beta-Turns in many biologically active peptides are important secondary structural elements which are critical for their biological activities. Hence, it is not surprising that beta-turn based pharmacophore design including beta-turn mimetics has become a central topic in medicinal chemistry in addition to alpha-helix or helical peptides. One of the advantages of such beta-turn mimetics is that they can better control torsion angles of the backbone of peptides and to some degree dihedral angles chi (X). These beta-turn mimicking scaffolds are designed to have a higher avidity for the acceptor by overcoming what otherwise is the inherent entropic cost paid for beta-turn formation upon binding to the acceptor. Among different synthetic strategies to bicyclic structures as beta-turn mimetics, consecutive formation of bicyclic structures using tandem acid-catalyzed N-acyliminium ion cyclization is attractive since this methodology was well established in the synthesis of natural product alkaloids. 1,3,6,8-Substituted tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,7-diones were designed and synthesized as internal beta-turn mimetics through an acid-catalyzed tandem acyliminium ion cyclization. Its development and synthesis are decribed in Chapter 2 to Chapter 4. Its application toward the development and synthesis of a small molecule ligand for melanocortin receptors is described in Chapter 5. In addition, the development of peptidomimetics for opioid receptors is explained in Chapter 6. On the other hand, a dicarba analogue having opioid receptor agonist, and dicarba analogues for MCRs were synthesized through solid phase synthesis including a ring closing metathesis reaction using Grubbs' catalyst (I) in Chapter 8.

This thesis describes the catalysed addition of X-H bonds (X = S, O and N) to alkynes using a range of novel rhodium(I) and iridium(I) complexes containing hybrid bidentate phosphine-pyrazolyl, phosphine-imidazolyl and phosphine-N heterocyclic carbene (NHC) donor ligands. The synthesis of novel bidentate phosphine-pyrazolyl, phosphine-imidazolyl (P-N) and phosphine-NHC (PC) donor ligands and their cationic and neutral rhodium(I) and iridium(I) complexes [M(P N)(COD)]BPh4, [M(PC)(COD)]BPh4, [Ir(P-N)(CO)2]BPh4 and [M(P-N)(CO)Cl] were successfully performed. An unusual five coordinate iridium complex with phosphine-NHC ligands [Ir(PC)(COD)(CO)]BPh4 was also obtained. Seventeen single crystal X-ray structures of these new complexes were determined. A range of these novel rhodium and iridium complexes were effective as catalysts for the addition of thiophenol to a variety of alkynes. Iridium complexes were more effective than rhodium analogues. Cationic complexes were more effective than neutral complexes. Complexes with hybrid phosphine-nitrogen donor were more effective than complexes containing bidentate nitrogen donor ligands. An atom-economical, efficient method for the synthesis of cyclic acetals and bicyclic O,O-acetals was successfully developed based on the catalysed hydroalkoxylation. Readily prepared terminal and non-terminal alkyne diols were cyclised into bicyclic O,O-acetals in quantitative conversions in most cases. The efficiency of a range of rhodium and iridium complexes containing bidentate P-N and PC donor ligands as catalysts for the cyclisation of 4-pentyn-1-amine to 2-methyl-1-pyrroline varied significantly. The cationic iridium complexes with the bidentate phosphine-pyrazolyl ligands, [Ir(R2PyP)(COD)]BPh4 (2.39-2.42) were extremely efficient as catalysts for this transformation. Increasing the size of the substituent on or adjacent to the donor led to improvement in catalytic activity of the corresponding metal complexes. The mechanism of the catalysed hydroalkoxylation was proposed to proceed by the initial activation of the alkyne via ?? coordination to the metal centre. The ?? binding of both aliphatic and aromatic alkynes to [Ir(PyP)(CO)2]BPh4 (2.44) was observed by low temperature NMR and no reaction between 2.44 and alcohols was observed. In contrast, the facility in which thiol and amine oxidatively added to 2.44 led the proposal that in the hydrothiolation and hydroamination reaction, the catalytic cycle commences with the activation of the X-H bond (X = S, N) by an oxidative addition process.

Cette thèse décrit le développement de nouveaux systèmes catalytiques à base de fer ainsi que l'étude de leur réactivité vis-à-vis de l'éthylène. Dans un premier temps, nous nous sommes intéressés au développement de précurseurs de fer(III) associés à des ligands monoanioniques tridentes. Deux voies de synthèse ont été envisagées. La première décrit la complexation d'un ligand anionique sur le précurseur FeCl3 et la seconde passe par l’oxydation d'un complexe de fer(II) associé à un ligand neutre conduisant à une espèce binucléaire. Activés par le MAO, ces catalyseurs de fer(III) constituent les premiers complexes du genre permettant l’oligomérisation de l'éthylène. L’accent a également été porté sur la recherche de nouveaux activateurs. Des complexes d’aluminium répondant à nos attentes ont été obtenus par réaction entre un alcool et le triméthylaluminium. Selon la nature de l'alcool, la structure des activateurs peut être soit binucléaire ou trinucléaire. Enfin, des complexes de fer et de nickel associés à des ligands imino-imidazoles possédant un bras hémilabile ont été synthétisés. Une fois activés, les systèmes à base de nickel ont montré de bonnes activités en catalyse. / This thesis describes the development of new catalytic systems based upon iron complexes and their reactivity toward ethylene. First, we focused our interest on the synthesis of iron(III) precursors chelated by monoanionic ligand. Those complexes were obtained either by reaction of the monoanionic ligand with FeCl3 or through oxidation of the iron(II) complex. The second reaction led to binuclear complexes. Then, another aim of the thesis was to design new well-defined cocatalysts for the activation of iron complexes. The study of the reaction between an alcohol and the trimethylaluminum allowed us to reach this aim. Aluminum complexes adopted either a binuclear framework or a trinuclear one, depending on the nature of alcohol reagent. Besides this work, new iron(II) and nickel(II) complexes chelated by imino-imidazole ligands bearing a pendant donor function L were synthesized. All complexes have been evaluated for the oligomerization of ethylene in the presence of EtAlCl2 or MAO as cocatalyst. Only nickel complexes were active toward ethylene transformation.

