The objectives of this project were to investigate the application of new methodologies for the preparation of benzyltetrahydroisoquinoline monomers and secondly, to synthesise the bisbenzyltetrahydroisoquinoline neferine and its analogues. Neferine was isolated from the roots of Nelumbo nucifera. This compound has been reported to exhibit important biological activities, which include anti-arrhymia, anti-platelet aggregation, anti-thrombosis, anti-cancer as well as anti-HIV activities. Moreover, neferine showed lower cytotoxicity compared to other isoquinolines. However, the total synthesis of this compound has not been reported. Two methodolologies based on the intramolecular hydroamination of aminostilbenes and aminoalkynes were investigated for the preparation of benzyltetrahydroisoquinolines with different oxygenation patterns. In these strategies, the aminostilbene and aminoalkyne precursors were successfully synthesised by the Heck and Sonogashira coupling reactions, respectively. The attempts to cyclise the aminostilbenes into the corresponding tetrahydroisoquinolines under base-catalysed, metal-catalysed and acid-catalysed conditions were unsuccessful. On the other hand, cyclisation of aminoalkynes into dihydroisoquinolines was achieved with the aid of titanium catalysts. Different titanium catalysts were tested for this hydroaminationation reaction. Optimum results were obtained with bis-(cyclopentadienyl)dimethyl titanium(IV) catalyst, albeit the yields were inconsistent when the reaction was performed on a larger scale. Induction of the desired stereochemistry on the dihydroisoquinolines prepared by the hydroamination of aminoalkynes was attempted with the chiral BINOL phosphoric acid catalyst without success. The catalyst was prepared in good yields and high enantiomeric excess from cheap and readily-available starting materials. Had this reaction been successful, this would have been a breakthrough in the stereoselective reduction of dihydroisoquinolines as most chiral catalysts, which are currently employed are expensive, difficult to prepare and some are air and moisture-sensitive. Although the first objectives of this project are not fully met, the results obtained in the synthesis of benzyltetrahydroisoquinolines by the hydroamination of aminostilbenes and aminoalkynes contribute greatly to the prevailing literature on the synthesis of benzyltetrahydroisoquinolines by these reactions. Presently, there is limited literature on the synthesis of benzyltetrahydroisoquinolines by these methods. Moreover, there is a need for the development of new synthetic strategies that would render benzyltetrahydroisoquinolines in minimum steps and good yields. It was planned that, upon successful synthesis of benzyltetrahydroisoquinolines from aminostilbene and aminoalkyne precursors, these modern methodologies would be applied in the synthesis of the two benzyltetrahydroisoquinoline scaffolds of neferine. However, these routes could not be pursued due to failure to ringclose the aminostilbenes and irreproducibility of results in the preparation of dihydroisoquinolines from aminoalkynes. Therefore, classical procedures were employed for the preparation of benzylisoquinoline nuclei of neferine. Three different synthetic routes were followed for the synthesis of neferine and its analogues. The first two methods were based on the Ullmann coupling reaction for the formation of the diaryl ether bond. The first method entailed an early construction of the ether link and late construction of the two isoquinoline rings on the ether bridge. The second method involved synthesis of the two isoquinoline nuclei, and coupling of the two units by the Ullmann reaction in the late stages of the synthesis. In the last synthetic strategy, the diaryl ether bridge was constructed by the nucleophilic aromatic substitution reaction. In all the three methods, the two isoquinoline rings were formed by the Bischler-Napieralski cyclisation reaction. In the first route, we succeeded in preparing the two major building blocks, which were N-(3,4-dimethoxyphenylethyl)-4-benzyloxy-3-iodophenylacetamide and [2- (4’-hydroxy-3’-methoxyphenyl)ethyl]carbamic acid tert-butyl ester. The Ullmann coupling of the two compounds afforded the diphenyl ether N-(3,4- dimethoxyphenylethyl)-4-benzyloxy-3-(4-(3-methoxyphenoxy)ethyl-tertbutylcarbamate) phenylacetamide, albeit in low yields. Although N-(3,4- dimethoxyphenylethyl)-4-benzyloxy-3-(4-(3-methoxyphenoxy)ethyl-tertbutylcarbamate) phenylacetamide was