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This thesis describes the development of new methodologies promoted by bifunctional Brønsted basic H-bonding catalysis and Lewis basic organocatalysts. Chapter 2 describes the synthesis of novel chiral guanidines and their application as Brønsted and Lewis base catalysts in a variety of processes. Chapter 3 screens an array of Brønsted basic organocatalysts for the synthesis of trans-dihydrobenzofurans. A tertiary amine-thiourea bifunctional catalyst is used for an intramolecular Michael addition using keto-enones. The desired dihydrozofurans were obtained in excellent yield and with excellent diastereo- and good enantiocontrol. Chapter 4 describes the use of an isothiourea catalyst, HyperBTM, for the formal [2+2] cycloaddition between homohydrides and perfluorinated ketones to furnish β-lactones. The products were obtained in excellent yield and with excellent diastereo- and enantioselectivity. A large scope of 36 examples is reported. The derivatizion of the obtained β-lactones via ring-opening with a range of nucleophiles gave access to an array of β-hydroxycarbonyl compounds. Oxetanes could be accessed by a two step protocol, consisting of β-lactone reduction to give a diol, followed by cyclization. Chapter 5 describes a mechanic investigation on the isothiourea-catalysed formal [2+2] cycloaddition. A variable time normalisation graphical analysis method was used to determine the partial orders for anhydride, ketone and catalyst. The catalyst resting state was determined to be free catalysts by use of a fluorine-labelled catalysts.

Made available in DSpace on 2014-12-02T11:16:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-10-23Bitstream added on 2014-12-02T11:21:21Z : No. of bitstreams: 1 000794658_20151023.pdf: 573251 bytes, checksum: 03d4df4f4429e43ceb32c45accc7a09d (MD5) Bitstreams deleted on 2015-11-03T14:38:58Z: 000794658_20151023.pdf,. Added 1 bitstream(s) on 2015-11-03T14:40:12Z : No. of bitstreams: 1 000794658.pdf: 2260681 bytes, checksum: c429d2be1406df635493710523100cc4 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O presente trabalho apresenta a síntese, caracterização e estudo da auto-associação em solução aquosa de derivados anfifílicos zwiteriônicos de quitosana com potencial para o transporte e a liberação controlada de fármacos. Derivados anfifílicos foram obtidos a partir de quitosana previamente desacetilada e degradada, que foram submetidos à reação de adição de Michael com o monômero hidróxido de 1-(3-sulfopropil)-2-vinilpiridina (SPP). O derivado hidrofílico obtido foi posteriormente por modificado com o grupo dodecil aldeído (DD) por meio de reação de aminação redutiva. Os graus de substituições (GS) pelos grupos DD e SPP foram determinados utilizando as técnicas de espectroscopia de ressonância magnética nuclear de hidrogênios RMN de 1H, espectroscopia no infravermelho IV e titulação potenciométrica essas técnicas foram utilizadas para caracterizar a quitosana e seus derivados. Os graus de substituição por SPP foram de 36 e 46% e com grupos dodecil variaram de 2 a 10%. A massa molar média foi determinada utilizando cromatografia de permeação em gel (GPC). E o estudo do comportamento associativo em meio aquoso foi realizado utilizando-se a espectroscopia de fluorescência, espectroscopia no UV-Vis, espalhamento de luz dinâmico (DLS) e microscopia eletrônica de transmissão (TEM). Os derivados hidrofílicos permaneceram solúveis em toda a faixa de pH e os derivados anfifílicos demostraram um comportamento similar aos surfactantes convencionais. As concentrações de agregação crítica (CAC), foram determinadas com a sonda fluorescente o pireno, os valores variaram de 0,005 até 0,017 g L-1 foi observado um decréscimo nos valores com o aumento do conteúdo hidrofóbico e pH. Medidas de DLS mostraram que os derivados formam agregados com diâmetros que variam de 100 a 1000 nm e o potencial zeta varia de acordo pH da solução. Imagens de TEM mostraram agregados esféricos de tamanhos variados ... / This work presents the synthesis, characterization and self-association study of amphiphilic zwitterionic derivatives of chitosan in aqueous solution as potential drug delivery systems. Amphiphilic derivatives were obtained from deacetylated and degraded chitosan, followed by Michael addition reaction with the monomer 1-(3-sulfopropyl)-2-vinylpyridine hydroxide (SPP). The hydrophilic derivative was further modified with dodecyl groups (DD) by reductive amination reaction. The degrees of substitution (DS) by DD and SPP groups were determined using H1-NMR, and FTIR and potentiometric titration techniques were used to characterize chitosan and its derivatives. The degrees of substitution by SPP were 36 and 46 % and by dodecyl groups varied from 2 to 10%. The average molecular weights were determined using the gel permeation chromatography (GPC). The study of the selfassociation in aqueous solution was performed by using fluorescence spectroscopy, UV-Vis, dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques. The hydrophilic derivatives were soluble in all pH range and the amphiphilic derivatives exhibited self-association behavior similar to conventional surfactants. The critical aggregation concentrations, determined from pyrene fluorescence, varied from 0.005 to 0.017 g l-1 and were shown to decrease with both, the increasing hydrophobic content and pH. DLS measurements showed that self-association of the amphiphilic derivatives leads to formation of aggregates having diameters varying from 100 to 1000 nm and the zeta potential varied according with the pH. The TEM images showed spheroidal aggregates of varied sizes in accordance with DLS measurements. Quercetin was used as a model for drug loading study and the results showed that solubilizing capacity increased from 17 to 54% with the hydrophobic content of the ...

