A radioisotope of rubidium, 82Rb is used in positron emission tomography. Neutral crown ethers and cryptands have been studied as carrier ligands for Rb+ but exhibit low ion carrying capacity and high toxicity. The present study involved investigating a lariat ether containing an ionizable phosphoryl moiety and a lipophilic sidearm. This kind of molecule is expected to be ionized at physiological pH. It should be able to form neutral complexes with Rb+ and may be able to cross the blood-brain barrier. Molecular modeling of crown ether-alkali metal cation complexes indicates that a macrocycle containing more than 18 but less than 21 atoms can incorporate Rb+ ion in its cavity. Molecular modeling of some of the complexes of phospho-lariat ethers with rubidium using the Spartan'02 software package revealed that a lariat ether containing 20 member macrocycle will probably form the most stable complex with Rb+ion. Also, it was thought that more flexibility could be imparted to the macrocycle if it contains propyleneoxy units instead of ethyleneoxy units which form most crown ethers. Molecular modeling of two phospho-lariat ethers with 16 and 20 membered rings revealed that 20 membered macrocycle may be a better choice due to the side arm's participation in the complexation with Rb+ to a greater extent. Molecular modeling was used to find the bond angles and bond distances in this molecule. The synthesis to obtain ionizable phospho-bipodands was performed using subsequent benzylation, phosphorylation and hydrogenation steps. The characterization of products was done using HPLC, NMR and ESI-MS techniques. The synthetic scheme used was demonstrated to be plausible and could be used to obtain ionizable phoshobipodands. Extraction using solid phase anion exchange columns proved to be a good clean up procedure for obtaining pure bipodand. This bipodand could be used as a precursor for synthesizing an ionizable 20 membered lariat ether.

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La réaction de macrocyclisation par métathèse est une réaction clé en synthèse organique et qui comporte de nombreux défis. Les méthodes traditionnelles de macrocyclisation impliquent par exemple la haute dilution du mélange réactionnel et l’emploie d’une pompe seringue. Dans cette thèse de doctorat, une méthode qui évite l’emploi des techniques de haute dilution a été développée. Cette méthode a été appliquée à la synthèse de cyclophanes macrocycliques. De plus, la synthèse totale de la néomarchantine A, un macrocycle bisbibenzylique, a été réalisée en 12 étapes à partir de produits commercialement disponibles avec un couplage d’Ullmann, un couplage de Wittig et une macrocyclisation par métathèse comme réactions clés. La chimie en débit continu, une méthode facilement applicable en milieu industriel, a été explorée. Cette technologie a été appliquée à l’étape clé de macrocyclisation par métathèse pour la synthèse de la néomarchantine A ainsi que pour la synthèse d’un musc macrocyclique breveté par la compagnie « International Flavors and Fragrances (IFF) ». / The macrocyclic metathesis reaction is a key reaction in organic synthesis and possesses numerous challenges. Traditional methods typically involve high dilution conditions and the use of a syringe pump. In this doctoral thesis, a method that avoids the use of dilution technics has been developed. This method has been applied to the synthesis of macrocyclic cyclophanes. Furthermore, total synthesis of neomarchantin A, a bisbibenzyl macrocycle, has been done in 12 steps from commercially available reagents with an Ullmann coupling, a Wittig coupling and a macrocyclic metathesis reaction as key steps. Continuous flow chemistry, a method easily applicable in an industrial setting, has been explored. This technology was applied to the key macrocyclization step of the neomarchantin A and for the synthesis of a macrocyclic musk patented by International Flavors and Fragrances (IFF).

