Intramolecular Bromoamination of Conjugated N-Tosylaminodienes Using N-Bromosuccinimide. Synthesis of Bromoallyl-Substituted N-Heterocycles and Their Applications as Building Blocks

The bromonium-promoted cyclization of conjugated aminodienes is described. The reaction proceeds smoothly in the presence of N-bromosuccinimide as halonium promoter, and using N-tosyl-protected aminodienes as substrates, to give the corresponding halocyclization products in high yields and with high diastereoselectivities. It can be envisaged that the formation of these products is the result of an SN2′-type ring-opening of a terminal bromonium intermediate in a 5-exo-trig or 6-exo-trig cyclization mode. The presence of an allyl bromide moiety in the haloamination products makes these molecules highly attractive from a synthetic point of view, as it opens the way for further transformations. Thus, allylic substitution reactions with different nucleophiles (acetate, azide, cyanide, and malonate), palladium-catalysed Suzuki coupling, and silver-mediated bromine displacement reactions were carried out successfully.

On the origin of the high capacitance of nitrogen-containing carbon nanotubes in acidic and alkaline electrolytes

The synthesis of nitrogenated carbon nanotubes (N-CNTs) with up to 6.1 wt% N, via the use of pyridine as the nitrogen containing carbon precursor, can provide a facile route to significantly enhance the low intrinsic specific capacitance of carbon nanotubes. The nitrogen functionalities determine this, at least, five-fold increase of the specific capacitance.

Nucleophilic substitution reactions of pyranose polytosylates

The 2,3,4-tri-toluenesulfonate ester derivatives of the methyl pyranosides of L-arabinose, D-ribose, D-lyxose, and D-xylose have been prepared, and their substitution reactions with various nucleophiles have been examined. For arabinose, xylose, and ribose, highly regioselective monosubstitutions were observed with benzoate, nitrite, and azide anions. These reactions have led to short and simple routes from D-xylose to L-arabinose derivatives, from L-arabinose to D-xylose derivatives, and from D-ribose to L-lyxose derivatives. The tritosylate derived from methyl alpha-D-lyxopyranoside was unreactive toward nucleophilic substitution reactions, giving instead a dihydropyran product arising from an initial E2 elimination reaction of the 2-tosylate.

Chemical synthesis of DNA and RNA containing thio-substituted bases and their post-synthetic modifications

Modified oligonucleotides containing sulphur group have been useful tools for studies of carcinogenesis, protein or nucleic acid structures and functions, protein-nucleic acid interactions, and for antisense modulation of gene expression. One successful example has been the synthesis and study of oligodeoxynucleotides containing 6-thio-2'-deoxyguanine. 6-Thio-2-deoxyguanosine was first discovered as metabolic compound of 6- mercaptopurine (6-MP). Later, it was applied as drug to cure leukaemia. During the research of its toxicity, a method was developed to use the sulphur group as a versatile position for post-synthetic modification. The advantage of application of post-synthetic modification lies in its convenience. Synthesis of oligomers with normal sequences has become routine work in most laboratories. However, design and synthesis of a proper phosphoramidite monomer for a new modified nucleoside are always difficult tasks even for a skilful chemist. Thus an alternative method (post-synthetic method) has been invented to overcome the difficulties. This was achieved by incorporation of versatile nucleotides into oligomers which contain a leaving group, that is sufficiently stable to withstand the conditions of synthesis but can be substituted by nucleophiles after synthesis, to produce, a series of oligomers each containing a different modified base. In the current project, a phosphoramidite monomer with 6-thioguanine has been successfully synthesised and incorporated into RNA. A deprotection procedure, which is specific for RNA was designed for oligomers containing 6-thioguanosine. The results were validated by various methods (UV, HPLC, enzymatic digestion). Pioneer work in utilization of the versatile sulphur group for post-synthetic modification was also tested. Post-synthetic modification was also carried out on DNA with 6- deoxythioguanosine. Electrophilic reagents with various functional groups (alphatic, aromatic, fluorescent) and bi-functional groups have been attached with the oligomers.