obtained in low yields, the successful formation of the diaryl ether bond from electron-rich haloacetamide and hydroxyphenethylamine is a great advancement in the synthesis of bisbenzyltetrahydroisoquinolines. In the second approach, the two benzyltetrahydroisoquinoline precursors for the Ullmann coupling reaction were successfully synthesised. These were the 7-hydroxybenzyltetrahydroisoquinoline and the 3’-iodobenzyltetrahydroisoquinoline. The Ullmann coupling reaction of the two isoquinolines did not give any fruitful results. In the last synthetic strategy, the formation of the diaryl ether bridge was based on the nucleophilic aromatic substitution reaction. In this route, we managed to synthesise the two coupling partners for the nucleophilic aromatic substitution reaction leading to Omethylneferine. One of the building blocks was the natural benzyltetrahydroisoquinoline, hydroxylaudanidine, and its coupling partner was N- [2-(4-fluoro-3-nitrophenyl)ethyl]-2-(4-methoxyphenyl)-N-methylacetamide. The major challenges in this route were encountered in the preparation the fluoroacetamide, which involved several low-yielding synthetic steps and tedious chromatographic purifications. The nucleophilic aromatic substitution reaction of the two precursors was attempted in vain. Even though the total synthesis of neferine could not be accomplished, it is strongly believed that the developed synthetic routes will enable us to complete the synthesis of the targeted compound and other naturally-occurring bisbenzyltetrahydroisoquinolines. The results obtained herein represent a significant advance considering the importance of the bisbenzyltetrahydroisoquinolines as biologically active compounds. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (M.Sc.), Memorial University of Newfoundland, 1999. / Bibliography: p.125-131.

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Submitted by Stella Renata Machado Silva Esteves null (stellarmse@gmail.com) on 2018-03-15T12:49:21Z No. of bitstreams: 1 tese doutorado arquivo unico.pdf: 3856356 bytes, checksum: d346b9a5b9474275d35a835574475d08 (MD5) / Approved for entry into archive by Silvana Alvarez null (silvana@ict.unesp.br) on 2018-03-16T15:51:18Z (GMT) No. of bitstreams: 1 esteves_srms_dr_sjc.pdf: 3856356 bytes, checksum: d346b9a5b9474275d35a835574475d08 (MD5) / Made available in DSpace on 2018-03-16T15:51:18Z (GMT). No. of bitstreams: 1 esteves_srms_dr_sjc.pdf: 3856356 bytes, checksum: d346b9a5b9474275d35a835574475d08 (MD5) Previous issue date: 2018-02-02 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo desse estudo foi avaliar um adesivo experimental com diferentes concentrações de água, bem como sua degradação morfológica, química, física e mecânica. A primeira etapa envolveu a manipulação do adesivo experimental contendo 45/55% de HEMA e BisGMA, 0.5% de canforoquinona, 0.5% EDMAB e 1% de DPIHP. Foram incorporadas diferentes concentrações de água a partir dessa formulação adesiva (0, 10 e 16%). Os modelos adesivos foram fotopolimerizados e as análises iniciais realizadas: Morfológicas (Estereomicroscopio e Micro-xct); Físicas (Rugosidade-Ru, Sorção-Sor, Solubilidade-Sol); Químicas (Grau de conversão-GC, Mapeamento do espécime com 16% de água e os monômeros liberados pela CLAE); Mecânicas (Resistência flexural-RF, Módulo de elasticidade-ME e Resistência a compressão-RC). Em seguida os espécimes foram divididos conforme a solução de envelhecimento (água, etanol e acetona). Foram realizadas novas análises após o envelhecimento por 2 e 84 dias. Os testes estatísticos ANOVA e Tukey (5%) foram realizados. Os resultados iniciais, sem o envelhecimento, mostraram que as diferentes concentrações de água influenciam as propriedades dos adesivos. Na análise morfológica notou-se a presença de bolhas no espécime com 16% de água. Para a Ru e GC os maiores valores foram encontrados para os espécimes com mais água em sua composição e os menores para 0%. Já nas análises mecânicas, para RF e ME os espécimes com 10% de água foram mais resistentes; e em RC os espécimes com 16% foram menos resistentes. Após o envelhecimento notou-se trincas nos espécimes 0% e 16% na solução de acetona. Nos testes físicos, os espécimes com 16% absorveram mais solução; o etanol mostrou menores valores de solubilidade; Para Ru a água e a acetona diferiram em todas as concentrações e períodos, o mesmo ocorrendo para as concentrações 0 e 16%. Nos testes químicos o GC não foi alterado pelo envelhecimento. O mapeamento na amostra com 16% de água mostrou que