Thesis (Ph. D.), Memorial University of Newfoundland, 1998. / Bibliography: leaves 239-247.

Thesis (Ph.D.)--Memorial University of Newfoundland, 1999. / Includes bibliographical references.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2005. / Includes bibliographical references (leaves 165-180). Also available in electronic version.

Thesis (Ph. D.)--University of Hong Kong, 2005.

The hydroformylation of unfunctionalised olefins (such as prop-1-ene and oct-1-ene) is an extremely valuable process and is practised on a massive scale industrially in the synthesis of commodity chemicals. In fact, it represents the worlds largest scale application of homogeneous catalysis. As a result, the majority of research carried out on this reaction has been in the study of catalytic systems which provide high rates and selectivity for the production of linear aldehydes from terminal unfunctionalised olefins, with the products finding use in the production of plasticizers and detergents. Asymmetric hydroformylation, the enantioselective variant of this reaction is extremely attractive, as low cost or easily accessible olefins are transformed into highly versatile value-added enantioenriched aldehydes in a single step. However synthetic organic chemists interested in the synthesis of fine chemicals, both in academia and industry, have been slow to adopt this attractive protocol for the production of chiral aldehydes. This is mainly due to the fact that in the past catalysts for this reaction exhibited low activity and/or selectivity in this process. However, the last two decades have seen major advances, mainly in the development of highly effective chiral ligands, and with these developments the time has come to tackle the vastly under-explored area of asymmetric hydroformylation of more functionalised olefins. To set the scene for the research carried out during this project a brief introduction will be given which highlights the historical development of highly efficient catalysts for the hydroformylation of olefins. This will be accompanied by some examples of the use of this methodology in the synthesis of pharmaceutically relevant compounds. It should become apparent from the introduction that the asymmetric hydroformylation of functionalised olefins and in particular nitrogen containing olefins, has received very little attention despite the fact that over half of all medicinal compounds contain at least one nitrogen containing functional group. Firstly we describe hydroformylation as a useful alternative to the classical synthesis of a delicate chiral building block, namely α-formyl amides. These compounds, traditionally only available through multi-step synthetic procedures from enantiopure starting materials, have been accessed by asymmetric hydroformylation of readily accessible and in some cases commercially available acrylamides. By judicious choice of reaction conditions and selection of the appropriately active chiral ligand enantioenriched α-formyl amides (e.e. up to 82%) were produced in high yield. A comparison is made between the classical route and the hydroformylation route to illustrate the potential of this efficient transformation. We have studied the hydroformylation of enamides, a much under-studied substrate class in hydroformylation and developed knowledge of how some more functionalised 1,1- and 1-2-subtituted olefinic amides react under hydroformylation conditions. This research illustrates the work still to be done in terms of development of more active and selective catalysts for this reaction but despite limitations we developed a potential route to gamma amino aldehyde derivatives which could be used in turn in the synthesis of physiologically important gamma amino butyric acid (GABA) derivatives. We provide an example of the highly efficient and selective asymmetric hydroformylation of a bicyclic olefinic lactam, which is of industrial importance in the synthesis of carbocyclic nucleosides. We demonstrate the efficiency of this synthetic methodology by synthesising the central pharmacophore of a potent anti- HSV-1 (herpes simplex virus) carbocyclic nucleoside via a hydroformylationreduction protocol. The classical synthesis of this pharmacophore involves nine synthetic transformations to produce racemic material, whereas the hydroformylationreduction protocol produces highly enantioenriched material in just two steps. We also demonstrate some downstream chemistry of the aldehyde products showcasing the synthetic versatility of the aldehyde functionality in the production of a variety of functionalised cyclopentanes. Finally the synthesis and catalytic testing of a group of novel phosphine-phosphite ligands for use in asymmetric hydroformylation is described, one of which produces unprecedented regioselectivity and state of the art enantioselectivity in the asymmetric hydroformylation of styrene. Highly selective asymmetric hydroformylation of the other two ‘model substrates' in this reaction namely, vinyl acetate and allyl cyanide is also achieved. Having shown high activity and selectivity over these ‘model substrates' this ligand takes its place among the small group of highly active and selective ligands available for asymmetric hydroformylation and may also help to broaden the substrate scope of this efficient and atom-economic transformation.