The metabolism of n-methyl compounds

The metabolism of compounds containing the N-methyl group is discussed with particular consideration being made to the possible role of the product of oxidative metabolism, the N-hydroxymethyl moiety, in the generation of potentially toxic, reactive electrophiles. Particular pathways which are considered are: (i), the production of formaldehyde; (ii), the generation of iminium ions or imines; and (iii), the formation of N-formyl compounds which might act as formylating agents. 4-Chloro-N-(hydroxymethyl)benzamide and 3-(4-chlorophenyl)-1-hydroxy-methyl-1-methylurea (the product of oxidative metabolism of 3-(4-chlorophenyl)-1,1-dimethylurea) are model carbinolamides which do not readily release formaldehyde. The electrophilic properties of these model carbinolamides were investigated: neither reacted with nucleophiles such as cyanide or glutathione under physiological conditions. In contrast, N-(acetoxymethyl)-4-chlorobenzamide yielded the cyanomethylamide with potassium cyanide and S-(4-chlorobenzamidomethyl)glutathione with glutathione. 4-Chloro-N-(hydroxymethyl)benzamide and 3-(4-chlorophenyl)-1,1-dimethylurea were not biotransformed to electrophilic moieties when incubated with mouse hepatic 9000 x g supernatant and Acetyl-CoA or PAPS-generating system. N-(Acetoxymethyl)-4-chlorobenzamide was non-mutagenic to Salmonella typhimurium in the short term bacterial assay; but toxicity to the bacteria was observed. 4-Chloro-N-(hydroxymethyl)benzamide and 3-(4-chlorophenyl)-1,1-dimethylurea showed no mutagenicity or toxicity in the mutagenicity assay including an Aroclor-induced rat hepatic 9000 x g supernatant. Addition of Acetyl-CoA or a PAPS-generating system did not produce a mutagenic response. 4-Chloro-N-formlbenzamide did not act as a formylating agent towards the weak nucleophile aniline. However, 4-chloro-N-formylbenzamide, N-formylbenzamide, 3-(4-chlorophenyl)-1-formyl-1-methylurea and 3-(4-chlorophenyl)-1-formylurea are all metabolised by mouse hepatic mirosomes and post-microsomal supernatant. The results demonstrate the potential for N-hydroxymethyl compounds to generate highly reactive species if these are substrates for conjugation with sulphate (or acetate). The model compounds employed here, apparently do not show any ability to be conjugated themselves, however, other N-hydroxymethyl compounds might be readily conjugated. The formation of N-formyl compounds does not appear to be toxicologically significant, as adjudged on limited experiments performed, but rather represent a detoxification pathway.

Preparation of 9-substituted pyridine-stretched adenines and hypoxanthines

9-Methylsulfanyl pyridine-stretched adenine and hypoxanthine derivatives have been prepared via regioselective reaction of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)malononitrile [(NC)C=C(SMe) ]. The 9-methylsulfanyl substituent can be replaced by sequential oxidation and substitution by nucleophiles including amines.

Facile synthesis and proposed mechanism of α,ω‐oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane) by an SN2(i) nitrato displacement method in basic media

