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Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascades is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (±)-epilupinine, (±)-tashiromine, and (-)-epimyrtine. Within the context of a longstanding interest in aromatic heterocyclic natural product synthesis, a concise synthetic strategy incorporating new tactics for key chemical transformations, as well as novel applications of existing synthetic methods was developed constructing the natural product meloscine. Meloscine was isolated in the 1970's from the New Caledonian plant Melodinus Scandens Forst, which is used in Chinese folk medicine for the treatment of meningitis and rheumatic heart disease. In route to meloscine, a facile synthetic method was developed toward several carboline type indoles. Also, progress has been made toward the total synthesis of the natural product meloscine. / text

In the interests of synthetic efficiency several cascade reactions involving iminium ion intermediates have developed to allow for the rapid assembly of complex molecules from relatively simple starting materials. A cascade methodology for the rapid, diastereoselective synthesis of quinolizidine ring systems has been expanded to encompass a greater range of substrates. The utility of this extension was demonstrated in the efficient syntheses of the tricyclic core structures found in halichlorine and the cylindricine family of alkaloids. Additionally a second cascade sequence has been developed that progresses through an S[subscript N]1 followed by nucleophilic attack on an N-acyl iminium ion to deliver the products of a formal [4+3] cycloaddition. This methodology has been successfully employed to synthesize a [3.3.2] bridgehead system that serves as a key intermediate in a proposed synthesis of (±)-actinophyllic acid. Synthesis of this compound represent progress in the ongoing effort to synthesize this natural product.

Reaction of 3-sulfonyl acetamides with various substituted methyl acrylate derivatives furnished pyroglutamate and glutarimidess via [3+2] and [3+3] cycloaddition respectively. The results were applied to the synthesis of pyrrolizidine skeleton, tylophorine, cryptopleurine and fused bicyclic glutarimides.

