New aromatic fluorinations

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Applications of transition metal-catalysed coupling reactions in organic synthesis

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New methods for spiroketal synthesis

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The synthesis of potential anti parasitic compounds

Novel members of a homologous series of N', N'-di-(2,6-dinitro-4-trifluoromethylphenyl) diamine dimers related to the anti-malarial compound trifluralin (2,6-dinitro-(N, Ndipropylamino- 4-trifluoromethyl)benzene) have been synthesised in good yields for screening against several tropical diseases such as Leishmaniasis, Trypanosomiais, and Malarial in both humans and animals. This was achieved in a single step reaction where the starting material chloralin (1-chloro-2,6-dinitro-4-trifluoromethylbenzene) was reacted with various aliphatic and aromatic diamines via the key step involving nucleophilic aromatic ipso-substitution. The final compounds were obtained via the intermediate Jackson-Meisenheimer complexes. The formation of the corresponding tri- and tetrasubstituted hydrazines were, however, not successful due to unfavourable steric interactions. Previous investigations by other researchers have postulated tubulin (a dimeric protein) as a potential site of drug action. Based on this theory such compounds were synthesised that may play a role in mapping distances between tubulin binding sites. As both the herbicides, trifluralin and oryzalin (3,5-dinitro-4-(N, N-dipropylamino) - benzenesulphonamide) have been shown to possess anti-leishmanial and anti-malarial activities against Leishmania mexicana (in vivo) and Plasmodium falciparum (in vitro) respectively, a new analogue of oryzalin, 4-(N, N-dipropylsulphamoyl)-2,6-dinitro-l- (N, N-dipropylamino)benzene has been synthesised for possible screening. The study was extended to the synthesis of julolidine (2,3,6,7-tetrahydro-IH, 5H-benzo[ij] quinolizine) and lilolidine (1,4,5,6-tetrahydro-2H-pyrrolo[3,2,1[ij]quinoline) analogues since the parent ring structures are known to exhibit anti-leishmanial activities. This was achieved by reacting several aromatic amines with a series of a, ß-ketoesters to give the intermediate amides, which were then cyclised (in situ) via Friedel-Crafts acylation using polyphosphoric acid to the corresponding substituted julolidine and lilolidine analogues. Spectroscopic data on trifluralins, julolidines and related compounds is presented in this thesis and were found to be consistent with the proposed structures. Although in this study the emphasis lies on synthetic aspects and spectroscopic evaluations some preliminary biological data is summarised in the Appendix, while the remaining testing will form part of an ongoing programme of work by others

The application of diastereoselective free radical reactions in carbohydrate chemistry

This thesis focuses essentially on the application of diastereoselective radical reactions to the preparation of O- and C-glycosidic linkages. As such, the introduction surveys both the general area of glycoside synthesis and diastereoselective radical reactions and in particular, their use in carbohydrate chemistry. Methyl [Phenyl 4,5,7-tri-O-benzyl-3-deoxy-2-sulphonyl-β-D-arabino-2-heptulopyranoside]onate (sulphone ester) was prepared from tri-O-benzyl-D-glucal according to a method previously developed in the laboratory. The highly diastereoselective preparation of 6-C-glycosides was achieved by reductive desulphonylation of the sulphone ester with lithium naphthalenide followed by quenching with an alkyl halide and ultimately by Barton reductive decarboxylation. Diastereoselectivities in excess of 95:5 were routinely observed. Thermal elimination of phenylsulphinic acid from the sulphone ester gave the corresponding 1-carbomethoxy glycal. cw-Hydroxylation with osmium tetroxide gave exclusively the gluco-isomer. Acetonation, saponification and reductive decarboxylation gave l,2-O-isopropylidene-3,4,6-tri-O-benzyl-β-D-gluco-pyranose as a single anomer and the first example of a 1,2-trans-isopropylidene derivative of a pyranose sugar. Other β-O-gluco-pyranosides were prepared as single anomers by related process. The extension of the methodology to the preparation of β-O-manno-pyranosides was investigated. The extrapolation of the method to the preparation of furanosidic linkages was investigated. 2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid was chosen as starting material and methods were developed for its selective deprotection and protection. The stereoselectivity of the radical decarboxylation step was investigated. Finally, in the context of the C-glycoside synthesis, 6-trimethylsilylethoxymethyl chloride (SEM-Cl) was developed as a practical equivalent to formaldehyde in low temperature, non-aqueous aldol type reactions

The Chemistry of Diphenyl N-Cyanocarbonimidate

The synthesis of a variety of heterocyclic compounds by the sequential addition of two nucleophiles to a one carbon equivalent is described. Treatment of this one carbon equivalent, diphenyl N-cyanocarbonimidate 53, with the first nucleophile leads to N-cyano-O-phenylisourea intermediates. These compounds were shown to be a mixture of isomers by variable temperature 1H n.m.r. spectroscopy and the origin of the stereoisomerism is discussed. The N-cyano-O-phenylisoureas were then treated with a second nucleophile which displaced phenol, giving an intermediate which spontaneously cyclised to produce a heterocyclic ring. In this way 6-substituted and 5,6-disubstituted-dihydro-4(3H)-pyrimidinones were synthesised together with 5,6-dihydro-4(3H)-pyrimidinones and imidazolidin-5-ones substituted with carbocyclic sugar analogues at N-3. An attempt to synthesise pyrimidine isonucleosides failed due to the steric hindrance present in the sugar. Several of the imidazolldin-5-ones were rearranged to dihydro-4(3H)-pyrimidinone-6-carboxylic acids by a ring expansion reaction. Investigations into the hydrolysis of the cyanoimine portion of several molecules using trifluoroacetic acid are reported. The synthesis of several triazoles, using the bifunctional nucleophile hydrazine and its analogues, is reported. A temperature dependent competition between synthesis of the triazole and the corresponding imidazole, via different cyclisation modes, is described, and a mechanism for the reaction is discussed

Addition and some other reactions of sulphanuric chloride

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