The synthesis of a novel heterocyclic–telechelic polymer, α,ω-oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane), is described. Infrared spectroscopy (IR), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR) spectroscopy have been used to confirm the successful synthesis, demonstrating the presence of the telechelic-oxetanyl moieties. Synthesis of the terminal functionalities has been achieved via displacement of nitrato groups, in a manner similar to that employed with other leaving groups such as azido, bromo, and nitro, initiated by nucleophiles. In the present case, displacement occurs on the ends of a nitrato-functionalized polymer driven by the formation of sodium nitrate, which is supported by the polar aprotic solvent N,N-dimethyl formamide. The formation of an alkoxide at the polymer chain ends is favored and allows internal back-biting to the nearest carbon bearing the nitrato group, intrinsically in an SN2(i) reaction, leading to α,ω-oxetanyl functionalization. The telechelic-oxetanyl moieties have the potential to be cross-linked by chemical (e.g., acidic) or radiative (e.g., ultraviolet) curing methods without the use of high temperatures, usually below 100°C. This type of material was designed for future use as a contraband simulant, whereby it would form the predominant constituent of elastomeric composites comprising rubbery polymer with small quantities of solids, typically crystals of contraband substances, such as explosives or narcotics. This method also provides an alternative approach to ring closure and synthesis of heterocycles.

Novel approaches for the synthesis of C-5 modified pyrimidine nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF 5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. ^ In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.^

Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.

Novel Synthesis of Carbocycles and Heterocycles Employing Zwitterions Derived from Allenic Esters

Carbon-carbon and carbon-heteroatom bond formations constitute the central events in organic synthesis. In view of this, much of the research in organic synthesis has been focused on devising novel and efficient methods for such bond constructions. In general, polar, pericyclic and radical methodologies are employed for this purpose. The polar and radical reactions proceed via reactive intermediates such as carbanions, enols/enolates, enamines, carbocations, radical cations, radical anions, carbenes, zwitterions etc. In recent years, there has been enormous interest in the chemistry of zwitterionic species largely from the standpoint of their applications in multicomponent reactions (MCRs) and organocatalytic reactions. Zwitterions formed by the addition of nucleophiles to electrophilic π-systems such as acetylenic esters and azoesters have been the subject of extensive investigations; their synthetic utility, however, remained largely unexplored. Investigations in a number of laboratories, including our own, have shown that zwitterions of the type mentioned above on reaction with electrophiles give rise to carbo- and heterocyclic products by 1,3- or 1,4-dipolar cycloadditions. Recently, allenoates, another class of active π-systems were introduced to this field. Against this background, a systematic investigation of the reactions of various zwitterions derived from allenoates with different electrophiles especially 1,2-diones, were carried out. The results of these studies are embodied in the thesis entitled “Novel Synthesis of Carbocycles and Heterocycles Employing Zwitterions Derived from Allenic Esters”.

Caracterização do estoque de anchoita (engraulis anchoita) da região Sul do Brasil e utilização desta matéria-prima na elaboração de produto de alto valor agregado

