Meperidine has been shown to have potent binding affinity for serotonin transporters (SERT) (Ki = 41 nM) and be an inhibitor of serotonin reuptake. Based upon these pharmacological results meperidine has been identified as a lead compound for the development of a novel class of serotonin-selective reuptake inhibitors (SSRIs). A variety of potent analogues of meperidine have been synthesized and evaluated in vitro as potential ligands for the serotonin transporter. Substitutions have been made on the aryl ring, the ester moiety and the piperidine nitrogen of meperidine. Potent analogues of the aryl substituted series that included 4-iodophenyl, 2-naphthyl, 3,4-dichlorophenyl and 4-biphenyl meperidine derivatives were synthesized and chosen for further optimization of the benzyl ester analogues. Benzyl ester analogues included 4-nitro, 4-methoxyl and 3,4-dichloro benzyl analogues and exhibited high potency for serotonin transporters and high selectivity over the dopamine transporter (DAT) and the norepinephrine transporter (NET). Also the N-demethylated analogues improve the binding affinity and selectivity for serotonin transporter. The analogue 4- (carboxymethoxybenzyl)-4-(4-iodophenyl) piperidine (69f), was found the most potent (Ki=0.6 nM) and selective ligand for serotonin transporter (DAT/SERT >4500; NET/SERT >4500) for the series and has been advanced to in vivo evaluation.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1937. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references: leaf [52].

M.Sc. (Chemistry) / The aim of this study was to investigate alternative routes for the stereocontrolled synthesis of hydroxylated indolizidine, piperidine and pyrrolidine alkaloids, starting from monosaccharides as chiral building blocks. This study was not aimed at improving consisting routes - it was rather aimed at developing new routes towards the synthesis of these alkaloids. Mixed results were obtained in the investigation into alternative routes for the synthesis of the bicyclic poly hydroxylated indolizidine alkaloids, but a new and efficient stereospecific synthesis of polyhydroxylated piperidine- and pyrrolidine alkaloids were developed. The aims and results can be summarised in more detail as follows: a. Stereospecific synthesis of castanospermine. The synthesis of this medium sized nitrogen-containing bicyclic molecule was approached in a unique way. The utilization of bifunctional Wittig- and Wittig-Horner reagents containing nitrogen functionalities was considered promising for the aims of this study. By the usage of known reactions, e.g. Wittig, Wittig-Horner, Schiff-base and Aza-Wittig reactions, it was foreseen that these bifunctional reagents could be coupled in two concurrent steps to dicarbonyl compounds to form a nitrogen containing rings. Several nitrogen containing Wittig reagents were prepared. At the one end of these reagents a phosphonate or phosphine group furnished the phosphorus moiety while the other end of these reagents comprised the nitrogen moiety by reduction of a nitrile group or azide displacement of a leaving group. No coupling was obtained between these bifunctional reagents and a dicarbonyl compound derived from D-glucose and the influence of two functional groups in such close proximity in the Wittig reagent is being further investigated. Coupling was, however, achieved by the utilization of an alternative bifunctional reagent in which a Wittig-Horner reaction was used. The successful implementation of this unique methodology in the synthesis of medium size nitrogen containing ring is being further investigated.

The importance of fluorinated organic molecules has grown over the last 50 years, particularly in the pharmaceutical and agrochemical industries. Therefore the development of new methods for fluorination is a very attractive research area. In Chapter 1, the properties and impact of the fluorine atom on organic molecules are overviewed. Existing electrophilic and nucleophilic fluorination methods are reviewed, and new developments in asymmetric fluorination are discussed. The emergence of the Prins fluorination reaction as a side product in BF₃.OEt₂ catalysed processes has been investigated as a synthesis method in Chapter 2. Indeed, it is possible to form 4-fluorotetrahydropyrans with some diastereoselectivity from an allylic alcohol and an aldehyde with a stoichiometric amount of BF₃.OEt₂. During this study, formation of 4-fluoropiperidines from N-tosyl-4-butenylamine was achieved. Optimisation of reaction conditions was investigated such as the solvent, the reaction temperature and the influence of substituents on the alcohol and the aldehyde reagents. A ring-opening reaction of 4-fluoro-2-phenyltetrahydropyran was successfully performed. Both oxa-Prins and aza-Prins fluorination reactions were investigated under microwave conditions, allowing reduced reaction times, a process that had a minimum impact on the diastereoselectivity. Attempt to form γ-hydroxy-α-vinylfluorides by the reduction-fluorination of propargylic alcohols with aluminium hydride, or by Horner-Emmons reaction with diethyl (fluoromethyl)phosphonate are reported in Chapter 3. Unfortunately these approaches were unsuccessful in the preparation of γ-hydroxy-α-vinylfluorides. Attempts to fluorinate epoxides by α-lithiation and then treatment with electrophilic fluorination reagents gave encouraging results, but the products could not be purified and characterised due to an apparent instability.