Made available in DSpace on 2015-07-13T12:10:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-23. Added 1 bitstream(s) on 2015-07-13T12:25:27Z : No. of bitstreams: 1 000825064_20160228.pdf: 307325 bytes, checksum: 19ac282fd1189c52ae2046a9f1acbd26 (MD5) Bitstreams deleted on 2016-02-29T12:16:24Z: 000825064_20160228.pdf,. Added 1 bitstream(s) on 2016-02-29T12:17:23Z : No. of bitstreams: 1 000825064.pdf: 6733720 bytes, checksum: 484cdda7e2b141896c1f3c18d4742888 (MD5) / Os biocatalisadores (enzimas e/ou micro-organismos) são amplamente utilizados na síntese de moléculas bioativas, em especial os fármacos, para gerar ou resolver centros quirais. O levetiracetam, comercialmente conhecido como Keppra®, é um composto quiral com propriedades anticonvulsivantes cuja atividade farmacológica está relacionada ao enantiômero (S). O aumento da opção pelo uso do levetiracetam em detrimento a outros fármacos anticonvulsivantes está intimamente associado à baixa ocorrência de efeitos colaterais provocados por este. Diversas rotas quimiossintéticas para sua produção são relatadas na literatura. A maioria delas envolve um elevado número de etapas, alto consumo energético, uso de catalisadores metálicos e baixos rendimentos globais. Em contrapartida, este projeto teve por objetivo empregar uma rota quimioenzimática, com menor número de etapas, condições mais brandas e ambientalmente amigáveis de reação para a síntese do levetiracetam e análogos (série alifática). A respectiva série aromática também foi sintetizada, uma vez que trata-se de blocos construtores quirais para a síntese de compostos com reconhecida atividade anti-malária. A primeira etapa consistiu na síntese das cianidrinas racêmicas seguida da substiuição da hidroxila destas por heterociclos nitrogenados. Uma coleção de enzimas do tipo nitrila hidratases (E.C. 4.2.1.84) foi empregada para catalisar a conversão das nitrilas α-substituidas por N-heterociclos nas respectivas amidas quirais. As enzimas foram utilizadas tanto na forma isolada (obtidas comercialmente) quanto em células íntegras de bactérias e leveduras da Coleção de Micro-organismos do Laboratório de Biocatálise do IQ-UNESP Araraquara. As reações enzimáticas foram conduzidas em meio aquoso tamponado e em sistemas binários líquido iônico : solução tampão (10, 20, 40 e 80%) a fim de avaliar a influência do... / Biocatalysts (enzymes and/or microorganisms) are widely used in the synthesis of bioactive molecules, in particular pharmaceuticals, to generate or resolve chiral centers. Levetiracetam, commercially known as Keppra®, is a chiral compound with anticonvulsant properties whose pharmacological activity is related to the (S)-enantiomer. The increase in option for the use of levetiracetam over the others anticonvulsant drugs is closely associated with low incidence of side effects caused by this. Several chemosynthetic routes for its production are reported in the literature. Most of them involve numerous synthetic steps, high energy consumption, use of metal catalysts and low overall yields. On the other hand, this project aims to develop a chemoenzymatic route, with fewer steps, milder conditions and environmentally friendly reaction for the synthesis of levetiracetam and analogues (aliphatic series). The respective aromatic series was also synthesized, since it is chiral building blocks for the synthesis of compounds with known antimalarial activity. The first step was the synthesis of racemic cyanohydrin followed by substitution of the hydroxyl group by nitrogen heterocycles. Collections of nitrile hydratase enzymes type (EC 4.2.1.84) were used to catalyze the conversion of N-heterocycles α-substituted nitriles in the respective chiral amides. The enzymes were used both in isolated form (obtained commercially) as in whole cells bacteria and yeast Collection of Microorganisms of Biocatalysis Laboratory of IQ-UNESP Araraquara. The enzymatic reactions were performed in buffered aqueous medium and ionic liquid : buffer (10, 20, 40 and 80%) binary systems in order to evaluate the influence of the solvent on the enantioselectivity and yield of these reactions. The ionic liquids synthesized and used in this work were 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium...

