β-Aminocarbonyl motifs are a privileged substructures in medicinal chemistry and peptidomimetics. As part of our efforts toward metal free aminations, we developed a method for intermolecular amino-carbonylation of alkenes using hydrazones. This method provides access to cyclic azomethine imines containing a β-aminocarbonyl motif. Conceptually, these dipoles can be derivatized into many bioactive compounds, such as 1,3-diamines, β-amino amides and β-amino acids. The first part of this thesis will present the results on the derivatization of our aminocarbonylation products into various nitrogen-containing molecules, such as β-amino amides, β-amino acids and pyrazolones. More specifically, a short, chromatography-free derivatization of azomethine imines into N-Boc-β-amino amides will be presented. Following these results, the next chapter will focus on attempts at develop novel aminocarbonylation reactivity between 1,2-diacylhydrazines and alkenes followed by results from our reductive N-N bond cleavage experiments on our cyclic hydrazides.

Le sujet de cette thèse porte sur la synthèse d'inhibiteurs spécifique de la Sérine-Thréonine phosphatase I (PP1). Un criblage de la chimiothèque de l'institut Curie, réalisé par l'équipe du Dr. Popov a permis d'identifier une 3-aryl-1(2H)isoquinolone, qui perturbe la dynamique des microtubules et qui s’est ensuite avéré être un inhibiteur sélectif de PP1. Dans une première partie, nous avons mis au point une nouvelle méthodologie de synthèse de ces composés hétérocycliques par une réaction tandem d’aminocarbonylation-cyclisation pallado catalysée. L’étude d’une seconde voie de synthèse de ces composés a été étudié par réaction d'arylation direct d'une 1(2H)isoquinolone. Dans le but de trouver d’autres hit, ligand de cette phosphatase, nous avons tenté de développer un test de triple hybride chimique, en collaboration avec la société Hybrigenics. Ce test est basé sur l’interaction de notre inhibiteur hit avec la phosphatase PP1. Pour cela, nous avons synthétisé une sonde à partir de la molécule hit initiale. La deuxième partie a trait à un développement de chimie médicinal pour optimiser le hit initial. Des dérivés de très bonne sélectivité pour l’enzyme cible ont été préparés. / This PhD thesis deals with the synthesis of serine threonine phosphatase I (PPI) inhibitors. This project started with the screening of the Institut Curie’s Library carried out by Dr. Popov team. They identified a 3-aryl-1(2H)isoquinolone (hit molecule) which strongly disturbs the microtubules dynamics. In the first part, we designed an original methodology to prepare those heterocycles, though a tandem palladium catalyzed aminocarbonylation/cyclization reaction. Then, we studied the direct arylation reaction to obtain the desired scaffold. In collaboration with Hybrigenics, we synthesize a probe for a triple hybrid system, based on the specific interaction of the hit molecule with its target PPI. Thanks to this system, one could identify new inhibitors of the targeted phosphatase protein. Eventually, a library of isoquinolones derivatives was synthesized. During the invitro tests, some of those molecules proved to be very specific for the serine threonine phosphatase I.

