<p>N-Heterocycles are ubiquitous in biologically active natural products and pharmaceuticals. Yet, new syntheses and modifications of N-heterocycles are continually of interest for the purposes of expanding chemical space, finding quicker synthetic routes, better pharmaceuticals, and even new handles for molecular labeling. There are several iterations of molecular labeling; the decision of where to place the label is as important as of which visualization technique to emphasize. </p><p>Piperidine and indole are two of the most widely distributed N-heterocycles and thus were targeted for synthesis, functionalization, and labeling. The major functionalization of these scaffolds should include a nitrogen atom, while the inclusion of other groups will expand the utility of the method. Towards this goal, ease of synthesis and elimination of step-wise transformations are of the utmost concern. Here, the concept of electrophilic amination can be utilized as a way of introducing complex secondary and tertiary amines with minimal operations.</p><p>Molecular tags should be on or adjacent to an N-heterocycle as they are normally the motifs implicated at the binding site of enzymes and receptors. The labeling techniques should be useful to a chemical biologist, but should also in theory be useful to the medical community. The two types of labeling that are of interest to a chemist and a physician would be positron emission tomography (PET) and magnetic resonance imaging (MRI). </p><p>Coincidentally, the 3-positions of both piperidine and indole are historically difficult to access and modify. However, using electrophilic amination techniques, 3-functionalized piperidines can be synthesized in good yields from unsaturated amines. In the same manner, 3-labeled piperidines can be obtained; the piperidines can either be labeled with an azide for biochemical research or an 18F for PET imaging research. The novel electrophiles, N-benzenesulfonyloxyamides, can be reacted with indole in one of two ways: 3-amidation or 1-amidomethylation, depending on the exact reaction conditions. Lastly, a novel, hyperpolarizable 15N2-labeled diazirine has been developed as an exogenous and versatile tag for use in magnetic resonance imaging.</p> / Dissertation

This dissertation is devoted to our synthetic studies towards the total synthesis of the natural product Nakadomarin A, and Manzamine A using the Pauson-Khand reaction as the key step. Chapter 1 reviews past work using Pauson-Khand technology. Chapter 2 reviews the N-alkyl piperidine family of natural products. Chapter 3 reviews published total syntheses of Manzamine A and Nakadomarin A. Chapter 4 explores our work using the Pauson-Khand reaction to form the ABC rings of Nakadomarin A and subsequent B ring expansion to form the ABC ring core of Manzamine A. Chapter 5 explores our approaches to the furan portion, as well as, our approaches to the macrocyclic F ring. Finally Chapter 6 contains the description of the experiments performed along with relevant analytical data. / text

Dans ce mémoire, il sera question de la formation de dérivés pipéridines en utilisant la fragmentation de Grob. Tout d’abord, une introduction sur les alcaloïdes ainsi que sur l’expertise du groupe Charette associée à leur formation démontrera l’importance de ces composés dans le domaine de la chimie organique. Cela sera suivi par un résumé de la fragmentation de Grob incluant les conditions de réactions utilisées, l’importance de la structure de la molécule initiale, les prérequis stéréoélectroniques ainsi que les modifications qui y ont été apportées. Le chapitre 2 sera dédié au développement de la méthodologie c’est-à-dire, à l’optimisation de tous les paramètres jouant un rôle dans la fragmentation de Grob. Par la suite, l’étendue de la réaction ainsi que des explications sur la régiosélectivité et la diastéréosélectivité de la réaction seront fournies. La méthodologie peut être exploitée dans un contexte de synthèse qui sera démontré dans le chapitre 3. De plus, elle servira pour une étude mécanistique qui est encore d’actualité à partir du concept d’effet frangomérique. Finalement, quelques projets futurs, notamment des améliorations possibles de la méthodologie, seront présentés dans le dernier chapitre. Le tout sera suivi d’une conclusion résumant l’ensemble des travaux effectués. / This thesis discusses the formation of piperidine derivatives using the Grob fragmentation. Firstly, an introduction of the important alkaloid family as well as previous work completed by the Charette group towards the synthesis of these compounds will be demonstrated. This will be followed by a summary of the Grob fragmentation including a discussion of the reaction conditions, molecular structures, stereoelectronic requirements and modifications of the Grob fragmentation. Chapter 2 will be dedicated to the development of the methodology and more precisely, to the optimization of all parameters necessary to the reaction. Furthermore, the scope of the reaction and some explanation of the regioselectivity and the diastereoselectivity of the reaction will be discussed. The developed methodology can be used in a total synthesis and will be demonstrated in Chapter 3. Moreover, using the frangomeric effect concept, a mechanistic study on the Grob fragmentation will be discussed. Finally, some future projects, especially possible improvement of the methodology, will be presented in the last chapter. This is followed by a conclusion and a summary of the work completed on this project.