O trabalho teve por objetivo caracterizar o estoque de anchoita (Engraulis anchoita) capturado na região sul do Brasil, visando à utilização deste recurso de alto valor biológico no desenvolvimento de produtos semi-prontos e de fácil preparo, tipo empanado. Os experimentos foram conduzidos com anchoita resultante de cruzeiros realizados pelo Navio Oceanográfico Atlântico Sul da Universidade Federal do Rio Grande (FURG), RS, Brasil. Os exemplares foram capturados entre a cidade de Rio Grande (32ºS, RS-Brasil) e 51ºW. Após captura, o pescado foi armazenado a bordo em mistura de gelo e água do mar, na razão 1:1. As amostras foram transportadas para o laboratório de Biotecnologia da FURG e mantidas sob congelamento a -18°C, até a realização das análises. O trabalho está constituído por uma revisão bibliográfica, que enfatiza a importância do recurso pesqueiro em estudo como potencial a ser explorado, discorre sobre ácidos graxos e perfil de voláteis, bem como, o desenvolvimento de produtos à base de pescado. O desenvolvimento do trabalho é expresso por quatro artigos. O primeiro teve como objetivo caracterizar o estoque de anchoita segundo a biometria, rendimento, composição proximal, compostos nitrogenados e ácidos graxos. O rendimento, a composição proximal e o perfil de ácidos graxos foram realizados nas três frações que compõe o peixe: músculo claro, escuro e vísceras. A análise dos resultados demonstrou a variabilidade dos componentes em função das frações avaliadas e da época de captura, o que pode contribuir para a escolha do processo tecnológico a ser aplicado no desenvolvimento de produtos de alto valor agregado a partir dessa matéria-prima. No segundo artigo foi determinado o perfil de ácidos graxos da anchoita e avaliado o comportamento destes compostos durante o armazenamento congelado, bem como, dos voláteis gerados. Os resultados demonstraram a influência do armazenamento na modificação dos ácidos graxos, em especial, EPA e DHA, e que os voláteis gerados podem ser um índice em potencial para avaliar a qualidade da anchoita congelada. No terceiro artigo objetivou-se selecionar e treinar julgadores para avaliação do odor a pescado utilizando os padrões referência obtidos a partir do perfil de voláteis. Neste sentido, foi levantada a terminologia que descreve o odor da anchoita, definido padrões referência, bem como, selecionado e treinado uma equipe de julgadores. Foram utilizados 20 candidatos, deste total, 9 foram selecionados pelo método das amplitudes. Os julgadores selecionados foram submetidos ao treinamento no uso de escala não estruturada e na avaliação da intensidade do odor a pescado. O desempenho dos julgadores foi definido utilizando como amostra solução de lavagem resultante do processo de obtenção de base protéica de anchoita. Os resultados foram avaliados com base no poder de discriminação, repetibilidade das respostas e concordância entre julgadores, segundo análise de variância, com duas fontes de variação (amostra e repetições). Foram obtidos os valores de Famostra e Frepetição, para cada julgador. Os julgadores com o valor de Famostra significativo (p≤0,30) e Frepetição não significativo (p>0,05), bem como, concordância de médias com os demais julgadores foram considerados treinados. Segundo esse processo a equipe foi constituída por 8 julgadores selecionados e treinados na avaliação do odor a pescado. Finalmente, no quarto artigo foi avaliada a possibilidade de uso de base protéica (BPP) de anchoita na elaboração de massa base de empanados, bem como, em substituição a farinha de cobertura. Para obtenção das BPPs, foram testadas duas soluções extratoras (3 ciclos de extração com ácido fosfórico 0,05% e 1 ciclo de ácido fosfórico seguido de 2 ciclos com água). A BPP obtida na melhor condição utilizada foi seca a 70°C e submetida ao processo de moagem em moinho de facas para ser utilizada como farinha de cobertura. Formulações de empanado utilizando diferentes concentrações (25, 50, 75 e 100%) de anchoita desidratada na cobertura foram testadas no produto frito e forneado. Um teste de preferência com consumidores em potencial foi aplicado às diferentes formulações. Os resultados indicaram que a melhor condição de lavagem para obtenção das BPPs testadas foi quando são utilizados 3 ciclos de extração com ácido fosfórico. A avaliação da preferência junto ao consumidor em potencial demonstrou que a anchoita desidratada pode ser utilizada como farinha de cobertura em empanados na concentração de até 75%.

Silanisation de polysaccharides en milieu liquide ionique et réactivité d’un organoalkoxysilane vis-à-vis de nucléophiles simples : vers des hydrogels injectables pour l’ingénierie tissulaire du cartilage

Tissue engineering is a real challenge for the treatment of cartilage pathologies. In this field, biomimetic hydrogels based on natural polymers are among the most commonly used matrices. A hydrogel made of silanized hydroxypropylmethylcellulose (HPMC-Si) is especially promising because it can be injected in cartilaginous lesions by minimally invasive surgery. However, the current synthesis of HPMC-Si is limited by the insolubility of hydroxypropylmethylcellulose (HPMC). This thesis work was focused on finding new synthesis conditions for the design of HPMC-Si hydrogel. In order to obtain a complete solubilization of HPMC and to improve its functionalization by the (3-glycidyloxypropyl) trimethoxysilane (GPTMS), the use of ionic liquids (IL), which are excellent solvents for polysaccharides, was undertaken. The beginning of this study was first devoted to the selection of an IL and then to the development of new reaction conditions. With these new conditions, higher silicon rates were obtained for HPMC modified in ionic liquid medium, however no hydrogel could be formed. The second part was therefore devoted to the synthesis of GPTMS 13C. Indeed, thanks to this radiolabeling, a structural characterization by 13C NMR of the HPMC-Si could be achieved. Finally, the reactivity in organic solvents of three organosilanes, including the GPTMS, was investigated toward nucleophiles representing the common functions found in natural polymers (e.g. -NH2, -OH, -SH). The results of this thesis have provided insights into the GPTMS reactivity in organic medium and thus paves the way to new conditions for the silanization of polysaccharides.