Les recherches présentées dans cette thèse découlent de problématiques rencontrées lors de précédents travaux effectués dans notre groupe au sujet de cyclisations séquentielles de Vilsmeier-Haack et de Mannich par une activation chimiosélective d’amides. Deux limitations avaient été soulevées : une faible réactivité lors de la seconde cyclisation de Mannich et aucune possibilité d’obtention de produit de double cyclisation de façon énantiosélective. Au chapitre un, une étude de double cyclisation de Vilsmeier-Haack et de Mannich est présentée, tout d’abord sur des substrats allylsilane-aldéhyde puis vératrol-aldéhyde. Une étude mécanistique est détaillée dans le but d’améliorer le rendement de la réaction. Les bases de notre méthodologie avec l’aldéhyde sont établies dans ce premier chapitre. Au chapitre deux, une étude de double cyclisation de Vilsmeier-Haack et de Mannich en présence d’une cétone est exposée. Les conditions de première cyclisation sont rapidement déterminées tandis que pour la seconde étape, les divers paramètres pouvant influencer la réaction sont examinés. Aussi, une tentative de formation de centres quaternaires produisant des squelettes carbonés de type quinolizidine et spirocyclique est présentée, ainsi qu’une variation de tailles de cycles formés. Au chapitre trois, l’étendue de notre méthodologie est étudiée et celle-ci est appliquée sur divers substrats. Les nucléophiles de type indole, pyrrole, éther d’énol et allylsilane sont couverts et la variation de taille de cycle est également testée. Au chapitre quatre, une étude sur le développement catalytique et un effort vers une version non racémique de notre méthodologie sera présentée. Diverses amines secondaires chirales sont investiguées et les excès énantiomériques mesurés. Le chapitre cinq propose des suites au projet de thèse, incluant des pistes au sujet de l’induction asymétrique en s’appuyant sur des exemples concrets de la littérature.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The part of our constant search for new bioactive secondary metabolites of plant origin, the aerial parts of three species of the genus Lupinus (Leguminoseae), and the bark of the roots of the species Waltheria douradinha Sain Hilaire (Sterculiaceae), were submitted to phytochemical investigation. In this research, they were isolated and identified 14 compounds, which was exposid several biological activities. Among the activities performed, the compounds were evaluated against antimicrobial, antioxidant enzyme (POP and DPPIV) and also bacteriolityc activity. Two of the isolated compounds, (+)Lanatina A (L. paranensis) and Antidesmona (W. douradinha) shawed bacteriolityc activity. The test showed that these compounds have bacteriolityc activity, especially against Gram-negative. The Antidesmona presented better lytic potential in the concentration of 12.5 μg/mL against the microorganism Salmonella typhimurium ATCC 14028. For this bacterium, Antidesmona alkaloid produced a cell wall lysis of approximately 30% between 4-6 hours (P <0.0001). The alkaloid extracts W. douradinha, collected in four different regions of Rio Grande do Sul - Brazil, was analyzing its chemical composition by HPLC. Analysis of the chemical composition of the basic extracts was compared with soil analyzes the place collection of plant. These results revealed significant differences in the chemical compositions of alkaloid extracts of Waltheria douradinha Sain Hilaire and were important guides of new collection sites these species. / Como parte da nossa busca permanente por novos metabólitos secundários bioativos, de origem vegetal, as partes aéreas de três espécies do gênero Lupinus, (Leguminoseae), e a casca das raízes da espécie Waltheria douradinha Sain Hilaire (Sterculiaceae), foram submetidas à investigação fitoquímica. Dessa investigação, foram isolados e identificados 14 compostos, os quais foram submetidos a diversas atividades biológicas. Dentre as atividades realizadas, os compostos foram avaliados frente a atividades antimicrobiana, antioxidante, enzimáticas (POP e DPPIV) e também atividade bacteriolítica. Dois dos compostos isolados, (+)Lanatina A (L. paranensis) e Antidesmona (W. douradinha), foram submetidos a atividade bacteriolítica. O teste demonstrou que esses compostos possuem atividade de lise, principalmente frente a Gram-negativos. A Antidesmona apresentou seu melhor potencial lítico na concentração de 12,5 μg/ml frente ao microrganismo Salmonella typhimurium ATCC 14028. Para esta bactéria, o alcaloide Antidesmona produziu uma lise de parede celular de aproximadamente 30% entre 4 e 6 horas (P<0,0001). Os extratos alcaloídicos de W. douradinha, coletada em quatro diferentes regiões do Rio Grande do Sul Brasil, passaram por análise de sua composição química por HPLC. A análise da composição química dos extratos básicos foi comparada com análises do solo do local de coleta da planta. Esses resultados revelaram diferenças significativas nas composições químicas dos extratos alcaloídicos de W. douradinha, e também foram importantes guias de novos locais de coleta dessa espécie.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / As a part of our ongoing search of new bioactive secondary metabolites of plant origin, the aerial parts of Lupinus lanatus were subjected to phytochemical investigation. Lupinus genus, belonging to the family of Leguminosae (Fabaceae), is widely distributed in south and western North America, in the Mediterranean region and Africa, with approximately 600 species. In Rio Grande do Sul, Brazil, the genus is represented by 13 species, among them, L. lanatus. This is a small shrub native to South America, mainly south Brazil (Rio Grande do Sul), Uruguai, Paraguai and Argentine. In Rio Grande do Sul, L. lanatus is called tremoço, and it is used in folk medicine as an antidiabetic, antifungal, antitumor and antioxidant agent. Quinolizidine alkaloids, such as lupanine, multiflorine, sparteine and argirine, are widely distributed in plants of the genus. Their biological effects, as antiarrhythmic, hypoglycemic, hypotensive, depressing CNS, hallucinogenic and respiratory stimulant activities, among others, has been studied previously. In the present paper, we describe the isolation and structural elucidation of a new quinolizidine alkaloid, lanatine A together with 13-α-cinnamoyloxylupanine, and hydroxylupanine from the leaves, and (-)multiflorine and (-)13-α-cis-tigloyloxymultiflorine from the seeds of L. lanatus. / Como parte da nossa busca permanente por novos metabólitos secundários bioativos de origem vegetal, as partes aéreas de Lupinus lanatus foram submetidas a investigação fitoquímica. O gênero Lupinus, pertencente à família das leguminosas (Fabaceae), é amplamente distribuída no sul e oeste da América do Norte, na região mediterrânica e na África, representado por cerca de 600 espécies. No Rio Grande do Sul, Brasil, o gênero está representado por 13 espécies, entre elas, L. lanatus. Este apresenta-se como um pequeno arbusto e está presente na América do Sul, no Brasil, Uruguai, Paraguai e Argentina. No Rio Grande do Sul, L. lanatus é conhecido popularmente Tremoço, e seu gênero é utilizado na medicina popular como agente antidiabético, antitumoral, antifúngico e antioxidante. Os alcalóides Quinolizidínicos, como lupanina, multiflorina, esparteína e argirina, são amplamente distribuídas em plantas do gênero. Seus efeitos biológicos, como antiarrítmicos, hipoglicemiante, hipotensor, depressor do SNC, alucinógenos e estimulante respiratório, entre outros, tem sido amplamente estudados. No presente trabalho, é descrito o isolamento e elucidação estrutural de um novo alcalóide quinolizidínico, Lanatina A, juntamente com o 13-α-cinnamoiloxilupanina e 13-α-hidroxilupanina oriundos das folhas, e (-)multiflorina e (-)13-α-cis-tigloiloximultiflorina isolados a partir das sementes de L. Lanatus.