Made available in DSpace on 2014-06-11T19:35:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-04-23Bitstream added on 2014-06-13T18:46:23Z : No. of bitstreams: 1 pivatto_m_dr_araiq.pdf: 3895401 bytes, checksum: 8f00934510e296fa101a80060a9db12a (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O presente trabalho teve como objetivo o estudo das vias biossintéticas dos alcalóides piperidínicos presentes em Senna spectabilis, motivado pela potente atividade anticolinesterásica e baixa toxicidade observada no derivado (–)-3-O-acetil-espectalina (15), eleito como composto líder para o desenvolvimento de fármacos anti-Alzheimer que estão em fase de estudos pré-clínicos. Por outro lado, o interesse acadêmico no conhecimento das vias metabólicas, pode levar a estudos futuros de engenharia genética para potencializar a produção desses metabólitos uma vez que a síntese é extremamente complexa em função da presença de três centros estereogênicos. Tendo isso em vista, foram selecionadas seis espécies de Senna e Cassia para avaliar a presença dos alcalóides e selecionar aquela que os produz em maior quantidade. Foram estudadas as flores de S. spectabilis, S. multijuga, S. macranthera, S. velutina, C. fistula, C. leptophylla, sendo que só foram detectados alcalóides piperidínicos e piridínicos em S. spectabilis e S. multijuga, respectivamente, utilizando a espectrometria de massas tandem. Embora sejam de classes diferentes, esses metabólitos têm padrão de substituição similar, porém, apresentaram atividade anticolinesterásica diferenciada. De S. spectabilis foram isolados os alcalóides piperidínicos: (–)-cassina (1), (–)-espectalina (9), (–)-3-O-acetil-espectalina (15), (–)-3-O-acetil-cassina (16) e identificados 7-hidroxi-carnavalina (71), 7-hidroxi-cassina (18) e/ou espicigerina (42) utilizando a EM. De S. multijuga foram isolados os alcalóides piridínicos: 7'-multijuguinona (67) e 12'-hidroxi-7'-multijuguinona (69) e identificados 7'-multijuguinol (68) e 12'-hidroxi-7'- multijuguinol (70). Para os estudos biossintéticos dos alcalóides piperidínicos foi inicialmente proposta a biogênese onde lisina e acetato foram eleitos potenciais... / The following work encompass as main goal the study of biosynthetic pathways to produce piperidine alkaloids using Senna spectabilis as natural matrix. Such research was instigated due to the high acetylcholinesterase activity and low toxicity showed by the derivative (–)-3-O-acetyl-spectaline (15), selected as a lead compound against Alzheimer’s disease and currently under pre-clinical trials. Still yet, the academic interest on researching metabolic pathways that may lead to further genetic engineering studies to enhance the production of these metabolites is of extremely importance, due to the inability of producing any commercially viable synthetic strategy for their stereogenic centers. We selected six Senna and Cassia species to evaluate the presence of these metabolites aiming to select which matrix will produce them the most. We studied flowers from S. spectabilis, S. multijuga, S. macranthera, S. velutina, C. fistula and C. leptophylla. From those, we were able to detect piperidine and pyridine alkaloids only in S. spectabilis and S. multijuga, respectively, using tandem mass spectrometry. Regardless of the different structural nature towards 15, those metabolites have similar substitution patterns and showed differential acetylcholinesterase activity. From S. spectabilis were isolated the piperidine alkaloids: (–)-cassine (1), (–)-spectaline (9), (–)-3-O-acetyl-spectaline (15), (–)-3-O-acetyl-cassine (16), and identified 7-hidroxy- carnavaline (71), 7-hidroxy-cassine (18) and/or spicigerine (42) by tandem mass spectrometry and from S. multijuga were isolated the pyridine alkaloids: 7'-multijuguinone (67), 12'-hydroxy-7'-multijuguinone (69) and, identified by MS: 7'-multijuguinol (68) and 12'-hydroxy-7'-multijuguinol (70). We initially proposed the incorporation of lysine and acetate as main precursors of the piperidine alkaloids biosynthetic pathway and thus... (Complete abstract click electronic access below)

