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Hydrolyse Assistée Par Micro-Ondes: Synthèse De Cystéines Α

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Hydrolyse Assistée Par Micro-Ondes: Synthèse De Cystéines Α Université de Montréal Hydrolyse assistée par micro-ondes : Synthèse de cystéines - substituées sur échelle multi-grammes; Synthèse catalytique énantiosélective d’alkylidènecyclopropanes 1,1-di-accepteurs par Dominic Fiset Département de Chimie, Université de Montréal Facultés des Arts et Sciences Mémoire présenté à la Faculté des études supérieures et postdoctorales en vue de l’obtention du grade de Maîtrise en Chimie Décembre 2012 © Dominic Fiset, 2012 i Résumé Le présent mémoire est subdivisé en deux principaux sujets. Le premier porte sur le développement d’une hydrolyse de thiazolidines assistée par micro-ondes en vue d’obtenir des cystéines -substituées. Le second est axé sur le développement d’une méthodologie pour la synthèse catalytique énantiosélective d’alkylidènecyclopropanes 1,1-di-accepteurs. Dans un premier temps, les rôles et les utilités des acides aminés quaternaires, plus spécifiquement des cystéines -substituées, seront abordés, puis une revue des différentes méthodes énantiosélectives pour accéder à ces unités sera effectuée. Par la suite, le développement d’une méthode rapide et efficace d’hydrolyse sous irradiation aux micro- ondes de thiazolines sera présenté. Finalement, les études menant à l’application de cette méthode à la synthèse de cystéines -substituées sur grande échelle au moyen de réacteurs en écoulement dynamique et à haut criblage seront détaillées. Dans la seconde partie, les applications ainsi que les synthèses générales des alkylidènecyclopropanes en synthèse organique seront décrites. Plus particulièrement, les applications spécifiques des alkylidènecyclopropanes 1,1-di-accepteurs ainsi que leurs synthèses seront traitées de manière exhaustive. Par la suite, le développement d’une méthodologie énantiosélective catalytique pour la synthèse d’alkylidènecyclopropanes 1,1- di-accepteurs sera présenté. L’extension de cette méthodologie à la synthèse de dérivés cyclopropanes et cyclopropènes, ainsi que l’application de réactions stéréospécifiques pour les alkylidènecyclopropanes 1,1-di-accepteurs seront brièvement discutées. Mots-clés : Acides aminés quaternaires, cystéines -substituées, irradiation aux micro- ondes, système MARS, alkylidènecyclopropanes 1,1-di-accepteurs, cyclopropanes, cyclopropènes, allènes. ii Abstract The present M.Sc. thesis will be divided into two main subjects. The first part will be focused on the development of an efficient microwave-assisted hydrolysis of thiazolidines for the synthesis of -substituted cysteines. The second part will be on the development of methodology for the asymmetric synthesis of 1,1-di-acceptor alkylidenecyclopropanes. First, the role and the importance of quaternary amino acids, more specifically of - substitued cysteines, will be described, then a review of the available enantioselective methods for their syntheses will be reported. Afterward, the development of a fast and efficient microwave-assisted hydrolysis of thiazolidines will be presented. Finally, the studies toward the applicability of the methodology for the multi-gram synthesis of - substituted cysteines using flow and high-throughput reactors will be detailed. In the second part, the general applications and syntheses of alkylidenecyclopropanes will be described. More specifically, the applications of 1,1-di- acceptor alkylidenecycloproanes as well as their syntheses will be exhaustively covered. Then, the development of a catalytic enantioselective methodology for the synthesis of di- acceptor alkylidenecyclopropanes will be presented. The extension of this methodology for the synthesis of cyclopropane and cyclopropene derivatives, as well as the applications of 1,1-diacceptor alkylidenecyclopropane in stereospecific derivatizations will be briefly discussed. Keywords : quaternary amino acids, -substituted cysteines, microwave irradiation, MARS system, 1,1-di-acceptor alkylidenecyclopropanes, cyclopropanes, cyclopropenes, allenes. iii Table des matières Résumé .................................................................................................................................... i Abstract .................................................................................................................................. ii Table des matières ................................................................................................................. iii Liste des schémas .................................................................................................................. vi Liste des tableaux .................................................................................................................. ix Liste des abréviations ............................................................................................................ xi Remerciements .................................................................................................................... xvi Chapitre 1 : Cystéines -substituées : rôles, utilités et synthèses. ................................... 1 1.1 Introduction .................................................................................................................. 1 1.1.1 Les acides aminés quaternaires et les cystéines -substituées .............................. 1 1.2 Synthèses énantiosélectives de cystéines -substituées ............................................... 3 1.2.1 Hydrolyse de la desferrithiocin ............................................................................. 3 1.2.2 Utilisation d’auxiliaires chiraux ............................................................................ 3 1.2.3 Ouverture d’aziridines ou de -lactones chirales par des anions thiolates ........... 6 1.2.4 Résolutions enzymatiques ..................................................................................... 8 1.2.5 Alkylations par transfert de phase ....................................................................... 10 1.3 Auto-régénération de stéréocentres (SRS) ................................................................. 11 Chapitre 2 : Hydrolyse de thiazolidines assistée par micro-ondes : synthèse de cystéines -substituées ....................................................................................................... 15 2.1 Études préliminaires, étendue réactionnelle et limitations ......................................... 15 2.1.1. Aperçue des réactions sous irradiation de micro-ondes ..................................... 15 2.1.2. Optimisation de l’hydrolyse assistée par micro-ondes....................................... 16 2.2.3 Étendue réactionnelle de la réaction et limitations ............................................. 18 2.2 Applicabilité de la méthode sur une échelle multi-grammes ..................................... 22 2.2.1. Études préliminaires ........................................................................................... 22 2.2.2. Utilisation du réacteur CEM Stop-flow Voyager ................................................ 26 2.2.3. Utilisation du système à haut criblage Microwaves Accelerated Reaction System (MARS) ......................................................................................................................... 28 iv 2.3. Conclusion ................................................................................................................ 29 Chapitre 3 : Les alkylidènecyclopropanes : réactivité, utilités et synthèses ................ 31 3.1. Réactivité et applications générales des alkylidènecyclopropanes ........................... 31 3.1.1 Introduction ......................................................................................................... 31 3.1.2 Les alkylidènecyclopropanes en réaction de cycloaddition ................................ 33 3.2 Applications et utilités des alkylidènecyclopropanes 1,1-di-accepteurs .................... 34 3.2.1. Réactions de cycloisomérisations ...................................................................... 35 3.2.2. Réactions de cycloadditions ............................................................................... 39 3.3.3 Réarrangements par ouverture de cycle .............................................................. 42 3.3.4. Iodolactonisation ................................................................................................ 45 3.3 Synthèse des alkylidènecyclopronanes ...................................................................... 45 3.3.1 Introduction ......................................................................................................... 45 3.4 Synthèse d’alkylidènecyclopropanes 1,1-di-accepteurs............................................. 49 3.4.1. Migration d’oléfines ........................................................................................... 49 3.4.2. Arylation cyclopropanative intramoléculaire catalysée par le palladium .......... 49 3.4.3. Addition-cyclisation en tandem sur des bromoallènes....................................... 51 3.4.4. Cyclopropanation d’allènes ................................................................................ 52 3.5 Cycloaddition-[2+1] catalysée par les métaux de transitions .................................... 54 3.5.1 Considérations mécanistiques et réactivité générale ........................................... 54 3.5.2 Cyclopropanation d’allènes énantiosélective au moyen d’un réactif diazoïque de type donneur-accepteur ................................................................................................ 56 Chapitre 4 : Synthèse catalytique
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