Nature provides fascinating and complicated molecular structures which offer synthetic organic chemists amazing opportunities for the design of new strategies for natural product synthesis. Among these, nitrogen containing aza-heterocycles are of unparalleled importance in natural product, bioorganic, and medicinal chemistry. Pyridine and its derivatives in particular are the most common aza-heterocycles encountered in natural products, medicinal and materials chemistry. Pyridine derivatives also serve as precursors to functionalized piperidines, which are likewise common structural motifs in bioactive and functionalized materials. Thus, developing synthetic methods suitable for the manipulation of pyridine ring systems remains an important objective in synthetic organic chemistry. The functionalization of pyridine derivatives via manipulation at the benzylic position has been investigated. First, the nucleophilicity of the benzylic position of the 4-alkyl pyridine substrates was used to engage in Brønsted acid-catalyzed aldol-like cyclizations with attached carbonyl electrophiles. These conditions afforded substituted pyridines with functionalized lactams. These substrates underwent an unusual dehydration/oxidation reaction when treated with thionyl chloride. In a similar study, 1,2-dialkylimidazoles afforded nucleophilic 2-alkylidene imidazolines upon treatment with an electrophilic activating group such as Boc2O. Positioning a ketone electrophile with in an N1-alkyl side chain results in cyclization at the imidazole 2-position to afford fused ring imidazoles through an aldol-like cyclization reaction. The stereoselective synthesis of a tricyclic analogue of the bis(piperidine) alkaloid xestoproxamine C was also investigated. Dearomatization of a tricyclic pyridine derivative afforded an alkylidene dihydropyridine (anhydrobase) intermediate which was subjected to catalytic heterogeneous hydrogenation to install the correct relative stereochemistry about the bis(piperidine) ring system. Other key features of these model studies included development of an efficient ring-closing metathesis procedure to prepare macrocyclic derivatives of 3,4-disusbstituted pyridines, intramolecular cyclizations of alkylidene dihydropyridines to establish pyridine-substituted pyrrolidines and piperidines, successful homologation of pyridine-4-carboxaldehydes using formaldehyde dimethyl thioacetal monoxide (FAMSO), and application of B-alkyl Suzuki coupling to assemble substituted pyridines. Lastly, a study was done to assess the feasibility of synthesizing one of the two chiral precursors needed for the asymmetric synthesis of xestoproxamine C via enzyme catalyzed transesterification of symmetric 1,3-diols. This resulted in successful transesterification of a symmetric 1,3-diol substrate with high enantioselectivity.