Resumo: O presente trabalho teve como objetivo o estudo das vias biossintéticas dos alcalóides piperidínicos presentes em Senna spectabilis, motivado pela potente atividade anticolinesterásica e baixa toxicidade observada no derivado (-)-3-O-acetil-espectalina (15), eleito como composto líder para o desenvolvimento de fármacos anti-Alzheimer que estão em fase de estudos pré-clínicos. Por outro lado, o interesse acadêmico no conhecimento das vias metabólicas, pode levar a estudos futuros de engenharia genética para potencializar a produção desses metabólitos uma vez que a síntese é extremamente complexa em função da presença de três centros estereogênicos. Tendo isso em vista, foram selecionadas seis espécies de Senna e Cassia para avaliar a presença dos alcalóides e selecionar aquela que os produz em maior quantidade. Foram estudadas as flores de S. spectabilis, S. multijuga, S. macranthera, S. velutina, C. fistula, C. leptophylla, sendo que só foram detectados alcalóides piperidínicos e piridínicos em S. spectabilis e S. multijuga, respectivamente, utilizando a espectrometria de massas tandem. Embora sejam de classes diferentes, esses metabólitos têm padrão de substituição similar, porém, apresentaram atividade anticolinesterásica diferenciada. De S. spectabilis foram isolados os alcalóides piperidínicos: (-)-cassina (1), (-)-espectalina (9), (-)-3-O-acetil-espectalina (15), (-)-3-O-acetil-cassina (16) e identificados 7-hidroxi-carnavalina (71), 7-hidroxi-cassina (18) e/ou espicigerina (42) utilizando a EM. De S. multijuga foram isolados os alcalóides piridínicos: 7'-multijuguinona (67) e 12'-hidroxi-7'-multijuguinona (69) e identificados 7'-multijuguinol (68) e 12'-hidroxi-7'- multijuguinol (70). Para os estudos biossintéticos dos alcalóides piperidínicos foi inicialmente proposta a biogênese onde lisina e acetato foram eleitos potenciais... (resumo completo, clicar acesso eletrônico abaixo) / Abstract: The following work encompass as main goal the study of biosynthetic pathways to produce piperidine alkaloids using Senna spectabilis as natural matrix. Such research was instigated due to the high acetylcholinesterase activity and low toxicity showed by the derivative (-)-3-O-acetyl-spectaline (15), selected as a lead compound against Alzheimer's disease and currently under pre-clinical trials. Still yet, the academic interest on researching metabolic pathways that may lead to further genetic engineering studies to enhance the production of these metabolites is of extremely importance, due to the inability of producing any commercially viable synthetic strategy for their stereogenic centers. We selected six Senna and Cassia species to evaluate the presence of these metabolites aiming to select which matrix will produce them the most. We studied flowers from S. spectabilis, S. multijuga, S. macranthera, S. velutina, C. fistula and C. leptophylla. From those, we were able to detect piperidine and pyridine alkaloids only in S. spectabilis and S. multijuga, respectively, using tandem mass spectrometry. Regardless of the different structural nature towards 15, those metabolites have similar substitution patterns and showed differential acetylcholinesterase activity. From S. spectabilis were isolated the piperidine alkaloids: (-)-cassine (1), (-)-spectaline (9), (-)-3-O-acetyl-spectaline (15), (-)-3-O-acetyl-cassine (16), and identified 7-hidroxy- carnavaline (71), 7-hidroxy-cassine (18) and/or spicigerine (42) by tandem mass spectrometry and from S. multijuga were isolated the pyridine alkaloids: 7'-multijuguinone (67), 12'-hydroxy-7'-multijuguinone (69) and, identified by MS: 7'-multijuguinol (68) and 12'-hydroxy-7'-multijuguinol (70). We initially proposed the incorporation of lysine and acetate as main precursors of the piperidine alkaloids biosynthetic pathway and thus... (Complete abstract click electronic access below) / Orientador: Vanderlan da Silva Bolzani / Coorientador: Maysa Furlan / Banca: Ian Castro-Gamboa / Banca: Frederico Guaré Cruz / Banca: Márcia Nasser Lopes / Banca: Maria Claudia Marx Young / Doutor

