[Part I] Desoxytigogenin was prepared by oxidation followed by Wolff-Kishner reduction of tigogenin. A number of methods were employed to open the side chain of desoxytigogenin to the corresponding dihydrodesoxytigogenin. Oxidation of dihydrodes-oxytigogenin yielded the corresponding C₂₆ aldehyde, which was isolated in pure form and characterised unambiguously. Bromination studies under varying conditions have been made on this aldehyde but the results have not been completed as yet. [Part II] The ground material from the bark of Diphlorynchus Mossambicensis was extracted with methanol, and methanol soluble concentrate was obtained. In addition a green gummy material, sparingly soluble in methanol, was obtained. The methanol concentrate was separated into acid, basic and neutral fractions and preliminary chemical investigations were made on these fractions. Two crystalline substances of empirical formulas C₃₀₋₃₅H₄₄₋₅₄O₂ and C₃₇₋₃₈H₅₂₋₅₆O₂ have been isolated, separated and purified from the green gummy material. Spectral and analytical data have been collected and a few chemical reactions have been made on these two compounds. / Science, Faculty of / Chemistry, Department of / Graduate

No description available.

The incorporation of a propargyl group to a natural product target allows for a streamlined approach to the investigation of structure activity relationships (SARs) and target identification in forward chemical genetics programmes using a ‘click’-based approach. To this end, an efficient synthesis of O-propargylated tyrosine derivatives was designed, and these have been used in the construction of peptide motifs both (a) derived from phage display libraries and (b) found in natural products. The L-tyrosine derivative Y* (compound I, X=H, R=H) was incorporated into a peptide sequence, PTTIYY, which is known to prevent the inhibition of p53 by the AG-2 protein. Y* has been included as both the terminal and the internal tyrosine in the peptide sequence. ELISA assays were carried out to determine how the binding of PTTIYY* and PTTIY*Y to AG-2 compared to that of the un-marked PTTIYY sequence. The results of these assays allowed new conclusions to be drawn regarding the important binding features of the peptide and possible sites for further optimisation of the AG-2 binding properties of this peptide through ‘click’ functionalisation of the modified tyrosine. The binding of the peptides incorporating Y* was also assessed using MCF-7 breast cancer cell lysate, known to contain the AG-2 protein. These results confirmed those seen for the purified AG-2 ELISA. The related bromo-D-tyrosine derivative (compound I, X=Br, R=Me) has been prepared and employed towards the synthesis of a bisebromoamide derivative. Bisebromoamide is a newly discovered polypeptide, and a promising anti-cancer agent. The bisebromoamide derivative contains a thiazole unit (Tzl), two N-methylated amino acids, and an oxopropyl pyrrolidine (Opp) moiety, which is unique to bisebromoamide in natural products. The activity of this bisebromoamide derivative will be investigated via ‘click’-based affinity chromatography using a new supported linker recently developed within the Hulme group.

Both bromodeprotonation and bromodesulphonation occur during aqueous bromination of sodium p-methoxybenzenesulphonate, A, and potassium l-methylnaphthalene-4-sulphonate, B. Extensive kinetic studies reported here suggest that bromodesulphonation of A proceeds by a two-step process with Br2 as the brominating species, but do not completely exclude Br+ (or H2OBr+) acting in either a one- or two-step process. For B, the kinetic data can be interpreted by either a one- or two-step process with Br2 as the brominating species. Kinetic sulphur isotope effects have been measured for the bromodesulphonation of A and B and found to vary with bromide-ion concentration, thus strongly supporting the two-step process involving molecular bromine. The kinetic results for the bromodeprotonation of A cannot distinguish between a one- and two-step process involving Br2l the two-step mechanism has been confirmed by the observation of a variation in kinetic hydrogen isotope effect with bromide-ion concentration. / Thesis / Doctor of Philosophy (PhD)

The free radical bromination of several cyclopropylarenes has been studied. The abstraction of a cyclopropyl hydrogen by bromine atom, which to date has been an unrecognized process, is demonstrated in this study. Specifically, when a cyclopropyl group is attached to the 9-position of an anthracene, an unprecedented hydrogen abstraction product, the corresponding cyclopropyl bromide, is obtained. This is believed to be due to stereoelectronic effects. Molecular mechanics calculations and X-ray crystallography have been used to demonstrate that 9-cycIopropylanthracene, unlike other cyclopropylarenes, is effectively locked in a conformation which places the a-cyclopropyl C-H bond in alignment with the p-orbitals of the aromatic system. This proper alignment activates the a-cyclopropyl hydrogen for abstraction by bromine atom. The relative reactivities of several 9-alkylanthracenes towards bromine atom are established, namely: 9-methyI- > 9-cyclopropyI- > 9-ethyl- >> 9-isopropylanthracene. Semi-empirical molecular orbital theory and molecular mechanics calculations have been utilized to demonstrate that the relative reactivities are not a function of bond dissociation energies but rather a function of the size of the dihedral angle between the a C-H bonds and the plane of the central ring of the various 9-alkylanthracenes in their lowest energy conformations. The absolute rate constants for the abstraction of hydrogen by bromine atom from 9-methyl-, 9-cyclopropyl-, and 9·ethylanthracene are estimated to be 1.1 x 10⁸ M⁻¹ sec⁻¹, 3.8 x 10⁷ M⁻¹ sec⁻¹ and 7.2 x 10⁶ M⁻¹ sec⁻¹ respectively. The value for the primary hydrogen/deuterium isotope effect for the abstraction of hydrogen by bromine atom from 9-cyclopropylanthracene is determined to be 2.6. All of the above observations lend support to the importance of stereoelectronic effects in the free radical bromination of the cyclopropylarenes and 9-alkylanthracenes. / Ph. D.

