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Ce mémoire a comme sujet principal les réactions d’ouvertures d’aziridines et leur application synthétique. Notre groupe de recherche a récemment mis au point une méthode d’aziridination énantiosélective catalysée au cuivre à partir de N-tosyloxycarbamates qui permet d’obtenir une grande variété d’arylaziridines protégées avec un groupement carbamate. Or, même si le motif aziridine se retrouve dans certains produits naturels, l’intérêt de sa synthèse provient en partie de l’accès facile à différents composés contenant une fonction amine protégée qui peuvent être obtenus suite à l’ouverture d’aziridines par différents nucléophiles. L’ouverture nucléophile des aziridines fut largement explorée pour une variété de nucléophiles et d’aziridines. Toutefois, puisque les arylaziridines protégées par un groupement carbamate n’étaient auparavant pas disponibles, leur régio- et stéréosélectivité est encore méconnue. Nous présentons ici dans un premier temps, les résultats obtenus lors de l’ouverture de la p-nitrophénylaziridine protégée par un groupement Troc avec différents nucléophiles. Puis, suite à l’obtention de bonnes diastéréosélectivités lors de la synthèse d’aziridines avec le dérivé chiral PhTrocNHOTs, des réactions d’ouvertures ont été tentées avec la p-nitrophénylaziridine protégée avec un groupement PhTroc. Les conditions optimisées d’ouverture impliquent l’acide de Lewis BF3∙OEt2 (10 mol%) à 23 °C avec une variété de nucléophiles. Ces conditions ont été appliquées à l’ouverture d’une gamme d’aziridines protégées par le groupement PhTroc dont les résultats sont décrits dans cet ouvrage. Finalement, le dernier chapitre de ce mémoire rapporte l’utilisation de ces conditions dans la synthèse du (R)-Nifenalol, un agent beta-bloquant qui a démontré une activité en tant qu’antiangineux et antiarythmique. / The main subject of this Master thesis is the ring-opening reactions of azirdines and their synthetic applications. Our group has recently developed a copper-catalyzed enantioselective aziridination reaction from N-tosyloxycarbamates which leads to a variety of carbamate-protected arylaziridines. Although the aziridine motif appears in some natural products, interest in these models comes from the easy access to amine-protected derivatives obtained via the nucleophilic ring-opening of aziridines. Nucleophilic ring-opening of aziridines has been thoroughly studied for a variety of nucleophiles and aziridines. However, as carbamate-protected arylaziridines were not previously available, little is known on either their reactivity or regio- or stereoselectivity. We present herein the results of the ring-opening of Troc-protected p-nitrophenylaziridines with a variety of nucleophiles. Furthermore, following the discovery that excellent diastereoselectivities could be achieved by using the chiral derivative PhTrocNHOTs, ring-opening reactions were attempted on PhTroc-protected p-nitrophenylaziridine. Optimized conditions were found to be 10 mol% of BF3∙OEt2 at room temperature with a variety of nucleophiles. These conditions were also used in the ring-opening of various PhTroc-protected aziridines and the results are disclosed herein. Finally, these conditions were applied to the synthesis of (R)-Nifenalol, a beta-blocking agent that has shown antianginal and antiarrhythmic properties as described in the third chapter.

Ce mémoire a comme sujet principal les réactions d’ouvertures d’aziridines et leur application synthétique. Notre groupe de recherche a récemment mis au point une méthode d’aziridination énantiosélective catalysée au cuivre à partir de N-tosyloxycarbamates qui permet d’obtenir une grande variété d’arylaziridines protégées avec un groupement carbamate. Or, même si le motif aziridine se retrouve dans certains produits naturels, l’intérêt de sa synthèse provient en partie de l’accès facile à différents composés contenant une fonction amine protégée qui peuvent être obtenus suite à l’ouverture d’aziridines par différents nucléophiles. L’ouverture nucléophile des aziridines fut largement explorée pour une variété de nucléophiles et d’aziridines. Toutefois, puisque les arylaziridines protégées par un groupement carbamate n’étaient auparavant pas disponibles, leur régio- et stéréosélectivité est encore méconnue. Nous présentons ici dans un premier temps, les résultats obtenus lors de l’ouverture de la p-nitrophénylaziridine protégée par un groupement Troc avec différents nucléophiles. Puis, suite à l’obtention de bonnes diastéréosélectivités lors de la synthèse d’aziridines avec le dérivé chiral PhTrocNHOTs, des réactions d’ouvertures ont été tentées avec la p-nitrophénylaziridine protégée avec un groupement PhTroc. Les conditions optimisées d’ouverture impliquent l’acide de Lewis BF3∙OEt2 (10 mol%) à 23 °C avec une variété de nucléophiles. Ces conditions ont été appliquées à l’ouverture d’une gamme d’aziridines protégées par le groupement PhTroc dont les résultats sont décrits dans cet ouvrage. Finalement, le dernier chapitre de ce mémoire rapporte l’utilisation de ces conditions dans la synthèse du (R)-Nifenalol, un agent beta-bloquant qui a démontré une activité en tant qu’antiangineux et antiarythmique. / The main subject of this Master thesis is the ring-opening reactions of azirdines and their synthetic applications. Our group has recently developed a copper-catalyzed enantioselective aziridination reaction from N-tosyloxycarbamates which leads to a variety of carbamate-protected arylaziridines. Although the aziridine motif appears in some natural products, interest in these models comes from the easy access to amine-protected derivatives obtained via the nucleophilic ring-opening of aziridines. Nucleophilic ring-opening of aziridines has been thoroughly studied for a variety of nucleophiles and aziridines. However, as carbamate-protected arylaziridines were not previously available, little is known on either their reactivity or regio- or stereoselectivity. We present herein the results of the ring-opening of Troc-protected p-nitrophenylaziridines with a variety of nucleophiles. Furthermore, following the discovery that excellent diastereoselectivities could be achieved by using the chiral derivative PhTrocNHOTs, ring-opening reactions were attempted on PhTroc-protected p-nitrophenylaziridine. Optimized conditions were found to be 10 mol% of BF3∙OEt2 at room temperature with a variety of nucleophiles. These conditions were also used in the ring-opening of various PhTroc-protected aziridines and the results are disclosed herein. Finally, these conditions were applied to the synthesis of (R)-Nifenalol, a beta-blocking agent that has shown antianginal and antiarrhythmic properties as described in the third chapter.