Orientadores: Woodruff Whitman Benson, Jose Roberto Trigo / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-06T14:03:47Z (GMT). No. of bitstreams: 1 Dall'Aglio-Holvercem_ChristianeGoncalves_D.pdf: 1459643 bytes, checksum: 5ed521529fb7303e231df7d9f2ebbda3 (MD5) Previous issue date: 2006 / Resumo: Este trabalho discute alguns aspectos da ecologia da formiga lava-pés Solenopsis invicta e seus parasitóides, as moscas do gênero Pseudacteon (familia Phoridae), e da taxonomia de S. invicta e S. saevissima, ambas nativas da América do Sul. A alometria de colônias de S. invicta no sudeste do Brasil foi estudada através de medições das dimensões do ninho acima do solo, seguidas por escavação e medida da profundidade, biomassa e número de operárias da colônia, assim como da largura média da cabeça das operárias. Análise de regressão dos dados para 28 colônias forneceu novas relações alométricas que podem ser usadas para estimar o volume do ninho (acima e abaixo da superfície do solo), a biomassa de formigas, e o número de operárias a partir do volume do ninho acima do solo. A biomassa de formigas por unidade de volume do ninho, o número de operarias por unidade de volume do ninho, o peso médio por operária, e a largura média da cabeça das operárias foram essencialmente independentes do tamanho da colônia. Em contraste, estas quatro quantidades aumentam com o tamanho da colônia entre colônias de S. invicta na América do Norte. O ciclo sazonal e abundância de moscas parasitóides do gênero Pseudacteon na vizinhança de colônias de S. invicta no sudeste do Brasil foi observado ao longo de um período de 3 anos em li áreas de gramíneas nos arredores de Campinas. O número médio N de forídeos atraídos para um ninho de formigas lava-pés ao longo de um período padrão de observação (15 min) foi usado como uma medida da abundância de forídeos. As dimensões do ninho e algumas variáveis meteorológicas foram também registradas em cada ninho de formigas lava-pés. Pseudacteon tricuspis foi a espécie mais comum (70.4%), seguido por P. curvatus (23.8%), P. obtusus (1.9%) e P.litoralis (3.9%). As características mais notáveis das flutuações sazonais da abundância de Pseudacteon são picos abruptos com duração aproximada de um mês (valores máximos de N entre 4 e 10 forídeos/ninho), que ocorreram em abril e junho de alguns anos; para comparação, valores típicos de N estavam entre 0.2 e 2 forídeos/ninho. As populações de forídeos parecem ser destruídas por incêndios e inundações, mas recuperam-se em uma escala de tempo da ordem de meses. Nenhuma correlação significativa foi encontrada entre a abundância de Pseudacteon e variáveis meteoro lógicas, densidade, ou volume de ninhos de S. invicta, sugerindo que a abundância de Pseudacteon não está diretamente ligada a abundância de S. invicta. Flutuações quase idênticas em abundância de Pseudacteon foram observadas ao longo de um período de 6 meses em duas áreas de estudo separadas por cerca de 3 km, o que pode ser causado por dispersão de forídeos e conseqüente uniformização de densidades sobre áreas de vários quilômetros quadrados. Os números de forídeos atraídos pelos vários ninhos de S. invicta incluídos neste estudo seguiram uma distribuição de Poisson em baixas abundâncias de Pseudacteon (N < 0,5 forídeos/ninho); a distribuição tornava-se mais e mais contagiosa com o aumento da abundância de Pseudacteon (até o máximo observado, de N = 10 forídeoslninho). Esta observação sugere que a atratividade de um ninho de formigas lava-pés aos parasitóides aumenta com o número de forídeos que foram previamente atraídos para o ninho. Critérios quantitativos eficientes foram desenvolvidos para distinguir entre S. invicta e S. saevissima, que são morfológicamente muito similares e cujas distribuições geográficas na América do Sul se sobrepõe significativamente. Estes critérios resultaram da análise de 68 amostras de formigas lava-pés de 9 localidades espalhadas pelo estado de São Paulo (sudeste do Brasil) através de cromatografia gasosa e espectrometria de massa. 