No description available.

<p> The acetate-catalyzed bromination of acetone is shown to occur by an enolization mechanism, although the reactions involved in this process are more complex than has been supposed.</p> <p> A study of the activation parameters for the enolization of some bromoacetones, and an observed linear free energy relationship between enolization rate constants, and acid ionization constants, shows that the transition state for this process resembles enolate and not enol.</p> <p> Bromine substitution in ketones accelerates enolization rates on both sides of the carbonyl group.</p> <p> The acetate-catalyzed enolization of 2-butanone favours the methylene group by a factor of nearly two. This fact is interpreted in terms of methyl groups being inductively electron-withdrawing in their effect in forming an enolate transition state.</p> / Thesis / Doctor of Philosophy (PhD)

<p> The regioselectivities of bromination and deuterium exchange of 2-butanone are shown to be the same, under identical conditions. This work firmly establishes that enolization is the rate-determining step for the former reaction, contrary to some recent reports in the literature.</p> <p> The steric effects and activation parameters in the bimolecular nucleophilic displacement reactions of a series of α-haloketones and alkyl halides are shown to be inconsistent with either a bridging or conjugation mechanism for the observed rate enhancements of haloketone over alkyl halide.</p> <p> The stereoelectronic requirements of this mechanism are tested in a system where the stereochemistry is known (cis- and trans-chlorocyclohexanones). The activation parameters suggest that only in the case where the geometry is correct for maximum conjugation (trans-chlorocyclohexanone) is there an appreciable difference in mechanism (stereoelectronically) from displacement at ordinary saturated carbon.</p> / Thesis / Doctor of Philosophy (PhD)

Essential to the entire field of Organic Chemistry is the nature of the carbon to carbon bond. Our current concepts and guiding principles concerning it are almost solely constructed from aliphatic compounds, certain simple ring species, and aromatic systems. Except for special cases, aliphatic and aromatic types are felt to be mildly strained or free from internal tension while the alicylic small and medium ring compounds are the so-called strained molecules. These strained compounds involve bending back or compression of two of the four carbon bonds from an equilibrium position. Distortions of more complex origin occur in the paracyclophanes and hexahelicine, etc. The theory considering strain of two of the four carbon bonds might well be extended to include three bonds. Simple caged compound core types testing three-bond strain. are the tetrahedron, trigonal prism , and cube. The successful synthesis of a unique compound, 4-methyl tricyclo[1.1.0.02-4] butane-1,2,3-tricarboxylic acid containing the three-bond strained tetrahedral core was reported by Beesley, Thorpe, and Ingold thirty eight years ago. With the exception of unsuccessful efforts by Woodward and Larson, this area of chemistry has remained virtually inactive since that time. Our reinvestigation of this remarkable synthesis has revealed method omissions vital to acquiring the compounds leading to l. These methods, a preliminary objective of this research and apparently commonplace in the laboratory of Thorpe, particularly involved the preparation of 1,1,1-ethane triacetic acid, II, and triethyl tribromo-1,1,1-ethane triacetate, III. The tri acid II was very difficult to purify by crystallizing with the techniques of frequent present-day use. Thorpe made no mention of temperature in his accounts, but obtained the acid in good condition. Our work has shown the acid can be easily purified by crystallizing from 50 % hydrochloric acid solution at 65°-70° C. This higher purity product can then be brominated with phosphorus pentabromide under special conditions. These are only partially stated by Thorpe. Our work has shown that III can be brominated by making phosphorus pentabromide in situ with slow bromine addition to a mixture of II and phosphorus tribromide. Compounds necessary to the acquisition of II and III are ethyl isodehydracetate IV, ethyl β-methyl glutaconate V, and ethyl a-cyano β,β-dimethylpropane tricarboxylate VI . Discussion of the plausible reasons for method omissions, the synthesis deletions and results of greater interest, reaction schemes leading each compound to it's successor, and the experimental details of compounds II through VI are presented in the Thesis. Appended is a proposed manuscript for publishing in the Journal of the American Chemical Society.

Specially prepared 2-arylquinolin-4(1H)-ones and their 2-aryl-1-methyl-4-quinolone derivatives were converted in high yield and purity to the corresponding C-3 brominated products using pyridinium tribromide in acetic acid at room temperature. The 2-arylquinolin-4(1H)-ones were reacted with iodine and Na2CO3 mixture in THF at room temperature to produce the 3-iodo-2-arylquinolin-4(1H)-one derivatives. The latter were, in turn, N-methylated using NaH-MeI mixture in dry THF to afford the corresponding 2-aryl-3-iodo-1-methyl-4-quinolone derivatives. The 3-iodo-2-arylquinolin-4(1H)-one and 2-aryl-3-iodo-1-methyl-4-quinolones were converted to 2,3-diarylquinolin-4(1H)-one and 2,3-diaryl-1-methyl-4-quinolones following Suzuki cross-coupling reaction method, respectively. The 2-aryl-3-bromoquinolin-4(1H)-ones, on the other hand, were converted to 2-aryl-3-bromo-4-chloroquinoline derivatives using phosphorus oxychloride under reflux. The 2-aryl-3-bromo-4-chloroquinoline were then transformed to the corresponding 2-aryl-3-bromo-4-N-(4'-chloroaryl)-4-aminoquinolines derivatives using 4-chloroaniline in ethanol under reflux. The products synthesized in this investigation were characterised using a combination of 1H NMR, 13C NMR, IR and mass spectroscopic techniques. / Chemistry / Chemistry / MSC (CHEMISTRY) / MSC (Chemistry)