The use of palladium-catalyzed reactions to introduce new carbon-carbon bonds is a fundamental synthetic strategy that has been widely embraced due to its high chemo- and regioselectivity and functional group tolerance. In this context, Pd(0)-catalyzed aminocarbonylations using Mo(CO)6 instead of toxic and gaseous CO and with allylamine as the nucleophile were investigated. The aminocarbonylated product dominated over the Mizoroki-Heck product, and (hetero)aryl iodides, bromides and chlorides gave N-allylbenzamides in good yields. In this thesis improvements to an existing protocol for the Pd(II)-catalyzed synthesis of aryl ketones from five benzoic acids and a variety of nitriles are also presented. Addition of TFA improved the yields and employing THF as solvent enabled the use of solid nitriles, and the aryl ketones were isolated in good yields. The pandemic of HIV infection is one of the greatest public health issues of our time and approximately 35.3 million people worldwide are living with HIV. There are currently many drugs on the market targeting various parts of the viral reproduction cycle, but the problems of resistance warrant the search for new drugs. HIV-1 protease makes the virus mature into infectious particles. In this thesis a new type of HIV-1 protease inhibitor (PI) is presented, based on two of the PIs on the market, atazanavir and indinavir, but it has a tertiary alcohol, as well as a two-carbon tether between the quaternary carbon and the hydrazide β-nitrogen. A total of 25 new inhibitors were designed, synthesized and biologically evaluated, the best compound had an EC50 value of 3 nM. Based on this series a project aimed at synthesizing macrocycles spanning the P1-P3 area was initiated. Macrocycles often tend to have an improved affinity and metabolic profile compared to their linear analogs. Introduction of a handle in the para position of the P1 benzyl group proved difficult, despite efforts to synthesize intermediates containing either a bromo-, hydroxy-, methoxy-, silyl-group protected hydroxy- or an alkyne-group. The lactone intermediate was abandoned in favor of an alternative synthetic route and initial studies were found to be promising. This new approach requires further investigation before the target macrocycles can be synthesized.

Over the past recent years, β-aminocarbonyls have been of great interest to medicinal chemists. As a practical method to obtain these moieties, alkene aminocarbonylation, accounting for the formation of a C-N and a C-C bond, has been the subject of limited research efforts (very specific intramolecular metal-catalyzed variants have been reported). Direct aminocarbonylation of alkenes constitutes a challenging and an important potential innovation in the synthesis of β-aminocarbonyls such as β-amino acids. The research efforts described in the present thesis have been primarily directed towards the development of concerted pathways for the amination of alkenes using hydrazine derivatives as bifunctional reagents. Building on our previous report on the reactivity of hydrazides, progress on the aminocarbonylation of alkenes along with the synthetic scope of this reactivity are herein provided. Therefore, the first part of the present thesis (Chapter 2) focuses primarily on the development of thermolytic conditions for the intramolecular aminocarbonylation of alkenes using amino-isocyanates. Alongside, development of imino-isocyanates have provided complementary synthetic tools for aminocarbonylation. The second part (Chapter 3) describes the work accomplished towards intermolecular aminocarbonylation of alkenes and the synthesis of complex azomethine imine products (Chapter 3). Finally, the last part of the discussion (Chapter 4) will be on the development of new hydrazide reagents for the intramolecular Cope-type hydroamination of alkenes. In doing so, description of the synthetic utility of amino-isocyanates as amphoteric reagents for cascade reactions and heterocyclic synthesis will be provided.

Nitrogen-containing heterocyclic compounds are very important to the pharmaceutical and agrochemical industries, among others. Over the past few years, the Beauchemin group has been exploring reactivity of N-substituted isocyanates and as part of this has developed a metal-free alkene aminocarbonylation process relying on imino-isocyanates to form azomethine imines. The azomethine imines formed are interesting since they contain a cyclic β-aminocarbonyl motif. Catalysis of this reaction using basic additives allowed milder reaction conditions with electron-rich C=C bonds such as enol ethers. Efforts have also been made towards the derivatization of these azomethine imines into useful products. It was discovered that upon reduction and aromatization of azomethine imines, pyrazolones could be obtained. This is providing a novel modular approach to these compounds, which have relevance in pharmaceuticals and agrochemicals. This reactivity was extended to include imino-isothiocyanates.