22 hidrocarbonetos cuticulares e 18 alcalóides piperidínicos foram identificados nas amostras estudadas, e suas abundâncias relativas foram analisadas utilizando análises de componentes principais e de funções discriminantes. Estas análises mostraram uma separacão nítida entre as duas espécies em um plano com certas coordenadas (P,Q), que são funções das abundâncias relativas dos hidrocarbonetos cuticulares. As amostras provenientes de uma das localidades (São José do Rio Preto) têm uma composição de hidrocarbonetos que é claramente diferente de todas as outras amostras consideradas neste estudo, mas também apresentam algumas caracteristicas em comum com cada uma das duas espécies. Uma possibilidade é que esta população constitua um hibrido de S. invicta e S. saevissima. As duas espécies também exibem uma separação razoavelmente nítida em um plano com coordenadas (R$), que são funções das abundâncias relativas de alcalóides piperidínicos. Os resultados das identificações de espécies baseados nestes critérios de separação quimica concordam com os resultados baseados em um critério morfológico, a presença ou ausência do dente clipeal mediano. A população "anômala" de São José do Rio Preto é morfologicamente classificada como S. invicta / Abstract: This work discusses some aspects of the ecology of the fire ant species Solenopsis invicta and its phorid parasitoid flies ofthe genus Pseudacteon, and ofthe taxonomy of S. invicta and S. saevissima, both of which are native to South America. The allometry of S. invicta colonies in southeast Brazil was studied by measurement of mound (aboveground) dimensions, followed by excavation and measurement of the colony depth, biomass, number of workers, and mean worker head width. Regression anaIysis of data for 28 colonies yielded new allometric relationships which can be used to estimate nest volume (above and below ground), ant biomass, and number ofworkers ITom mound (aboveground) volume. Ant biomass per unit nest volume, number of workers per unit nest volume, mean worker weight, and mean worker head width were nearly independent of colony size. In contrast, these four quantities increase with colony size among S. invicta colonies in North America. The seasonal cycle of abundance of Pseudacteon phorid flies in the vicinity of S. invicta colonies in southeast Brazil was observed over a 3-year period in 11 grass-covered areas in the outskirts of Campinas. The average number N of phorids attracted to a fire ant nest over a standard observation period (15 min) was used as a measure of phorid abundance. Mound dimensions and meteorological variables were also recorded at each fIre ant nest. Pseudacteon tricuspis was the most common species (84.2%), followed by P. curvatus (12.6%), P. obtusus (2.7%) e P. litoralis (0.5%). The most remarkabIe featores of the seasonal fluctuations of Pseudacteon abundance are sharp month-Iong peaks (peak N values between 4 and 10 phorids/nest) which occurred in Abril and June of some years; for comparison, at other times N was typically between 0.2 and 2 phorids/nest. Phorid populations seem to be destroyed by rifes and floods, but recover on a time scale of months. No significant correlation was found between Pseudacteon abundance and meteorological variables, density, or volume of S. invicta nests, suggesting that Pseudacteon abundance is not determined by, and does not determine, the abundance of S. invicta. Almost identical fluctuations in Pseudacteon abundance were observed over a 6-month period in two study areas separated by about 3 km, which may be due to phorid dispersaI and consequent density uniformization over areas of several square kilorneters. The nurnbers of phorids attracted by the various S. invicta nests inc1uded in this study followed a Poisson distribution at 10w Pseudacteon abundances (N < 0.5 phorids/nest), becoming more and more contagious at high Pseudacteon abundances (up to N= 10 phorids/nest). This observation suggests that the attractiveness oftire ant nests to phorid parasitoids increase with the nurnbeer ofphorids which have been previously attracted to the nest. Efficient quantitative criteria were developed for distinguishing between S. invicta and S. saevissima, which are morphologically very similar and whose geographical ranges in South Arnerica significantly overlap. These criteria resulted from the analysis of 68 tire ant samples from 9 localities across São Paulo state (southeast Brazil) via gas chromatography/mass spectrometry. 