Ph.D. / The work described in this thesis was directed at advancing the applications of Al(OTf)3, a metal triflate, in organic synthesis. Lewis acids play an important role in catalysis and catalyse reactions with high selectivities, unique reactivities under mild conditions. Metal triflates have become the Lewis acids of choice for acid catalysed organic transformations. A detailed literature study of metal triflates provided numerous examples of their use in organic transformations. Al(OTf)3 has been widely neglected as a Lewis acid which is contrasting to the attention the other metal triflates have received. Previous work in our laboratories had established Al(OTf)3 as an effective Lewis acid catalyst for the ring-opening of epoxides with simple alcohols and amines. The alcoholysis of epoxides provides a ready access to β-alkoxy alcohols. Whilst this reaction has been shown to occur with Al(OTf)3 as a catalyst, the established protocol calls for the use of the nucleophilic alcohol in an excess amount. Whilst this proves no problem when simple alcohols are employed as nucleophiles in the ring-opening reaction, it is a problem when more complex and expensive alcoholic nucleophiles are utilised. A modified procedure utilising Al(OTf)3 as a catalyst was developed which tolerates the use of only 1 equivalent of the nucleophilic alcohol for the ring opening reaction. The desymmetrisation of a meso-epoxide with chiral alcoholic nucleophiles was also investigated and the outcome of the diastereoselectivity of the reaction reported. The aminolysis of epoxides has been established utilising Al(OTf)3 as the Lewis acid catalyst. However, this has only been demonstrated for the ring opening of simple epoxides with simple amines. Piperazine derived β-amino alcohols with known biological activity were chosen as substrates with which to test the Al(OTf)3 catalysed aminolysis of epoxides in the synthesis of more complex β-amino alcohols. The various starting epoxides and amine nucleophiles were synthesised. During which a new approach towards the synthesis of - glycidyl amines was developed utilising a two step approach with the first step being catalysed by Al(OTf)3. It was also found that the optimal method for forming the β-amino alcohol bond was one in which the glycidyl motif was placed on the less basic heteroatom and ring opened by the more nucleophilic piperazine amine.