ÉTUDES VERS LA SYNTHESE TOTALE DE LA (+)-TAUTOMYCETINE: La (+)-tautomycétine (2 ,TTN), polycétide naturel isolé en 1989 à partir de souches de Streptomyces griseochromogenes possède, en plus de sa structure chimique unique, des activités biologiques prometteuses. Plus récemment, comme étant un inhibiteur spécifique des sérine/thréonine phosphatases de type 1 (PP1) et 2A (PP2A). Nous nous sommes intéressés au développement d'une voie de synthèse pour accéder à la (+)-tautomycétine. Nous avons réussi à synthétiser les deux fragments principaux de la tautomycétine, le fragment B2 correspondant à la partie C1-C12 et compos 260, qui constitue la partie C7'-C13. Ces deux fragments contiennent tous les carbones de la TTN. / STUDIES TOWARD THE TOTAL SYNTHESIS OF (+)-TAUTOMYCETIN: (+)-Tautomycetin is a polyketide natural product isolated in 1989 from Streptomyces griseochromogenes with antifungal activity. Currently, TTN is best known for its activity in serine/threonine phosphatase proteins. We developed a convergent synthetic route to this natural product. Two key fragments of (+)-tautomycetin were synthesized, the B2 fragment containing the C1-C12 chain and the compound 260, corresponding to the C7'-C13 fragment of (+)-tautomycetin. The synthesis of fragment B2 employed a stereoselective chiral epoxide opening reaction as a key step, which consist of a novel strategy to prepare the desoxypropionate moiety of TTN. The synthesis of 260 employed a novel method for bis-esterification of anhydrides developed in the Dias-Campagne groups

Efavirenz, a drug that is still inaccessible to millions of people worldwide, is potent non nucleoside reverse transcriptase inhibitor (NNRTI), is one of the preferred agents used in combination therapy for first-line treatment of the human immunodeficiency virus (HIV). NNRTIs attach to and block an HIV enzyme called reverse transcriptase, by blocking reverse transcriptase; NNRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body. Efavirenz can't cure HIV/AIDS, but taken in combination with other HIV medicines (called an HIV regimen) every day helps people with HIV live longer healthier lives. Efavirenz also reduces the risk of HIV transmission and can be used by children who are suffering from HIV/AIDS. All the above therapeutic uses of efavirenz prompted us to identify the novel and hopefully cost efficient synthetic methodology for the preparation of efavirenz. In this thesis a new synthetic method for asymmetric synthesis of efavirenz is described. This route started from commercially available starting materials and it is first established in traditional batch chemistry and further the parameters transferred to a semi continuous flow protocol for optimization.

Several camphor and pinane derivatives have been synthesised and evaluated for use as chiral auxiliaries in asymmetric synthesis. Various blocking groups have been attached to the camphor skeleton in attempts to improve stereofacial selectivity; these include α-methoxybenzyl and xylyl groups, and novel stereoisomeric ketal moieties derived from meso- and (R,R)-(-)-2,3-butanediol. Benzylation reactions carried out on the lithium enolates of ester derivatives of the camphor-derived chiral auxiliaries afforded α-benzylated products in 5-60% diastereomeric excess. Stereochemical aspects have been explored using high resolution NMR, X-ray crystallographic and computer modelling techniques, and hydrolysis of selected α-benzylated products has permitted the diasteroselective bias to be confirmed. Opposite configurations at the new stereogenic centre are clearly favoured by the xylyl and ketal blocking groups - an observation rationalised in terms of the presence or absence of chelating potential in the blocking group. Baylis-Hillman reactions carried out on a series of specially prepared camphor-derived acrylic esters containing the ketal blocking group exhibited both low diastereoselectivities (0-30% d.e.) and very long reaction times. Chiral silyl enol ethers, synthesised using both pinane and camphor derivatives as chiral auxiliaries, showed up to 20% diastereomeric excess in MCPBA oxidation, alkylation and Mukaiyama reactions. Attempts to bring the prochiral centre in the silyl enol ether substrates closer to the chiral auxiliary, and thus improve the stereofacial selectivity, proved unsuccessful. The silyl enol ether derivatives, however, display interesting fragmentation patterns in their electron impact mass spectra, which were investigated using a combination of high resolution MS, comparative low resolution MS and metastable peak analysis.

No description available.