Resumo: O presente trabalho objetivou o estudo fitoquímico dos frutos de Senna spectabilis e o estudo comparativo do perfil alcaloídico entre S. spectabilis e Cassia leptophylla, outra espécie vegetal relatada como fonte de alcalóides piperidínicos. O estudo fitoquímico dos frutos de S. spectabilis forneceu 4 alcalóides piperidínicos: cassina (1), 3-O-acetil-cassina (20), 3-O-feruloil-cassina (18) e um estereoisômero da cassina (19), cujas configurações, ralativa e absoluta, ainda não foram determinadas. Dentre estes, somente a cassina (1) já era conhecida e foi isolada, em nosso grupo de pesquisa, como o alcalóide majoritário das flores da mesma espécie. Estes alcalóides foram avaliados quanto às atividades seqüestradora de radicais livres (DPPH) e inibidora da enzima acetilcolinesterase. As substâncias 1, 2 e 4 apresentaram forte atividade anticolinesterásica, com concentração inibitória mínima semelhante à galantamina, utilizada como padrão positivo. Quanto à atividade seqüestradora de radicais livres, o único que apresentou leve estabilização do radical foi o derivado feruloil piperidínico (18), quando comparado com a rutina, utilizada como padrão positivo. Entretanto, a maior concentração do alcalóide não atingiu a concentração inibitória de 50% (IC50), observada para a rutina. O estudo do perfil químico entre as espécies S. spectabilis e C. leptophylla foi inicialmente baseado em experimentos comparativos de cromatografia em camada delgada e ressonância magnética nuclear de hidrogênio. Os resultados obtidos demonstraram que somente os extratos das flores e frutos de S. spectabilis apresentavam substâncias alcaloídicas como metabólitos detectáveis. Por outro lado, a análise por espectrometria de massas permitiu evidenciar metabólitos alcaloídicos piperidínicos em ambas as espécies estudadas, levando-nos a concluir sobre a importância desta técnica na bioprospecção de metabólitos minoritários. / Abstract: The present work aimed the phytochemical study of the fruits of Senna spectabilis and a comparative analysis of the alkaloid profile between S. spectabilis and Cassia leptophylla, another species reported as a source of piperidine alkaloids. The phytochemical study of the fruits of S. spectabilis furnished 4 piperidine alkaloids: cassine (1), 3-O-acetyl-cassine (20), 3-O-feruloyl-cassine (18) and a stereoisomer of cassine (19), whose absolute and relative configurations were not stablished yet. Among these, only cassine (1) was already known and it had been previously isolated as the major alkaloid of the flowers in the same species. These alkaloids were evaluated for their potential as free radical scavengers towards DPPH and acetylcholinesterase inhibitors. Substances 1, 2 and 4 showed strong activity in inhibition of acetylcholinesterase, with a minimum inhibitory concentration similar to galantamina, used as a reference compound. In the free radical scavenger assay, compound 18 was the only active, showing a slightly radical stabilization, when compared with the rutina, used as a reference compound. However, the largest concentration of the alkaloid didn't reach the inhibitory concentration for 50% (IC50), obtained by rutina. The chemical profile study between S. spectabilis and C. leptophylla species was initially based on comparative experiments using thin layer chromatography, and proton nuclear magnetic resonance. The results indicated that alkaloidal metabolites were present only in the S.spectabilis extracts. On the other hand, analysis by tandem mass spectrometry revealed the presence of piperidine alkaloids in both species, leading us to conclude the relevance of this technique in bioprospecting of minority metabolites. / Orientador: Vanderlan da Silva Bolzani / Coorientador: Ian Castro-Gamboa / Banca: Dulce Helena Siqueira Silva / Banca: Norberto Peporine Lopes / Mestre