Considerando-se a necessidade brasileira de se obterem fármacos a preços competitivos e usando tecnologia nacional, visamos sintetizar um fragmento do Indinavir empregando como material de partida a L-serina, um aminoácido natural de baixo custo. Desta maneira, desenvolvemos a seguinte rota, em 6 etapas: p-tosilação da serina, pelo uso de cloreto de p-tosila / NaOH; amidação da p-tosilserina, empregando-se o sal de terc-butilamônio da N-hidroxissuccinimida / DCC; ciclização da (S)-2-terc-butil-N-p-tosilserina, em condição de transferência de fase, com cloreto de p-tosila / carbonato de potássio / TEBAC; abertura regiosseletiva do anel da aziridina pela 3-picolilamina; N,N-bis-alquilação da resultante diamina, com triflato de vinildifenilsulfônio e destosilação da piperazina obtida, promovida por HBr 30%, em ácido acético. Deste modo, o fragmento (S)- N-terc-butil-4-(piridin-3-ilmetil)piperazina-2-carboxamida foi obtido em 7 % de rendimento global e pode ser usado em uma rota alternativa para a síntese do Indinavir. / Considering the Brazilian need to obtain drugs at competitive prices and using national technology, we aimed to synthesize a fragment of Indinavir using L-serine, an inexpensive natural amino acid. Thus, we developed the following route in 6 steps: p-tosylation of serine by using p-tosyl chloride / NaOH; amidation of p-tosylserine employing the N-hydroxisuccinimide terc-butylammonium salt / DCC; cyclization of (S)-2-terc-butyl-N-p-tosylserine under phase transfer catalysis with p-tosyl chloride / potassium carbonate / TEBAC; aziridine ring opening with 3-picolylamine; N,N-bisalkylation of the resulting diamine with vinyldiphenylsulfonium triflate and detosylation of the obtained piperazine promoted by HBr 30% in acetic acid. In this way, the (S)-N-terc-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide fragment was obtained in 7 % overall yield and can be used in an alternative route for the synthesis of Indinavir.

Considerando-se a necessidade brasileira de se obterem fármacos a preços competitivos e usando tecnologia nacional, visamos sintetizar um fragmento do Indinavir empregando como material de partida a L-serina, um aminoácido natural de baixo custo. Desta maneira, desenvolvemos a seguinte rota, em 6 etapas: p-tosilação da serina, pelo uso de cloreto de p-tosila / NaOH; amidação da p-tosilserina, empregando-se o sal de terc-butilamônio da N-hidroxissuccinimida / DCC; ciclização da (S)-2-terc-butil-N-p-tosilserina, em condição de transferência de fase, com cloreto de p-tosila / carbonato de potássio / TEBAC; abertura regiosseletiva do anel da aziridina pela 3-picolilamina; N,N-bis-alquilação da resultante diamina, com triflato de vinildifenilsulfônio e destosilação da piperazina obtida, promovida por HBr 30%, em ácido acético. Deste modo, o fragmento (S)- N-terc-butil-4-(piridin-3-ilmetil)piperazina-2-carboxamida foi obtido em 7 % de rendimento global e pode ser usado em uma rota alternativa para a síntese do Indinavir. / Considering the Brazilian need to obtain drugs at competitive prices and using national technology, we aimed to synthesize a fragment of Indinavir using L-serine, an inexpensive natural amino acid. Thus, we developed the following route in 6 steps: p-tosylation of serine by using p-tosyl chloride / NaOH; amidation of p-tosylserine employing the N-hydroxisuccinimide terc-butylammonium salt / DCC; cyclization of (S)-2-terc-butyl-N-p-tosylserine under phase transfer catalysis with p-tosyl chloride / potassium carbonate / TEBAC; aziridine ring opening with 3-picolylamine; N,N-bisalkylation of the resulting diamine with vinyldiphenylsulfonium triflate and detosylation of the obtained piperazine promoted by HBr 30% in acetic acid. In this way, the (S)-N-terc-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide fragment was obtained in 7 % overall yield and can be used in an alternative route for the synthesis of Indinavir.