Thesis (MSc)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: A series of di- and mono-substituted acyl(aroyl) thioureas were examined for the extraction and transportation of Au(III). Two-phase metal ion extraction experiments were employed to investigate the extraction behaviour of these ligands. The effect of varying ligand concentration on the extraction trend of these ligands was investigated. The results show that the different substituent groups on the benzoyl ring can affect the extraction pattern of the metal. Furthermore, the alkyl substituents on the thiourea moiety and varying the ligand concentration have an influence on the percentage of metal ion extracted. With the exception of the H2L2(N,N-di-propyl-N'- benzoylthiourea ) ligand the di-alkyl substituted thioureas were more efficient for the metal ion extraction than the mono-alkyl ligands. In almost all the experimental set ups there was reduction of the Au(lIl) to Au(l) and Au(O) but it was more pronounced with HL3 (N,N-di-(2-hydroxyethyl)-N'-benzoylthiourea). Transport experiments were also conducted, the experimental set up for transportation was a concentric type cell involving a 3-phase system - 2 aqueous phases ( source and receiving phase) separated by a chloroform membrane incorporating the ligand. The transport results however only gave a satisfactory result of about 5% of gold transported by the HL1 (N,N-dibutyl-N'-benzoylthiourea). All other ligands attempted resulted in metal ion being present in the organic phase, but no metal ion present in the receiving phase. To help drive the transport of the metal ion to the receiving phase CN-, S203 2- and perchloric acid were incorporated into the receiving phase. The transport results were not enhanced with these substances being present in the aqueous receiving phase. The aqueous source and receiving phases were analyzed by flame atomic absorption spectroscopy (FAAS). Finally the N,N-diethyl-N'-camphanoylthiourea (HL10) ligand and its complex with Au(l) were synthesised. Single crystals of the complex were grown for X-ray crystallography and the crystal and molecular structure of the complex was determined. The complex crystallizes in the monoclinic space group P21. The cell parameters are a = 10.7356(7)A b = 16.3443(11)A c = 10.9268(7)A f3 = 103.1450(10t , and final R-factor of 1.76%. The coordination sphere around Au(l) shows a nearly linear arrangement of sulphur and chloride. / AFRIKAANSE OPSOMMING: In hierdie proefskrif is In aantal mono- en di-gesubstitueerde asiel(ariel) thioureums ondersoek vir die transportasie en ekstraksie van Au(III). Twee-fase metaalioon vloeistof-vloeistof ekstraksie eksperimente is gebruik om die ekstraksie patroon van hierdie ligande te ondersoek. Die effek van verskillende ligand konsentrasies op die ekstraksie neiging van hierdie ligande is ondersoek. Resultate toon dat die verskillende substituente op die benziel ring die ekstraksie patroon van die metaalioon beïnvloed. Verder, is gevind dat die alkiel substituente op die thioureum saam met varierende ligand konsentrasies geensins die metaalioon ekstraksie beïnvloed nie. Met die uitsondering van H2L2 (N,N-dipropiel-N'-benzielthioureum) is die di-alkiel gesubstitueerde ligande meer effektief vir metaalioon ekstraksie in vergelyking met die mono-alkiel ligande. In baie van die eksperimente is In reduksie van Au(llI) na Au(l) en Au(O) gesien en dit is baie duidelik met ligand HL3 (N,N-di(2- hidroksie-etiel)N'-benzielthioureum). Alle waterige fases is ge-analiseer met gebruik van Atoomabsorpsie Spektroskopie (AAS). Transportasie eksperimente is ook uitgevoer met gebruik van In drie-fase selsisteem. Twee waterige fases (bron- en ontvang-fase) is geskei met die chloroform membraan fase wat die ligande bevat. Hierdie eksperimente het net In 5% Au(lll) transportasie getoon met HL1(N,N-dibutiel-N'-benzielthioureum). Daar was geen transportasie van Au(lIl) met enige van die ander ligande. Analise van die twee waterige fases het getoon dat die metaalioon eindelik goed ge-ekstraeer is en is teenwoordig in die membraan fase. Om die transportasie van Au(lIl) aan te spoor, is CN-, s2ol- en perchloorsuur in die ontvang-fase geinkorporeer. Die resultate was geensins beïnvloed nie. N,N-di-etiel-N'-kamfonielthioureum (HL10)ligande en die kompleks daarvan met Au(l) is ook gesintetiseer. Enkel-kristalle van die kompleks is verkry en X-straal kristallografiese analiese is onderneem. Hierdie kompleks kristalliseer in die monokliniese ruimtegroep P21,met a =10.7356(7)Á, b=16.3443(11)Á, c=10.9268(7)Á en ~=103.1450(10t. Die finale R-faktor is 1.76%. Die koordinasie om Au(l) toon In liniêre geometrie met swael en chloor.

