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Méthodologie De Synthese D'acides Amuies Azacydoalcanes Enantiopurs En Solution Et Sur Support Solide

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Méthodologie De Synthese D'acides Amuies Azacydoalcanes Enantiopurs En Solution Et Sur Support Solide Universi té de Montréal Méthodologie de synthese d'acides amuies azacydoalcanes enantiopurs en solution et sur support solide Francis Gosselin Département de chimie Faculté des arts et des sciences These presentée A la Faculté des etudes sup4rieures en vue de l'obtention du grade de Philosophiae Doctor (Ph.D.) en chimie Décembre, 1999 @ Francis Gosselin, 1999 National Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Welliqîon Street 395. rue Weilingtoci Ottawa ON K1A ON1 O(tawa0N K1AON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive Licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seli reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic fonnats. la fome de microfiche/nlm, de reproduction sur papier ou sur fomat électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Universi té de Montréal Faculte des etudes superieures Cette these intitulbe: M6thodologie de synthese d'acides amines azacydoalcanes énantiopurs en solution et sur support solide prbsentée par: Francis Gosselin a éte evalube par un jury compose des personnes suivantes: Professeur Denis Grave1 prbsident du jury Professeur William D. Lubeli directeur de recher Professeur Yvan Guindon membre du j Professeur George Just examinateur ext Professeur Stephen Michnidc representant . ni* acceptée le :......&.&M.& ......a?.- Sommaire Cette thèse relate le développement d'une methodologie de synthese d'acides aminés azacycloalcanes enantiopurs en solution et sur support solide. Nos travaux de synthèse en solution ont port6 sur le développement d'une approche générale visant un contrôle de la dimension des systèmes h&érocydiques et des centres st&réog6niques,et qui offre la possibilité d'introduire des fonctions chimiques qui miment les chaînes latérales des acides amines. Par ailleurs, nos travaux sur support solide ont porte sur l'élaboration d'une stratégie de protection et de manipulation de compos& a-amino carbonyles ainsi que l'application d'une nouvelle technique d'analyse spectroscopique de la chimie organique sur support solide. En utilisant une séquence d'oléfination de Horner-Wadsworth- Emmons / amination réductrice diast&éosélective / cydisation de lactarne, nous avons synthetisé l'aade amine indoluidine-9sne :! partir de I'aade aspar tique. Subséquemment, l'blabora tion des acides aminés quinolizidine-2-one et pyrroloazépine-2-one a demontré l'aspect général, versatile et pratique de notre approche. L'importance de la dimension des héte!rocycles sur la géométrie des angles diedres a éte démontree par l'analyse Enstallographique des acides aminbs. Nous avons dbveloppé une stratégie de synthèse des acides aminés azabicydo[X.Y.O]alcanes qui rend maintenant possible l'étude systématique de la relation conformation- activité des peptides d'interêt biologique. L'utilisation de l'acide N-(B0C)aminé (2S, 6R, 8s)-indolizidine-9-one en mimetisme peptidique a indique son potentiel en tant que structure capable d'induire un repliement de type dans les peptides biologiquement actifs. Nous avons incorpore cet acide aminé dans les structures peptidiques de la leucine-enidphdine et de l'hormone de libbration de la gonadotropine (GnRH). Les résultats d'etudes conformationnelles par spectroscopie de résonance magnetique nucleaire (RMN) et dichroïsme circulaire (DC), ainsi que l'évaluation biologique semblent indiquer que i'acide aminé indolizidine-9-one stabilise la conformation bioactive de la leucine-enképhaline. L'extension de la méthodologie mise sur pied pour la synthese des systernes azabicyc1o[X.Y.0]alcanesta foumi une synthèse pratique des acides aminés 6-alkylpipecoliques hantiopurs par une sequence de condensation aldolique / amination réductrice diastér6osélective partir du P-aldehyde de l'acide aspartique. L'étude de I'equilibre conformationnel d'analogues N -ac&yles N'-me thylpipecolinamides comme peptides modéles a démontrb l'effet produit par l'introduction d'un groupe stériquement encombrant en position 6 des pipecolinamides. Une augmentation de la population des isomères acétamides cis ainsi qu'une diminution de l'énergie d'activation du processus d'isomérisation (AGSI des acétamides ont été observh Ces travaux ont indiqué i'impact de la dimension des h4térocydes sur l'équilibre conformationnel des acetamides. Dans un dewieme temps, nous avons effectué les premiers pas d'une transition de la synthese