Made available in DSpace on 2014-06-11T19:29:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-12-01Bitstream added on 2014-06-13T19:58:51Z : No. of bitstreams: 1 pivatto_m_me_araiq.pdf: 4500291 bytes, checksum: 41c36cab9b65c53f1fe92528b346a70e (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O presente trabalho objetivou o estudo fitoquímico dos frutos de Senna spectabilis e o estudo comparativo do perfil alcaloídico entre S. spectabilis e Cassia leptophylla, outra espécie vegetal relatada como fonte de alcalóides piperidínicos. O estudo fitoquímico dos frutos de S. spectabilis forneceu 4 alcalóides piperidínicos: cassina (1), 3-O-acetil-cassina (20), 3-O-feruloil-cassina (18) e um estereoisômero da cassina (19), cujas configurações, ralativa e absoluta, ainda não foram determinadas. Dentre estes, somente a cassina (1) já era conhecida e foi isolada, em nosso grupo de pesquisa, como o alcalóide majoritário das flores da mesma espécie. Estes alcalóides foram avaliados quanto às atividades seqüestradora de radicais livres (DPPH) e inibidora da enzima acetilcolinesterase. As substâncias 1, 2 e 4 apresentaram forte atividade anticolinesterásica, com concentração inibitória mínima semelhante à galantamina, utilizada como padrão positivo. Quanto à atividade seqüestradora de radicais livres, o único que apresentou leve estabilização do radical foi o derivado feruloil piperidínico (18), quando comparado com a rutina, utilizada como padrão positivo. Entretanto, a maior concentração do alcalóide não atingiu a concentração inibitória de 50% (IC50), observada para a rutina. O estudo do perfil químico entre as espécies S. spectabilis e C. leptophylla foi inicialmente baseado em experimentos comparativos de cromatografia em camada delgada e ressonância magnética nuclear de hidrogênio. Os resultados obtidos demonstraram que somente os extratos das flores e frutos de S. spectabilis apresentavam substâncias alcaloídicas como metabólitos detectáveis. Por outro lado, a análise por espectrometria de massas permitiu evidenciar metabólitos alcaloídicos piperidínicos em ambas as espécies estudadas, levando-nos a concluir sobre a importância desta técnica na bioprospecção de metabólitos minoritários. / The present work aimed the phytochemical study of the fruits of Senna spectabilis and a comparative analysis of the alkaloid profile between S. spectabilis and Cassia leptophylla, another species reported as a source of piperidine alkaloids. The phytochemical study of the fruits of S. spectabilis furnished 4 piperidine alkaloids: cassine (1), 3-O-acetyl-cassine (20), 3-O-feruloyl-cassine (18) and a stereoisomer of cassine (19), whose absolute and relative configurations were not stablished yet. Among these, only cassine (1) was already known and it had been previously isolated as the major alkaloid of the flowers in the same species. These alkaloids were evaluated for their potential as free radical scavengers towards DPPH and acetylcholinesterase inhibitors. Substances 1, 2 and 4 showed strong activity in inhibition of acetylcholinesterase, with a minimum inhibitory concentration similar to galantamina, used as a reference compound. In the free radical scavenger assay, compound 18 was the only active, showing a slightly radical stabilization, when compared with the rutina, used as a reference compound. However, the largest concentration of the alkaloid didn't reach the inhibitory concentration for 50% (IC50), obtained by rutina. The chemical profile study between S. spectabilis and C. leptophylla species was initially based on comparative experiments using thin layer chromatography, and proton nuclear magnetic resonance. The results indicated that alkaloidal metabolites were present only in the S.spectabilis extracts. On the other hand, analysis by tandem mass spectrometry revealed the presence of piperidine alkaloids in both species, leading us to conclude the relevance of this technique in bioprospecting of minority metabolites.

α,α′-Bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene enhances human blood platelet membrane integrity by exerting a stabilizing action at the level of the dense tubular system in surface membrane complexes known to sequester platelet calcium.

The unexpected monoamine oxidase (MAO) substrate properties of 1-cyclopropyl-4-substituted-1 ,2,3,6-tetrahydropyridines have been interpreted in terms of partitioning of these tertiary cyclic allylamines between substrate turnover and ring opening inactivation processes. To evaluate further this proposal, we examined the bioactivities of the related saturated analogs. Several 1,4-disubstituted piperidine derivatives were synthesized and their interactions with MAO-A and MAO-B were characterized. These compounds displayed poor substrate properties toward MAO-A and MAO-B and led to the expected α-carbon oxidized metabolites which were fully characterized. Both the N-methyl and N-cyclopropyl derivatives were good inactivators of MAO-B, suggesting that some species other than the radical resulting from cyclopropyl ring opening is responsible for the inactivation. Both the N-methyl and N-cyclopropyl derivatives also inactivated MAO-A. In this instance, the N-cyclopropyl analogs were much more potent inactivators than the N-methyl analogs. These results suggest that the radical derived from cyclopropyl ring opening may be involved in this inactivation process. The MAO substrate/inactivator properties of these piperidine analogs are discussed in terms of current proposed mechanisms for the MAO catalyzed oxidation of amines. / Master of Science

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.