22 cuticular hydrocarbons and 18 piperidine alkaloids were identified in the studied samples, and their relative abundances were analyzed using principal component and discrirninant function analyses. These analyses showed a sharp separation between the two species in a plane with certain coordinates (P,Q), which are functions of the relative abundances of cuticular hydrocarbons. The fire ant samples from one of the localities (São José do Rio Preto) had a hydrocarbon composition which was markedly different from ali other samples considered in this study, but had some features in common with each ofthe two species. One possibility is that this population constitutes a hybrid of S. invicta and S. saevissima. The two species also show a reasonably sharp separation in a plane with coordinates (R,S), which are functions of the relative abundances of piperidine alkaloids. The species identification results based on these chernical separation criteria agree with those based on a morphological criterion, the presence or absence of the median clypeal tooth. The "anomalous" population from São José do Rio Preto is rnorphologically c1assified as S. invicta / Doutorado / Ecologia / Doutor em Ecologia

Les alcaloïdes de la pipéridine sont des composés présents à la fois dans le règne animal et végétal. L'approche générale que nous avons développée au cours de ce travail de thèse est basée sur l'utilisation de différents -aminonitriles qui ont été préparés soit par réduction de sels de pyridinium chiraux soit par cyanation anodique d'amines tertiaires dérivées de l'-phényl-éthylamine. Dans le premier cas, la modification de la réaction de Fry nous a permis de préparer les deux énantiomères de la coniine qui constitue l'agent toxique de la grande cigüe (Conium maculatum). En combinant cette méthode avec la métallation de Beak, nous avons pu accéder à la (+)-solénopsine A qui est l'un des constituants du venin des fourmis tropicales Solenopsis invicta. La seconde méthode qui utilise la voie électrochimique, a permis de synthétiser la (+)-myrtine qui est une indolizidine isolée de Vaccinium myrtillis et l'alcaloïde (+)-241D qui est extrait de sécrétions cutanée des grenouilles tropicales Dendrobates speciosus. Enfin, une nouvelle synthèse de la (–)-perhydrohistrionicotoxine (isolée de Dendrobates histrionicus) a été mise au point et cette dernière est basée sur l'alkylation diastéréosélective d'un α-aminonitrile chiral non racémique préparé par voie électrochimique. / Piperidine alkaloids are found in both animal and vegetal kingdoms. In this work, we have developed the synthesis and the utilization of several -aminonitrile systems which have been prepared either from the reduction of chiral non racemic pyridinium salts or from the anodic cyanation of piperidine ring system. In the first case, the modification of the Fry cyanation allowed the synthesis of both enantiomers of coniine which is the toxic component of hemlock (conium maculatum). By virtue of the Beak's lithiation–alkylation procedure, we have been able to synthesize the trans 2,6-piperidine (+)-solenopsin A which is one of the constituents of the venom of fire ant solenopsis invicta. As an alternative process, the anodic cyanation of piperidone derivatives allowed us to prepare the quinolizidine alkaloid (+)-myrtine (vaccinum myrtillis) and the all cis-2,4,6-piperidine alkaloid (+)-241D which is extracted from the skin of brightly colored neotropical frog dendrobates speciosus. Our final synthetic approach has been devoted to the stereoselective construction of spiropiperidine (–)-perhydrohistrionicotoxin whose tertiary chiral center was elaborated through the diastereoselective alkylation of an α-aminonitrile system which has been prepared by electrochemical means.

