N-aminopeptides synthesis. Toward the synthesis of new foldamers

Ce travail décrit la synthèse, l’oligomérisation et l’étude structurale de [alpha-N-amino]mères. En extrapolant une stratégie de synthèse originale d’alpha-hydrazinoacides optiquement purs développée au LCPM nous avons pu obtenir de manière satisfaisante les N-aminodipeptides, précurseurs indispensables à la suite du projet. Nous avons pu montrer que l’activation du partenaire acide impliqué dans la réaction clé de Mitsunobu, habituellement obtenue par l’utilisation du groupement phtalimide, pouvait être avantageusement réalisée par l’introduction d’une fonction hydrazone à caractère fortement électroattracteur. Une extension de cette méthode de synthèse sur résine est un résultat qui constitue une mise en œuvre efficace de la réaction de Mitsunobu en SPS. Les N-aminodipeptides obtenus ont ensuite été engagés dans des réactions d’oligomérisation. Une étude préliminaire en phase liquide a permis de démontrer la faisabilité d’un couplage peptidique classique entre deux unités pseudopeptidiques déprotégées. La suite de l’étude a été effectuée sur phase solide et nous a permis d’obtenir les tous premiers oligomères à squelette alpha-N-aminopeptidique jamais synthétisés à ce jour. Enfin, dans le troisième chapitre, ces oligomères ont été étudiés par modélisation moléculaire et par différentes méthodes spectroscopiques (RMN, IR) qui ont permis de mettre en évidence un repliement par l’établissement de liaisons hydrogène intramoléculairesThis work describes the synthesis, the oligomerization and the structural study of N-aminopeptides. By extrapolating an original strategy of hydrazinoacids synthesis developed in the LCPM we were able to obtain N-aminodipeptides in high optical purity in a satisfactory way. These compounds were the indispensable precursors in order to continue the project. We were able to show that the activation of the acidic partner involved in the key reaction of Mitsunobu usually obtained by the use of the phtalimide group, could be advantageously realized by the introduction of a hydrazone moiety with strong electron-withdrawing character. An extension of this method on solid support is a result which constitutes an effective application of a Mitsunobu protocol in Solid Phase Organic Chemistry. The N­aminodipeptides thus obtained were studied in reactions of oligomérisation. A preliminary study in liquid phase allowed to demonstrate that a classic peptidic coupling reaction could occur between two pseudopeptidic units. The continuation of the study was made on solid phase and allowed us to obtain the first [alpha-N-amino]peptides never synthesized to this day. Finally, in the third chapter, these oligomers were studied by molecular modelling and various spectroscopic methods (NMR, IR) who allowed to suggest a folding by the establishment of intramolecular hydrogen bond

Synthèse de N-aminopeptides. Application à la synthèse de nouveaux foldamères

This work describes the synthesis, the oligomerization and the structural study of N-aminopeptides. By extrapolating an original strategy of hydrazinoacids synthesis developed in the LCPM we were able to obtain N-aminodipeptides in high optical purity in a satisfactory way. These compounds were the indispensable precursors in order to continue the project. We were able to show that the activation of the acidic partner involved in the key reaction of Mitsunobu usually obtained by the use of the phtalimide group, could be advantageously realized by the introduction of a hydrazone moiety with strong electron-withdrawing character. An extension of this method on solid support is a result which constitutes an effective application of a Mitsunobu protocol in Solid Phase Organic Chemistry. The N­aminodipeptides thus obtained were studied in reactions of oligomérisation. A preliminary study in liquid phase allowed to demonstrate that a classic peptidic coupling reaction could occur between two pseudopeptidic units. The continuation of the study was made on solid phase and allowed us to obtain the first [alpha-N-amino]peptides never synthesized to this day. Finally, in the third chapter, these oligomers were studied by molecular modelling and various spectroscopic methods (NMR, IR) who allowed to suggest a folding by the establishment of intramolecular hydrogen bondsCe travail décrit la synthèse, l'oligomérisation et l'étude structurale de [alpha-N-amino]mères. En extrapolant une stratégie de synthèse originale d'alpha-hydrazinoacides optiquement purs développée au LCPM nous avons pu obtenir de manière satisfaisante les N-aminodipeptides, précurseurs indispensables à la suite du projet. Nous avons pu montrer que l'activation du partenaire acide impliqué dans la réaction clé de Mitsunobu, habituellement obtenue par l'utilisation du groupement phtalimide, pouvait être avantageusement réalisée par l'introduction d'une fonction hydrazone à caractère fortement électroattracteur. Une extension de cette méthode de synthèse sur résine est un résultat qui constitue une mise en oeuvre efficace de la réaction de Mitsunobu en SPS. Les N-aminodipeptides obtenus ont ensuite été engagés dans des réactions d'oligomérisation. Une étude préliminaire en phase liquide a permis de démontrer la faisabilité d'un couplage peptidique classique entre deux unités pseudopeptidiques déprotégées. La suite de l'étude a été effectuée sur phase solide et nous a permis d'obtenir les tous premiers oligomères à squelette alpha-N-aminopeptidique jamais synthétisés à ce jour. Enfin, dans le troisième chapitre, ces oligomères ont été étudiés par modélisation moléculaire et par différentes méthodes spectroscopiques (RMN, IR) qui ont permis de mettre en évidence un repliement par l'établissement de liaisons hydrogène intramoléculaire