Ph.D. (Chemistry) / The bridged chiral benzopyrans were strategically ring opened via acetolysis to yield either galactose based chromenes or chromans, depending on the reaction conditions. A proposal relating to the mechanism of this selective ring opening acetolysis is discussed. The benzopyrans (chromenes, chromans and bridged chiral benzopyrans) were de-acetylated via triethyl amine catalysed transesterification. Interestingly, the chromenes did not yield the anticipated hydrolysis product (triol) but a new class of bridged chiral benzopyrans which were a result of intramolecular oxa-Michael addition. A chromene that formed during the selective ring opening of the bridged chiral benzopyrans was employed to develop a method for the synthesis of a carbohydrate derived oxepane. The oxepane synthesis was achieved, albeit in the face of numerous challenges from side reactions. The difficulties encountered in the synthesis are discussed...

Ph.D. / The research described in this thesis was directed at advancing the application of metal triflates, Al(OTf)3 in particular, in organic synthesis, on the one hand and to contribute to the understanding of the underlying basis for their catalytic activity. The study was undertaken against the background and on the bases of a detailed literature study of metal triflates, their chemical and catalytic properties and applications thereof. Amongst others, it deals with the possible role of metal-bound water that give rise to Brønsted type acidity and that this induced Brønsted acidity may be responsible for the catalytic activity that is observed. The study was prompted by the realisation that Al(OTf)3 was largely neglected as a potential reusable catalyst. This is in marked contrast to the attention paid to other metal triflates, the rare earth metals in particular. Earlier work in this laboratory has shown that Al(OTf)3 is stable in water from which it can be recovered easily for reuse. In addition it showed promise as a Lewis acid catalyst and is relatively soluble in several organic solvents. New applications for the use of Al(OTf)3 have now been demonstrated. These include the efficient formation of acetals from aldehydes and ketones. The conversions can be carried out in an alcohol/orthoester mixture or preferably in neat orthoester. Other metal triflates, notably Sc(OTf)3 and In(OTf)3, are useful alternative catalysts. Al(OTf)3 can be easily recycled without loss of activity. This methodology also can be applied to aldehydes and ketones containing TBDMS groups without effecting deprotection of the ethers. In view of the sensitivity of the TBDMS groups to hydrolysis in the presence of triflic acid the results suggest little hydrolysis (or alcoholysis) of the metal triflates in the protic solvents used, which would generate trifluoromethanesulfonic acid as a consequence of such metal based hydrolysis. Al(OTf)3 was also found to be a good catalyst for the formation of THP ethers. It proved to be excellent for Friedel Crafts reactions using alkynes as substrates. Al(OTf)3 together with other triflates offers a mild alternative to the more traditional water sensitive Lewis acids, e.g. BF3, AlCl3 and TiCl4, which are difficult to recover and require the use of extremely dry solvents.

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The present investigation has involved a kinetic and mechanistic study of the thermal cyclization of 3-acetoxy-3-(2-pyridyl)-2-methylenepropanoate esters and related compounds to 2-substituted indolizines. Substrates for the kinetic study were prepared via the Baylis-Hillmann reaction of pyridine-2-carboxaldehydes with acrylate esters, acrylonitrile and methyl vinyl ketone. The resulting hydroxy compounds were then acetylated to afford the acetoxy derivatives, thermal cyclization of which gave the corresponding 2-substituted indolizines. The cyclization reactions was followed using 'H NMR spectroscopy and were shown to follow firstorder kinetics. The influence of the various substituents on the observed first-order rate constants has been examined and variable temperature studies have permitted evaluation of activation parameters for the formation of methyl indolizine-2-carboxylate and ethyl indolizine-2-carboxylate. An alternative route to 2-substituted indolizines via halogenated derivatives was explored and several halogenated 2-pyridyl derivatives were synthesised and their thermal cyclization to indolizines was attempted. Novel 5-methylindolizine-2-carboxamides were prepared as part of this investigation and dynamic NMR spectroscopy was used to study internal rotation about the amide N-CO bond in these compounds.