This thesis is a study of α-(4-aminophenylsulfonyl)-acetophenone derivatives; n-diphenylmethyl and n-fluorenyl piperidines.

Le noyau pipéridine est un des motifs les plus courant dans les produits naturels et pharmaceutiques ce qui explique que la synthèse énantiosélective de piperidines polyfonctionnalisées soit un domaine particulièrement dynamique. De par sa capacité à associer une fonction amine à un groupement carbonylé, la réaction de Mannich est un outil efficace pour former une liaison C-C de manière énantiosélective tandis que la réaction d’hydroamination intramoléculaire d’alcynes est pratique pour construire des hétérocycles azotés par formation de liaisons C-N. Dans cette thèse, nous avons combiné ces deux stratégies pour former de manière concise et énantiosélective des pipéridines polysusbstituées. Un couplage énantiosélectif de Mannich anti-sélectif fut employé pour préparer des amines chirales contenant une fonction alcyne connectée à un noyau aromatique riche en électrons. En présence d’acide de Brønsted, une réaction d’hydroamination cyclisante eut lieu démontrant une réactivité arylogue d’ynolethers et d’ynamines, la régiosélectivité de la cyclisation dépendant fortement de la densité électronique de l’alcyne. Ainsi lorsque la densité électronique est insuffisante, des pyrrolidines à cinq chainons furent obtenus tandis que lorsque la densité électronique est élevée des piperidines furent isolées, illustrant la passage d’une activation de triple liaison par liaison hydrogène à sa protonation. A partir des tetrahydropyridines et piperidines, une étude fut lancée dans le but d’achever la première synthèse totale énantiosélective du produit naturel koumine, un alcaloïde de type Gelsemium. / Piperidine ring is one of the most common heterocycles in natural products and the motif is especially well represented in pharmaceuticals. Consequently, enantioselective synthesis of multi-substituted piperidines is an important topic of investigation. For the synthesis of nitrogen-containing compounds, asymmetric Mannich coupling is a useful strategy while intramolecular hydroamination of alkynes is a practical route to construct N-heterocyclic products. In this thesis, the two strategies were combined. anti-Selective enantioselective Mannich reactions were thus employed to prepare chiral arylalkynyl amines. Connected to various aromatics, the reactivity of the triple bond was then studied in the framework of the intramolecular hydroamination reaction promoted with Brønsted acid. It was shown that depending on the electronic density of the alkyne, these adducts were converted into 5- or 6-membered rings, highlighting the balance between H-bonding and protonation. Tetrahydropyridines and piperidines were thus obtained with high regio-, diastereo-, and enantioselectivity and further functionalizations were also investigated in view of the first enantioselective total synthesis of Gelsemium alkaloid koumine.

Chapter 1 gives an overview of the fluorine chemistry field, from its early developments to recent applications in medicinal chemistry. The development of asymmetric electrophilic or nucleophilic installation of fluorine in organic molecules is highlighten. Chapter 2 of this thesis discusses the enantioselective synthesis of α-fluoroamides. The study is applied to the synthesis of fluoroenantiomers of the bioactive molecule capsaicin and short-chain analogues. The biological activity of these compounds is assayed with the TRPV1 receptor. Results show that enantioselective α-fluoroamides (R)-97, (R)-99 and (S)-99 can generate differentiated biological responses, from TRPV1 agonists to TRPV1 antagonists. Chapter 3 focuses on the optimisation and development of 2-(aminomethyl)piperidine (R)-251 dihydrochloride. The development of 2-(aminomethyl)piperidine (R)-251 as its ditetrafluoroborate salt proved to offer excellent reactivity and solubility for the preparation of derivatives. This tetrafluoroborate salt was used to improve the syntheses of organocatalysts 2,2,2-trifluoro-N-(piperidin-2-ylmethyl)acetamide 363 and 4-methyl-N-(piperidin-2-ylmethyl)benzenesulfonamide 364.The catalytic properties of these latter two molecules for asymmetric Mannich reaction is demonstrated. Both (R)-363 and (R)-364 show up to 86% ee, in a typical 20 mol% loading, but loading of (R)-363 as low as 5 mol% still induces the catalysis.