d'azacycloalcanes en solution vers une synthese sur support solide. Nous avons voulu établir une stratégie flexible et applicable A la synthese d'azacycloalcanes énantiopurs sur support soiide. Puisque l'approche envisagée impliquait la synthese et la manipulation de compos4s a-amino carbonyles configurationnellement stables, nous avons développé un nouveau groupe protecteur, le 9-brome 9-p-bromoph4nylfluorène, pour la fonction amine des acides amines. Ce groupe protecteur permet la synth&se, l'ancrage au moment desiré, et la manipulation de composes a-amino carbonyles sur support solide. Nous avons evalue et validé le potentiel de cette approche par la synthke et la manipulation d'un a-amino aldehyde dans la préparation d'amino-alcools énantiopurs sur support solide. Nous avons développé une nouvelle technique d'analyse non- destructive de la chimie organique sur support solide utilisant la spectroscopie infra-rouge photoacoustique h transformée de Fourier (FTTR- PA). Lors de ces travaux, nous avons developpé une nouvelle synthese des acides deshydroaminés en solution et sur support solide. L'application de la technique ETIR-PA lors de la synthese d'un acide déshydroaminé a permis de suivre chaque &ape des manipulations chimiques sans destruction ni perte de matériel. Les résultats obtenus lors de ces travaux auront un impact sur le design et le développement de nouveaux mim4tismes peptidiques. En particulier, l'unification des divers aspects illustres plus haut pourrait faciliter, acc&rer et systematiser la conception et la production d'acides aminés énantiopurs et de structures h6t4rocydiques plus elaborees. Ces composés auront la capacitt! de mimer et de stabiliser les structures secondaires et la disposition spatiale des chaînes laterales des acides amines a l'intérieur de peptides biologiquement actifs. Note Je désire enoncer explicitement ma contribution à cette thèse de Ph.D. dans le but d'éviter un questionnement inopportun et une confusion de la part du lecteur quant b ma contribution aux niveaux intellectuel et scientifique, de la conception des stratégies de synthèse, du travail au laboratoire et de la rédaction des artides scientifiques. J'ai, bien sûr, entierement rédigé le chapitre 1 de cette these. Les articles du chapitre 2, qui décrivent la méthodologie de synthèse des acides aminés azabicyclo[X.Y.O]alcanes ont en tièrement été rédigés par moi-même, sous la supervision du professeur William D. Lubell. Jfai conçu et effectue l'ensemble des travaux de recherche décrits dans ce chapitre. L'article du chapitre 3, décrivant l'utilisation de l'acide amine indolizidine-9-one en mimétisme peptidique a et6 redige par moi-méme, sous la supervision des professeurs William D. Lubell et Dirk Tourwe. J'ai effectué l'ensemble des travaux de laboratoire décrits dans ce chapitre, sauf les experiences pour I'evaluation de l'activité biologique du peptide [19~~]2,3-leuane-enké~haline. Les articles du chapitre 4, qui décrivent la synthèse des acides 6- alkylpipecoliques ont éte rédiges en collaboration avec Martin E. Swarbridc et le professeur William D. Lubell. J'ai conçu et développé la méthodologie de synthgse des 6-alkylpipecolates. J'ai préparé le btert-butylpipecolate et j'ai étudie l'équilibre conformatio~eldes acetamides N-terminales de ce composé. J'ai etudié la stabilité du p-amino aldéhyde de l'aspartate et déterminé la structure de son produit de d4composition. Mon collegue a amélioré la synthese du $-aldhhyde de l'aspartate en modifiant les conditions de réduction. En utilisant la methodologie que j'ai développé, mon collegue a prépare les autres pipecolates, et détermine, avec ma collaboration, leur purete énantiomérique. L'artide du chapitre 5 decrit le developpement d'une méthodologie d'ancrage et de synthese sur support solide. L'artide a été redigé par moi- même, en collaboration avec mes collegues et le professeur William D. Lubell. J'ai conçu et effectué la synthese du groupe protecteur, des composes a-amino carbonyles, l'ancrage aux divers supports solides, la synthese de l'a-amino aldéhyde et l'ensemble des manipulations sur support solide et détermine la pureté &nantiornérique du produit final. Mes coIIegues ont préparé le polystyr&ne non-réticule, ils ont amélioré le rendement du couplage de Suzuki et les conditions de déprotection des produits lies au support solide. L'article du chapitre 6 dkit rutilisation d'une nouvelle technique d'analyse de la chimie organique sur support solide. L'artide a été rédigé par l'ensemble des collaborateurs. J'ai conçu la synthèse de I'acide déshydroamine sur support solide et en solution.
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