Thesis (MSc (Chemistry and Polymer Science))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: This investigation comprises the synthesis and characterisation of new macrocyclic ligands with pendant arms appended to the nitrogen donor atoms of 1,5,9-triazacyclododecane (12aneN3) and their coordination to various transition metal ions. The five macrocyclic ligands, 1,5,9-tris[(2S)-2-hydroxypropyl]-1,5,9-triazacyclododecane (THPTACD), 1,5,9- tris(2-hydroxy-2-methylpropyl)-1,5,9-triazacyclododecane (THMPTACD), 1,5,9-tris[(2S)-2- hydroxy-2-phenylethyl]-1,5,9-triazacyclododecane (THPETACD), 1,5,9-tris[(2S)-2- hydroxybutyl]-1,5,9-triazacyclododecane (THBTACD) and 1,5,9-tris(2-mercaptopropyl)- 1,5,9-triazacyclododecane (TMPTACD) were prepared by addition of pendant arms that contain alcohol or thiol end groups to a preformed 12aneN3 macrocycle. The 12aneN3 was synthesised from simple starting materials using 1,3-propanediol and bis(3-aminopropyl)- amine. The macrocycles with oxygen donor atoms on the pendant arms were prepared from the corresponding epoxides whereas for the one that contained sulphur donor atoms, propylene sulphide was used. The reaction progress was followed by 13C and 1H NMR spectroscopy and the final macrocyclic ligands were further analysed by mass spectrometry and in some instances, elemental analysis was also performed. Protonation constants of the free ligands were determined using potentiometric titrations at 25 oC and the ionic strength was kept constant at 0.1000 mol dm-3 using NaNO3. The log K1 values were 11.47, 10.96 and 10.47 for THPTACD, THBTACD and THMPTACD, respectively, whereas the corresponding values of 5.81, 6.02 and 5.94 were obtained for log K2. THPTACD is the most basic mainly due to less steric hindrance whereas THMPTACD is the least basic owing to high steric hindrance to both solvation and formation of strong hydrogen bonds of the protonated species to solvent molecules during the solvation step in a Born Haber-type cycle of the complete process. Protonated THBTACD is the most basic of the three mono-protonated ligands, a result that may be explained in terms of better correlation between inductive and steric effects. The second protonation constant is mostly influenced by inductive effects unlike the first protonation constant which is mostly determined by steric effects. The third protonation constant could not be established because of lack of sensitivity of the glass electrode in very high acidic medium. The complex stability constants of Co(II), Zn(II), Cd(II) and Pb(II) cations were similarly determined using potentiometric titrations at 25 ¡ÆC in 0.1000 mol dm-3 NaNO3. Log K values with THPTACD are 15.45, 21.22, 14.03 and 16.11 for Co(II), Zn(II), Cd(II) and Pb(II), respectively. THBPTACD has corresponding values of 13.93, 20.02, 13.55 and 15.01, whereas for THMPTACD the values of 14.63, 18.08, 12.91 and 14.36 log units were obtained. The Zn(II) 1:1 complexes are the most stable and those of Cd(II) the least stable. A crystal structure determination of [Zn(THPTACD)]2+ shows that optimal interaction between the Zn(II) metal ion and the donor atoms with their short Zn(II)-N bond lengths occurs. The short Zn(II)-N distances indicate that the metal ion is situated very close to the macrocyclic hole. On the other hand, each half of the hydrogen-bonded dimeric molecular structure of [Cd2(THPTACD)2]4+ has long Cd(II)-N bond lengths. Although metal nitrates, perchlorates and acetates were used in attempted crystal structure determinations, only metal nitrates formed suitable crystals. THPTACD complexes with Co(II), Mn(II), Ni(II), Cu(II), Zn(II) and Cd(II) were subjected to such determinations. Each central metal ion in these complexes is six coordinate to the three N atoms of the parent macrocyclic ring on one plane and the three O atoms of the pendant hydroxypropyl arms forming another plane on the other face of the metal ion. The geometry of all six molecular structures is pseudo octahedral with the Cu(II) complexes being the most twisted towards a trigonal prismatic arrangement. The change towards trigonal prismatic can be attributed to packing forces overriding octahedral crystal field stabilisation effects. The overall chirality of the isomorphic complexes of Zn(II), Co(II), Mn(II), Ni(II) and Cu(II) with THPTACD is [¥Ë((2¥ë.)¥ä.¥ä)] whereas the overall chirality of each half of the dimeric [Cd2(THPTACD)2]4+ complex is [¥Ë(¥ë.(2¥ä.)