Thesis (MScEng) -- Stellenbosch University , 2001. / ENGLISH ABSTRACT: The electrochemical analysis of selected metal ions with the newly biodegradable chelating agents, lminodisuccinic acid (IDS) and Polyaspartic acid (PASP) was performed by cyclic voltammetry using a thin mercury film glassy carbon microelectrode. IDS and PASP are of interest from an environmental perspective. They were introduced as alternatives to chelants and dispersants. The thermodynamic stability constants of these selected metal complexes were determined by cyclic voltammetry (CV). A comparison with similar data obtained using potentiometric methods shows a good correlation between the two methods. This reaffirms that CV is a useful and facile means for evaluating metal-ligand complex thermodynamic data. Furthermore, our results were used to validate the predicted models obtained using an Equilibrium Speciation model JESS program. Capillary Electrophoresis (CE) was used to separate metal-IDS and metal-PASP complexes at different pH's. The separation of these chelates was achieved within 7 minutes. The obtained results were compared with speciation and a reasonable agreement was observed, although the separation ofmetal-PASP showed poor broad peaks. / AFRIKAANSE OPSOMMING: Die elektrochemiese analise van geselekteerde metaal-ione met nuwe biodegredeerbare chelate, Iminodisuksien suur (IDS) en Polyaspartiese suur was gedoen met sikliese voltametrie deur gebruik te maak van 'n dun laag kwik glasagtige koolstof mikroelektrode. Vanaf'n omgewingsstandpunt is IDS en PASP van belang. Hulle was voorgestel as alternatiewe vir chelate en verspreidingsagente. Die termodinamies stabiliteits konstantes van hierdie uitgesoekte metal komplekse was bepaal deur middel van sikliese voltametrie (CV). 'n Vergelyking met soortgelyke data, wat met potensiometriese metodes bepaal was, dui 'n goeie korrelasie aan tussen die twee metodes bepaal was. Dit bevestig die feit dat CV 'n bruikbare en maklike manier is om metal ligand komplekse se termodiniese data te evalueer. Die resultate was ook gebruik om die voorspelde model, wat verkry was deur gebruik te maak van "Equilibrium Speciation model JESS program, te bevestig. Kapillere elektroforese (CE) was gebruik om metal-IDS en metal-PASP komplekse by verskillende pH's te skei. Die skeiding van hierdie chelate was binne sewe minute verkry. Hierdie resultate was vergelyk met die spesiasie data en 'n aanvaarbare ooreenstemming was waargeneem, alhoewel die skeiding van die Metaal-PASP swak pieke toon.

Different diphosphine ligands having the structure shown below have been studied for carbonylation and hydroformylation reactions. Depending on the substituent on the phosphorus atoms the electronic and steric properties can be tuned to direct the reaction towards the desired products. Palladium methoxycarbonylation of a large variety of unsaturated compounds has been attempted under very different conditions. The outcome of these reactions was the achievement of the linear products with a selectivity higher than 99.5 % under mild conditions of pressure and temperature. Chloroaromatic compounds have also been employed as substrates in methoxycarbonylation reactions. Unexpected results were observed since carbonylation was possible only when a strong electron withdrawing group was present. The origin of the many side products from these reactions has been elucidated. Rhodium hydroformylation was not as successful as palladium Methoxycarbonylation since relatively severe conditions had to be used to get good rates and good selectivity. In no case were there as good as those obtained in the carbonylation reactions. However, unusual factors, such as the presence of chlorine in the reaction media, have been found to influence either the conversion or the selectivity.

A series of novel monodentate and bidentate phosphine ligands substituted with bulky tert-butyl and fluorinated aryl groups have been synthesised. Borane protection has proved to be an excellent method for easy synthesis and purification of bidentate ligands in some cases. However, several of the bulky fluorinated ligands do not form stable borane complexes leading to complications in the synthesis and purification of these compounds. By reaction with transition metal platinum and palladium precursors, it was possible to form dichloride complexes from the synthesised ligands, which were characterised by X-ray crystallography. The complexes were found to be effective catalysts for the hydroxycarbonylation of vinyl arenes (yields of up to 95 % with 3 mol% catalyst). An unsymmetrical bidentate complex (3.18) in combination with paratoluenesulfonic acid and LiCl promoters has given exceptional (for a diphosphine ligand) regioselectivity for the branched acid (98.7 % branched) in the hydroxycarbonylation of styrene. The role of the promoters has been found to be crucial in deciding the activity and selectivity in this reaction.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy