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Pyrrolidines: Optimized Synthesis Via Hydrogenation of Calix[N]Furan[4-N]Pyrroles, Conformational Study and Preliminary Work on Their Transition Metal Complexes

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Pyrrolidines: Optimized Synthesis Via Hydrogenation of Calix[N]Furan[4-N]Pyrroles, Conformational Study and Preliminary Work on Their Transition Metal Complexes Université de Neuchâtel Faculté des Sciences Calix[n]tetrahydrofuran[4-n]pyrrolidines: Optimized synthesis via hydrogenation of calix[n]furan[4-n]pyrroles, conformational study and preliminary work on their transition metal complexes Thèse soutenue le 23 septembre 2016 à l’Université de Neuchâtel pour l’obtention du titre de Docteur ès Sciences par William Maupillier Ingénieur Chimiste diplômé de l’École Nationale Supérieur de Caen (ENSICAEN) Membres du jury : Prof. Reinhard Neier (Directeur de thèse) Prof. ass. Bruno Therrien (Rapporteur interne) Prof. Helen Stoeckli-Evans (Rapporteur interne) Prof. Christophe Thomas (Rapporteur externe) Institut de Chimie – 2016 Remerciements Ce travail a été effectué d’octobre 2012 à septembre 2016 à l’institut de Chimie de l’université de Neuchâtel sous la direction du Prof. Reinhard Neier. Je tiens tout particulièrement à le remercier pour m’avoir donné l’opportunité de travailler au sein de son groupe de recherche et la confiance qu’il m’a apportée avec l’objectif de conclure un sujet qui lui tient à cœur : le sujet « calix ». Je voudrais le remercier pour la liberté de travail qu’il m’a offerte et son enthousiasme pour la recherche. J’adresse mes sincères remerciements aux Prof. Helen Stoeckli-Evans, Prof. Bruno Therrien et Prof. Christophe Thomas qui ont pris part à mon jury de thèse, pris le temps de lire et corriger le manuscrit ainsi qu’apporter de précieux conseils concernant mon manuscrit lors de la présentation privée de thèse. Je remercie tout particulièrement le Prof. Helen Stoeckli- Evans pour l’élucidation de nouvelles structures rayon X, sa disponibilité, sa gentillesse ainsi que sa patience pour l’analyse répétitive d’une même structure lors de la recherche de polymorphe. Je tiens à remercier chaleureusement le Dr. Aurora Cruz-Cabeza pour avoir réalisé les calculs d’énergies de mes composés ce qui a donné une nouvelle dimension au projet grâce à cette étude conformationelle. Je tiens à remercier tous les apprentis que j’ai encadrés lors de ces quatre années pour leur implication et leur sérieux dans leur travail ainsi que leur bonne humeur : Csilla Horvath (nos incompréhensions linguistiques ont provoqué de nombreux fous rires entre nous), Line Wehren, Loic Da Costa, Sébastien Capelli, Tracy Rosselet et Edy Flückiger. J’adresse mes remerciements aux membres du service analytique de Neuchâtel (NPAC) : Dr. Armelle Vallat, Dr. Gaétan Glauser et Laurence Lachat (spectrométrie de masse) ainsi que Dr. Claudio Dalvit et Dr. Diego Carnevale (spectroscopie RMN). Merci pour leur travail de caractérisation analytique indispensable à la synthèse organique. Je tiens à adresser un énorme merci à tous les membres de notre groupe pour les moments passés ensembles à l’institut ou en dehors autour d’une bonne bière : Dr. Damien Thevenet, Dr. Christian Invernizzi, Dr. Sara Santi, Ewa Banach, Dr. Christelle Schenk ainsi que les anciens que j’ai pu croiser lors de plusieurs événements comme Dr. Guillaume Journot, Dr. Christophe Letondor, Dr. Inga Zaitseva et Dr. Anca Pordea. Je remercie tout particulièrement toutes les personnes que j’ai rencontrées à Neuchâtel et qui ont égayés ma vie ici: mes colocataires Thomas et Mendes pour toutes les soirées passées dans le salon, sur la console ou les sorties en ville, Damien avec qui j’ai partagé mon labo et de nombreuses fondues chinoises, mes italiens préférés Christian, Sara et Matteo, Julien (a.k.a bûcheron) pour m’avoir motivé au fitness, Minghui et la nouvelle génération Marie, Fan, Cristina, Giau et Yassine. Mes pensées vont également à tous les autres étudiants doctorants et post-doctorants de l’université de Neuchâtel. Je voudrais aussi remercier tous mes amis de France. Les moments partagés ensembles ces dernières années ont été limités mais essentiels lors de mes retours. Un merci particulier pour Iano, Paulo, Ben & Jess, Flow, Stéphanie, Jérémy, Baptiste ainsi qu’à ma team de l’ENSICAEN avec Marine, Élodie, Christelle, Adèle, Sandra, Simon, Din, Tony et Ben. Je tiens à remercier chaleureusement Zsofia Tatar qui partage ma vie pour m’avoir supporté et épaulé durant toutes ces années. De nouvelles perspectives s’offrent à nous maintenant et je sais que tu te réjouis de me retrouver les weekends. Enfin, ces remerciements se concluent par un énorme merci à toute ma famille, particulièrement à mes parents Christine et Marc ainsi qu’à mon frère Thomas pour leur soutien tout au long de ces années et leur précieuses visites à Neuchâtel. “Every chemical substance, whether natural or artificial, falls into one of two major categories, according to the spatial characteristic of its form. The distinction is between those substances that have a plane of symmetry and those that do not. The former belong to the mineral, the latter to the living world.” (Louis Pasteur) Kewords Calix[n]furan[4-n]pyrrole, calix[n]tetrahydrofuran[4-n]pyrrolidine, macrocycle, optimized synthesis, hydrogenation, plate and bowl conformations, transition metal complexes, ligand Abbreviations AcOH: Acetic acid AcONH4: Ammonium acetate CHCl3: Chloroform CH2Cl2: Dichloromethane CH3CN: acetonitrile DFT: Density Functional theory DNA: Deoxyribonucleic acid Equiv.: Equivalent EtOAc: Ethyl acetate GC: Gas Chromatography HCl: Hydrochloric acid HIV: Human Immunodeficiency virus UPLC: Ultra Performance Liquid Chromatography IR: Infrared IUPAC: International Union of Pure and Applied Chemistry MS: Mass Spectroscopy NMR: Nuclear Magnetic Resonance spectroscopy r.t.: Room temperature SCE: Saturated calomel electrode TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin-layer chromatography Summary An hydrogenation method for the reduction of the easy accessible meso- octaalkylporphirinogen (calix[4]pyrrole) has previously been reported in our group. This “standard method” leads to an unsatisfactory conversion to the saturated analogue, calix[4]pyrrolidine (18% yield determined by GC). However using large excess of the catalyst leads to total conversion. In order to study the sequence of the reduction reaction, the replacement of one or several pyrrole ring(s) by furan ring(s) in the macrocycle was proposed and studied. For this study an access to the mixed calix[n]furan[4-n]pyrrole analogues had to be developed. Some of these macrocycles mixing furan and pyrrole rings have been reported in the literature by French almost 60 years ago: the yields reported were extremely low. No other method leading to the four isomers was described in the literature and only six studies were reported on these products. The previously developed procedure was fully optimized giving access to the four isomers by a selective ring-opening of calix[4]furan followed by a ring-closing reaction to form the pyrrole rings. This optimized procedure led to sufficient amounts of the four isomers to study their hydrogenation under our previously developed “standard conditions”. Hydrogenation of these isomers gave good to excellent yields compared to the hydrogenation of calix[4]pyrrole with an impressively high diastereoselectivity. Computational and NMR in solution conformational studies were carried out to characterize the conformational equilibria of these fully saturated calix[n]tetrahydrofuran[4-n]pyrrolidines as observed in solution and in the solid state. In a preliminary study the synthesis of a series of transition metal complexes using these macrocycles was undertaken. Table of Contents Chapter 1. Introduction ............................................................................................................. 1 1. Macrocycles present in Nature ........................................................................................ 1 2. “Pigments of life” ............................................................................................................ 5 3. Calix[4]arenes and heterocyclic calix[4]arenes macrocycles ......................................... 8 4. Simple synthetic nitrogen- and oxygen-containing macrocycles .................................. 12 4.1. Synthetic polyazamacrocycles ............................................................................... 12 4.2. Crown ethers and azacrown ethers......................................................................... 14 4.3. Bridged azamacrocycles and cryptands ................................................................. 16 5. Known hydrogenations of heterocyclic calix[4]arenes ................................................. 17 5.1. Hydrogenation of calix[4]furan 2 .......................................................................... 17 5.2. Hydrogenation of calix[4]pyrrole 1 ....................................................................... 18 6. Goals .............................................................................................................................. 20 Chapter 2. Synthesis of calix[n]furan[4-n]pyrroles ................................................................ 23 1. Introduction ................................................................................................................... 23 2. Our synthetic approach .................................................................................................. 24 3. First results (Thesis of Guillaume Journot)[108] ............................................................. 26 3.1. Synthesis of calix[2]furan[2]pyrroles 8 and 9 ....................................................... 26 3.2. Synthesis of calix[3]furan[1]pyrrole 10 ................................................................. 28 4. What had to
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