In modern synthetic organic chemistry, chemists are driven to develop efficient methods for important C-C and C-N bond formation reactions. The challenge lies with establishing new uses for readily available substrates. In this regard, the synthesis of β-aminocarbonyl compounds from alkenes remains a long-standing challenge. Innovation in reaction discovery often requires finding new reagents, or rare reagents with underappreciated value in synthesis. In Chapter 1, N-isocyanates and other heterocumulenes are introduced as versatile amphoteric reagents. Their amphoteric properties are valuable in the discovery of new synthetic approaches, especially in cycloaddition reactions. While C-isocyanates are bulk industrial chemicals, the formation and reactivity of N-isocyanates remains underexplored. Chapter 2 describes the development of reactivity with rare imino-isocyanates. This includes methods to access the reagent in situ with a blocking group approach, and the establishment of intermolecular cycloaddition reactivity with a variety of alkenes. This stereospecific reaction provides complex N,N’-cyclic azomethine imines, and enables access to β-aminocarbonyl compounds from alkenes. β-Amino amides and esters, pyrazolidinones, and pyrazolones were accessed by reductive derivatization of the aminocarbonylation products. Exploration into the limits of this reactivity gave insight into fundamental properties of imino-isocyanates. This includes the first detection of imino-isocyanates by IR spectroscopy. A kinetic resolution of the azomethine imines obtained from this alkene aminocarbonylation reaction was then developed, which gave access to enantioenriched β-amino carbonyl compounds (Chapter 3). This was accomplished by Brønsted acid catalysed reduction, with a selectivity factor of 13-43. This was the first example of the enantioselective reduction of azomethine imines, and represents a new activation mode for reactions of N,N’-cyclic azomethine imines. Using this reductive method, both enantiomers of the β-amino amide could be obtained from a racemic azomethine imine in ≥ 97% ee. The discovery of new reactivity of imino-isocyanates with imines in described in Chapter 4, which allowed the synthesis of eight new azomethine imines with the triazolone core. Our initial scope studies revealed different trends with imines than with alkenes, including increased reactivity, which led to investigation of the mechanism of this reaction. In addition, this was shown to be a valuable new approach for the synthesis of triazolones from imines.

<p>HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. </p><p>In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. </p><p>A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.</p><p>Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.</p>

HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'. Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-04-18T17:37:33Z No. of bitstreams: 1 wiliamcaneschi.pdf: 24031147 bytes, checksum: 55a6b3c64e0dad5d05212886301c8aa2 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-04-19T11:42:35Z (GMT) No. of bitstreams: 1 wiliamcaneschi.pdf: 24031147 bytes, checksum: 55a6b3c64e0dad5d05212886301c8aa2 (MD5) / Made available in DSpace on 2017-04-19T11:42:35Z (GMT). No. of bitstreams: 1 wiliamcaneschi.pdf: 24031147 bytes, checksum: 55a6b3c64e0dad5d05212886301c8aa2 (MD5) Previous issue date: 2016-12-20 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Os heterociclos oxadiazólicos estão presentes em inúmeras estruturas com diversas propriedades biológicas, por esse motivo, o interesse nessa pesquisa. Desse modo, este trabalho encontra-se dividido em dois capítulos: o primeiro refere-se a síntese de oxadiazóis com intuito de verificar seu potencial biológico, enquanto o segundo, baseia-se no desenvolvimento de novas metodologias para síntese dos derivados 1,2,4 e 1,3,4oxadiazólicos. No primeiro capítulo, vinte e uma substâncias derivadas do heterociclo 1,2,4oxadiazólico foram obtidas por meio de reações de substituição nucleofilica de segunda ordem e trinta e dois novos derivados 1,3,4-oxadiazólicos foram obtidos a partir de reações do tipo Mannich. Os compostos foram testados quanto as suas propriedades citotóxicas e antibacteriana. De um modo geral, os derivados 1,2,4-oxadiazólicos não apresentaram interessantes atividades biológicas. Por outro lado, os regioisômeros 1,3,4- demonstraram um perfil de atividade interessante, sendo mais ativas que aquelas moléculas contendo o grupo piperazina alquilado com doze átomos de carbono. Para a atividade antitubercular, foi verificada uma melhor atividade para os 1,3,4-oxadiazóis alquilados com quatorze átomos de carbono. A busca cada vez maior por metodologias mais simples e eficientes na síntese de novas substâncias, propiciou, neste segundo capítulo, a síntese de uma série de derivados 1,2,4- e 1,3,4-oxadiazólicos obtidos por reações de aminocarbonilação catalisadas por paládio. Vários nucleófilos hidrazidas e amidoximas foram passíveis de reação com diferentes brometos de arila e monóxido de carbono produzido ex situ, em uma reação multicomponente, possibilitando a formação desses heterociclos em altos rendimentos. Essa metodologia se mostrou eficaz na marcação isotópica de ¹³C para diferentes compostos bem como permitiu a síntese do fármaco ataluren com rendimento global de 43%. / Oxadiazoles heterocycles are present in many structures with different biological properties, therefore, the interest in this research. So, this work is divided in two chapters: the first refers to the synthesis of these heterocycles in order to verify its biological potential, while the second is based on the development of new methodologies for synthesis of derivatives 1.2, 4 and 1,3,4-oxadiazoles. In the first chapter, twenty one 1,2,4-oxadiazoles derivatives were obtained by nucleophilic substitution reactions of second order and thirty two new 1,3,4oxadiazoles derivatives were obtained through Mannich-type reactions. The compounds were tested for their anticancer and antibacterial properties. In general, 1,2,4-oxadiazoles derivatives did not show interesting activity against the tested pathologies. On the other hand, 1,3,4-regioisomers demonstrated interesting activity profile, being most active those molecules containing the alkylated piperazine group with twelve carbons chain. For the antitubercular activity, a better activity was verified for the alkylated 1,3,4oxadiazoles with fourteen carbon chain. The search for efficient and simple methods for the synthesis of new molecules, allowed in the second chapter, the synthesis of a number of 1,2,4- and 1,3,4-oxadiazoles derivatives obtained by reactions palladium-catalyzed aminocarbonylation reactions. Various nucleophiles hydrazides and amidoximes were able of reaction with different aryl bromides and carbon monoxide produced ex situ in a multicomponent reaction, enabling the formation of such heterocycles in high yields. This methodology was effective for isotopic ¹³C labeling for different compounds as well as allowed the synthesis of the drug ataluren in an 43% overall yield.