While unprotected amino aldehydes are typically not isolable due to imine formation and consequent polymerization, stable unprotected aziridine aldehydes are useful and available reagents. Moreover, reversible hemiacetal and hemiaminal formation enable these compounds to reveal both their electrophilic and nucleophilic functional groups. This exceptional arrangement allows for aziridine aldehyde dimers to participate in and disrupt the mechanisms of an array of well-known organic reactions, including isocyanide-based multicomponent reactions. The scope and selectivity patterns of aziridine aldehyde induced amino acid or peptide macrocyclization have been investigated. A small library of constrained tri-, tetra-, and penta-peptide macrocycles – representing the most difficult cyclic peptides to synthesize – has been prepared. The scope of aziridine aldehyde participation in multicomponent reactions was also expanded to Ugi and Passerini reactions that do not employ tethered amine and acid functional groups. In order to facilitate cellular imaging of peptide macrocycles a fluorescent isocyanide reagent was prepared and applied to prepare mitochondrial targeting macrocycles. Thioester isocyanide reagents were synthesized to enable rapid assembly of cycle-tail peptides through ligation technology.

Due to inherent rigidity of oligoproline peptides, forcing the C- and N-terminus in proximity for cyclization can be of significant challenge. To address this issue, a cyclization condition involing the help of amphoteric aziridine aldehydes has been developed. This one step cyclization protocol generally proceeds in high yields and goes to completion in relatively short period of time. Despite their cyclic nature, the resulting molecules display spectroscopic characteristics of polyproline II helices. These macrocycles should facilitate systematic studies of various conformational states of polyproline-containing protein regions.

Due to inherent rigidity of oligoproline peptides, forcing the C- and N-terminus in proximity for cyclization can be of significant challenge. To address this issue, a cyclization condition involing the help of amphoteric aziridine aldehydes has been developed. This one step cyclization protocol generally proceeds in high yields and goes to completion in relatively short period of time. Despite their cyclic nature, the resulting molecules display spectroscopic characteristics of polyproline II helices. These macrocycles should facilitate systematic studies of various conformational states of polyproline-containing protein regions.

Chiral molecules as with biological activity are plentiful in nature and the chemical literature; however they represent a smaller portion of the pharmaceutical drug market. As asymmetric methodologies grow more powerful, the tools are becoming available to synthesize chiral molecules in an enantioselective and efficient manner. Recent breakthroughs in our understanding of phosphoric acid now allow for Lewis acid catalysis via pairing with alkaline earth metals. Using alkaline earth metals with chiral phosphates is an emerging approach to asymmetric methodology, but already has an influential record. The development of new conditions for the phosphoric acid-catalyzed highly enantioselective ring-opening of meso-aziridines with a series of functionalized aromatic thiol nucleophiles is described in this thesis. This methodology utilizes commercially available aromatic thiols, a series of meso-aziridines, and a catalytic amount of VAPOL calcium phosphate to explore the substrate scope of this highly enantioselective reaction. Additionally, the development of new conditions for a catalytic asymmetric aza-Darzens aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium phosphate salt is described in this thesis. Using simple substrates, this methodology explores the scope and reactivity of a new magnesium catalyst for an aziridination reaction capable of building chirality and complexity simultaneously.

While unprotected amino aldehydes are typically not isolable due to imine formation and consequent polymerization, stable unprotected aziridine aldehydes are useful and available reagents. Moreover, reversible hemiacetal and hemiaminal formation enable these compounds to reveal both their electrophilic and nucleophilic functional groups. This exceptional arrangement allows for aziridine aldehyde dimers to participate in and disrupt the mechanisms of an array of well-known organic reactions, including isocyanide-based multicomponent reactions. The scope and selectivity patterns of aziridine aldehyde induced amino acid or peptide macrocyclization have been investigated. A small library of constrained tri-, tetra-, and penta-peptide macrocycles – representing the most difficult cyclic peptides to synthesize – has been prepared. The scope of aziridine aldehyde participation in multicomponent reactions was also expanded to Ugi and Passerini reactions that do not employ tethered amine and acid functional groups. In order to facilitate cellular imaging of peptide macrocycles a fluorescent isocyanide reagent was prepared and applied to prepare mitochondrial targeting macrocycles. Thioester isocyanide reagents were synthesized to enable rapid assembly of cycle-tail peptides through ligation technology.