Toward Bis C , C -Glycosyl Compounds and Anomeric γ-Glycoamino Acids through Michael Addition Reaction of Nitromethane on Z / E Push-Pull Sugar Olefins

International audienceThe nucleophilic addition of a nitronate anion on push‐pull anomeric sugar olefins has been studied and the results reveal that this reaction opens a new and efficient access to anomeric γ‐nitro esters when applied to furanoglycosylidenes. The 1,4‐addition reaction occurs mainly from the less‐crowded face, i.e. the opposite side to the 4,5‐isopropylidene protecting group. Very different reactivities for E and Z isomers were observed and this experimental finding was rationalized on the basis of quantum mechanical calculations. Chemical manipulation of the nitro function of these bis C,C‐glycosyl compounds led to a series of new γ‐glycoamino acids, which are chiral building blocks that may be useful for the synthesis of glycopeptides oligomers or scaffolds for the construction of bioactive compounds. Under the same reaction conditions, pyranoglycosylidenes were more prone to migration of the double bond than to the expected 1,4 addition reaction

Synthesis of new C-glycosyl aza-beta3-amino acids building blocks

International audienceNew C-glycosylated Nb-protected aza-beta3-amino acid building blocks have been prepared from C-glycosyl aldehydes of gluco and galacto configuration by reductive amination and subsequent N-alkylation. These moieties were elaborated to b-dipeptides by elongation at the C- or the N-terminus establishing their ability to be incorporated in original glycosylated foldamers

Robust Synthesis of <i>N</i>‑Sulfonylazetidine Building Blocks via Ring Contraction of α‑Bromo <i>N</i>‑Sulfonylpyrrolidinones

A simple and robust <i>one-pot</i> nucleophilic addition–ring contraction of α-bromo <i>N</i>-sulfonylpyrrolidinones has been achieved toward α-carbonylated <i>N</i>-sulfonylazetidines. In the presence of potassium carbonate, various nucleophiles, such as alcohols, phenols or anilines, have been efficiently incorporated into the azetidine derivatives. Moreover, the α-bromopyrrolidinone precursors could be selectively obtained in good yields by monobromination of cheap and easily available <i>N</i>-sulfonyl-2-pyrrolidinone derivatives

New Chiral Zinc Complexes: Synthesis, Structure, and Induction of Axial Chirality

We describe an efficient methodology for the preparation of new chiral zinc complexes by assembling dynamically racemic biphenol derivatives and chiral 1,2-diamines with suitable zinc­(II) precursors. Mononuclear and dinuclear zinc­(II) complexes were formed from differently substituted biphenols. The solid-state and solution structural characterization of the resulting compounds allowed us to demonstrate a preferential sense of induced axial chirality for mononuclear complexes, a phenomenon that was not observed for the dinuclear ones

New Chiral Zinc Complexes: Synthesis, Structure, and Induction of Axial Chirality

We describe an efficient methodology for the preparation of new chiral zinc complexes by assembling dynamically racemic biphenol derivatives and chiral 1,2-diamines with suitable zinc­(II) precursors. Mononuclear and dinuclear zinc­(II) complexes were formed from differently substituted biphenols. The solid-state and solution structural characterization of the resulting compounds allowed us to demonstrate a preferential sense of induced axial chirality for mononuclear complexes, a phenomenon that was not observed for the dinuclear ones