut être catalysé par des complexes de ruthénium (Schéma 1 ) comme décrit par Tunge 1 puis par Lacour. 2 Bien que le domaine de la substitution allylique soit extrêmement étendu, ce type de réactions catalysées par des complexes de ruthénium est globalement peu décrit dans la littérature. O O O O 6 [CpRu(η -C10H8)][PF6] (10 mol%) N O L18f (10 mol%) N THF, 60 °C O b l L18f R R R b:l jusqu'à 99:1 ee jusqu'à 87 % Schéma 1: Réarrangement de Carroll catalysé par un complexe du type CpRu. Les expériences décrites dans ce manuscrit montrent que la famille des pyridine- monooxazolines est une classe de ligand appropriée pour l’étude du réarrangement de Carroll catalysé par des complexes de type Cp-ruthenium. En particulier le ligand L18f a permis d’obtenir de bonnes réactivités (jusqu’à 20 fois supérieure qu’avec les pyridine-imines), de bonnes régiosélectivités (jusqu’à > 99:1) et de bonnes énantiosélectivités (jusqu’à > 80 %). O O Le mécanisme de la réaction a été O O R O étudié en détail. Même s’il n’a été R O Ar [Ru*] possible de caractériser précisément les Ar espèces intermédiaires, les nombreuses [Ru*] expériences ont permis de rassembler CO2 O suffisamment d’indices non équivoques R pour pouvoir proposer un cycle O O [Ru*] catalytique raisonnable très proche de R R Ar celui décrit dans la littérature dans le Ar Ar b l cas des réactions catalysées au Schéma 2: Cycle catalytique postulé. palladium ( Schéma 2 ). 1 Burger, E. C.; Tunge, J. A. Org. Lett. 2004 , 6, 2603-2605. Burger, E. C.; Tunge, J. A. Chem. Commun. 2005 , 2835-2837. 2 Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 2082-2085. Constant, S.; Tortoioli, S.; Muller, J.; Linder, D.; Buron, F.; Lacour, J. Angew. Chem. Int. Ed. 2007 , 46 , 8979-8982. - iii - Résumé en français Ces résultats mécanistiques ont par ailleurs permis de développer une stratégie de co-catalyse basée sur l’utilisation synergique de sels de magnésium. De meilleures réactivités ont ainsi été obtenues ; permettant de réaliser la réaction à température ambiante et par conséquent d’améliorer sensiblement les sélectivités. Dans un second temps, le système catalytique développé a été testé dans le cadre de réactions de substitutions allyliques classiques (Schéma 3 ). Il est apparu dans ces cas que l’utilisation de sels de lithium donne de bons résultats en termes de régiosélectivité (généralement 9:1) pour des réactions de substitutions allyliques sans ajout de base avec une grande variété de prénucléophiles activés. L’ensemble de ces expériences souffre malheureusement du fait que la diastéréosélectivité obtenue pour les produits branchés est médiocre (généralement 1:1) et aucune piste prometteuse ne peut être proposée à ce jour pour contourner ce problème. O Z X Z X 6 O R' [CpRu(η -Napht)][PF6] (2 mol%) O O L18f (2.4 mol%) Z R'' O LiOMe (1 mol%) X THF, 60 °C b l R R R b:l jusqu'à 92:8 r d. de 45:55 à 56:44 Schéma 3: Réactions de substitution allylique dîtes classiques . Il a aussi été montré que la même stratégie pouvait être appliquée au réarrangement décarboxylatif de carbonates et carbamates dérivés de l’alcool cinnamique. Le cas des nucléophiles azotés demeure relativement problématique puisque ni la chimiosélectivité (réactions de double alkylation) ni la régiosélectivité n’ont pu être contrôlées de manière satisfaisante. Au contraire, le cas de nucléophiles oxygénés est apparu comme bien plus prometteur puisque de bonnes sélectivités ont pu être obtenues. 6 La combinaison du précatalyseur stable à l’air [CpRu( η -C10 H8)][PF 6] avec le ligand L18f a permis de développer une nouvelle stratégie pour effectuer des réactions de substitutions allyliques avec des conditions expérimentales relativement simples. Le ligand L18f est par ailleurs apparu comme particulièrement intéressant non seulement à cause de sa synthèse extrêmement directe, mais aussi du fait que les deux énantiomères de l’aminoalcool dont il est issu sont commerciaux sous forme énantiopure pour un prix relativement modéré ((+)- or (–)- aminoindanol 5g ~ 200 CHF).
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