Using Different Co-Adjuvant Activating Agents to Improve Activated Carbon Adsorption Capacities

Activated carbon (AC) has proved to be an effective adsorbent for the removal of an assortment of organic and inorganic pollutants from aqueous or gaseous media. However, the pursuit for more effective and cheaper AC is still very active and a diversity of textural and chemical treatments are described as a way to expand their applications. It is well known that the surface area and surface chemistry of AC strongly affect their adsorption capacity [1-3]. In particular, an increase in the nitrogen content has been related to an increase of the basic character and also to the development of the porous structure. In most published work this was achieved through an AC post treatment, including either a reaction with nitrogen containing reagents, such as ammonia, nitric acid, or a diversity of amines. However, the AC prepared directly from a nitrogen rich precursor through a physical or chemical activation is referred to as presenting the best characteristics, namely high nitrogen content, high basic character, low nitrogen leaching and also a good thermal stability [4]. To improve the AC adsorption capacities for acidic pesticide removal from the aqueous phase, we intend to improve the porous structure and introduce nitrogenated groups directly into the AC matrix, using different co-adjuvant activating agents as a nitrogen source, by chemical activation, with potassium hydroxide, of cork or poly(ethyleneterephthalate) (PET) precursors.

Sintesi e caratterizzazione strutturale di derivati piperidinici e morfolinici chirali

The topic of this thesis concerns the study of catalytic processes for the synthesis of chiral 3,4,5-trisubstituted piperidine and 2,6-disubstituted morpholine. Substrates possessing an α,β-unsaturated ester and a ketone moiety, able to undergo addition/cyclization cascade reactions with different pro-nucleophiles (thiophenols, acetone cyanohydrin and malononitrile), have been evaluated. Chiral and achiral systems for phase-transfer catalysis have been applied as catalysts. Moderate enantiomeric excesses have been obtained for the morpholinic products and good to excellent values for the piperidinic products, by using cyclopeptoids and quaternary ammonium salts derived from Chincona alkaloids as catalysts respectively. Moreover, the absolute configuration of the 3,4,5-trisubstituted piperidines has been determined through quantomechanical simulations of their chirooptical spectra. Finally, the relative configuration of the 2,6-disubstituted morpholines has been assigned through NMR experiments.

A DFT study on chemodivergent preparation of piperidinic and morpholinic heterocycles

The topic of this thesis is the DFT computational study of the mechanisms for the synthesis of chiral 3,4,5-trisubstituted piperidines and 2,6-disubstituted morpholines. The goal of this synthesis is to use, the same substrate containing two electrophilic sites: an α,β-unsaturated ester and a ketone, which evolve according to the nucleophile used (cyanide, phenyl sulfide) through different addition and cyclization reactions. A quaternary ammonium salt is used as a catalyst for these reactions, which leads to a diastereoisomeric excess both for the reactions of morpholine and piperidine products. Studies in silico of the pathways of these reactions explain the chemoselection and diasteroselection deriving from the two nucleophiles used. In this case of piperidine products, it was also possible to validate the hypothesis of a concerted nucleophilic addition mechanism on the α,β-unsaturated site and cyclization due to an intramolecular Michael addition.