inicialmente perto do poro o GC é menor e a quantidade de HEMA é maior; longe do poro a relação é inversa. Porém, após o envelhecimento, o GC próximo ao poro se tornou similar ao distante do poro. Através da CLAE observou-se uma maior liberação de componentes do espécime com 0% de água que os espécimes com 10% e 16%. Os testes mecânicos mostraram que o envelhecimento em acetona foi mais prejudicial que em água. Para a RF e ME os espécimes com 0% de água foram mais afetados que os espécimes com 10% e 16% em 2 e 84 dias. Para a RC após 2 dias o espécime com 16% foi mais afetado que 0 e 10%, no entanto, após 84 dias o espécime com 0% foi mais afetado pelo envelhecimento. Pode-se constatar que a quantidade de água e o tipo de envelhecimento afetam as propriedades dos sistemas adesivos baseados na composição 45/55% HEMA/BisGMA. / The aim of this study was evaluated an experimental adhesive with different water content, as well the degradation morphological, physical, chemical and mechanical. Firstly the dental adhesive was manipulated with 45/55% of HEMA and BisGMA, 0.5% of CQ, 0.5% EDMAB e 1% of DPIHP. Was added different water content (0, 10 and 16%). The adhesive model was cured and the analysis was done: Morphological (Stereomicroscope and Micro-xct); Physical (Surface Roughness), Sorption, Solubility); Chemical (Degree of convertion, Map of the pore on 16% water content sample and the released monomers- HPLC); Mechanicals (Flexural strength, Modulus of elasticity and Compressive strength). After the these analyzes, the samples were divided to each evaluation into 3 groups according to solution for performed ageing (water, ethanol and acetone). Further analyzes were performed after aging for 2 and 84 days. Statistical tests of ANOVA and Tukey (5%) were performed. Initial results, without aging, showed that the different water content influence adhesive properties. In the morphological analysis, bubbles were present on the sample with 16% water. For Ru and DC all specimens differed from each other, with the highest values for the specimens with 16% and the lowest to 0%. In the mechanical analyzes, for RF and ME the specimens with 10% water were more resistant; and in RC the specimens with 16% were less resistant. After aging it is possible notice cracks on the border of specimens 0% and 16% in the acetone. In the physical tests, the specimens with 16% absorbed more solution; ethanol showed lower values of solubility; For Ru, water and an acetone are differed in all concentrations and periods, the same for the concentration 0 and 16%. In the chemical tests DC was not altered by aging. The mapping in the sample with 16% of water showed that near to the pore the DC is smaller and a quantity of HEMA is larger; far from the pore this relation is inverse. However, after aging solutions, the DC near the pore became similar to the far from pore. Through HPLC was possible observed that release more components of the sample with 0% than 10% and 16%. The mechanical tests showed that the acetone damage more samples than water. For an RF and ME the specimens 0% were more affected than 10% and 16% after 2 and 84 days. For a RC after 2 days the sample with 16% was more affected than 0 and 10%, however, after 84 days the specimen with 0% was more affected by aging. It can be seen that the amount of water and the type of aging affect the adhesive properties of the database systems based on the 45/55% HEMA / BisGMA composition.

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<p> An experimental investigation of polymerisation of several monomers in wood was performed using free radical initiators such as benzoyl peroxide and 2-azo-bis-isobutyronitrile. The most promising comonomer system appeared to be styrene and acrylonitrile. As a result of copolymerisation of styrene and acrylonitrile in the cell cavities of wood, many improvements in physical properties of wood resulted. The improvement in physical properties of wood containing thermo-catalytically copolymerised styrene and acrylonitrile was found to be better than those of radiation initiated graft copolymerised wood. Thermo-catalytically produced wood polymer combinations showed as much improvement in physical properties as shown by those produced by radiation initiation without the use of swelling agents.</p> / Thesis / Master of Science (MSc)

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Thesis (M.S.)--Rutgers University, 2008. / "Graduate Program in Chemistry." Includes bibliographical references (p. 63-64).