<p>The HIV protease is an essential enzyme for HIV replication and constitutes an important target in the treatment of HIV/AIDS. Efficient combination therapies using inhibitors of the reverse transcriptase and protease enzymes have led many to reevaluate HIV infections from a terminal condition to a chronic-but-manageable disease in the developed world. Unfortunately, the emergence of drug resistant viral strains and severe treatment-related adverse effects limit the benefits of current anti-HIV/AIDS drugs for many patients. Furthermore, less than one in ten patients infected with HIV in low- and middle-income countries have access to proper treatment. These important shortcomings highlight the need for new, cost effective anti-HIV/AIDS drugs with unique properties.</p><p>Microwave heating has recently emerged as a productivity-enhancing tool for the medicinal chemist. Reaction times can often be reduced from hours to minutes or seconds and chemistry previously considered impractical or unattainable can now be accessed.</p><p>In this thesis, the search for unique HIV-1 protease inhibitors and the development and application of new microwave-promoted synthetic methods useful in small-scale medicinal chemistry applications are presented. Protocols for rapid amino- and hydrazidocarbonylations were developed. Mo(CO)₆ was used as a solid source of carbon monoxide, enabling a safe, efficient and simple way to exploit carbonylation chemistry without the direct use of toxic carbon monoxide gas. The aminocarbonylation methodology was applied in the synthesis of two series of new HIV-1 protease inhibitors. A biological evaluation suggested that <i>ortho</i>-substitution of P1 and/or P1’ benzyl side chains might provide a new approach to HIV-1 protease inhibitors with novel properties. To assess the scope and limitations of the <i>ortho</i>-substitution concept, a new series of compounds exhibiting fair potency was prepared by various microwave-heated, palladium-catalyzed coupling reactions. Finally, computer modeling was applied to rationalize the binding-modes and structure-activity relationships of these HIV-1 protease inhibitors.</p>