¥ä)]. The Cu(II) complex with THPETACD has the same overall chirality as the Cu(II) complex with THPTACD but is less twisted towards trigonal prismatic geometry. Both Cu(II) complexes exhibited strong evidence of Jahn-Teller tetragonal distortion in the solid state with tetragonality parameter values of 0.87 and 0.81, respectively. The structure of a new di-¥ì-chloro bridged binuclear complex of Cd(II)-12aneN3 was also determined. The molecule contains an inversion centre coinciding with the crystallographic centre of symmetry. Finally, the molecular structure of the protonated 1,5-bis[(2S)-2- hydroxybutyl]-1,5,9-triazacyclododecane shows that the oxygen donor atoms of the two pendant arms are pre-organised for meridional coordination. The hydrogen bond network in this structure emphasises the important role that such weak interactions play in stabilising the proton even in solution during determination of protonation constants in triazamacrocycles with pendant arms carrying oxygen donor atoms.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: In this study, two novel ligands were synthesized and separately two crown ether derivatives were all immobilized onto four different silica substrates. These immobilized ligand systems were used to extract six different metal and metalloid ions in water. The extraction capacity of the different immobilized ligands was compared with each other to determine whether the substrates had any influence on the extraction capabilities of these ligands. After the extraction experiments, recovery of the immobilized ligands was attempted by re-protonating the ligands so as to displace the metal ions. Two free parent ligands, 1,4,7-tris-[(S)-2-hydroxypropyl]-1,4,7-tri-azacyclodecane (THTD) and 1,4,8-tris-[(S)-2-hydroxypropyl]-1,4,8-tri-azacycloundecane (THTUD), were synthesized. Previous formation constant data indicated that THTD and THTUD form very stable complexes with Cd2+ which should make these ligands ideal for the extraction of Cd2+. These two ligands are less symmetric due to the carbon bridges between the nitrogen atoms, which differ in length. This gives the ligands the special feature that they can form five - and six membered rings during complexation with the metal ions. The ligands were fully characterized by NMR, mass spectrometry and elemental analysis. Characterization of the silica substrates was done using BET, low angle X-ray diffraction and FTIR. MCM-41 has the highest surface area, followed by SBA-15, Si gel (60 Å) and HMS. Although MCM-41 has the largest surface area, it was not the best support to use. HMS and Si gel (60 Å) have the smallest and almost identical surface areas. Yet, Si gel (60 Å) was a far better support to use than HMS, and even better than MCM-41. The worst supports were SBA-15 and HMS. A spacer, 3-Glycidyloxypropyl-trimethoxysilane (glymo), was introduced to immobilize the ligands to the silica substrates. Solid state NMR and FTIR analysis confirmed that the spacer could indeed be successfully immobilized on the various silica supports. The immobilized ligands were fully characterized with the use of solid state NMR and FTIR. The thermal stability of the immobilized ligands was determined by means of TGA. The immobilized ligands are stable up to 200ºC where after they started to disintegrate. According to literature, 15-crown-5 and 18-crown-6 are suitable ligands for the extraction of Sr2+ and UO22+. Since these ligands were to be immobilized, (2-aminomethyl)-15-crown-5 and (2-aminomethyl)-18-crown-6 were used because of the amino group that can be used as an anchor for immobilization. To immobilize these ligands onto the activated silica substrates, two methods were used: 1) directly onto the substrate by using the amino groups at the end of the carbon arm and 2) by means of the glymo spacer which connects the (2-aminomethyl)-15-crown-5 and (2-aminomethyl)-18-crown-6 to the silica substrates. The immobilization was confirmed and the ligand-substrate moiety fully characterized by solid state NMR and FTIR. The thermal stability of the immobilized crown ethers was determined by means of TGA as stable up to 200ºC where after they disintegrated. Extraction experiments were conducted at 25ºC and atmospheric pressure. The extractions were done at pH values of 4.5 and 5.9. The extraction capacity of the immobilized ligands was determined by ICP analysis. As expected, the extraction done at pH 5.9 was significantly better than at pH 4.5. Cr6+ was the best-extracted metal ion. The best extraction results were obtained with Si gel (60 Å) as support. It was also noticeable that the extraction capacity increased with a spacer added to the support, except for the extraction of UO22+. Better extraction for the uranyl was obtained using the 15-crown-5 and 18-crown-6 immobilized directly onto the supports, rather than with a spacer added. Recovery of the metal ions and the immobilized ligands was attempted, but without success. This aspect will be examined again in future work. In conclusion, ligands were successfully synthesized and immobilized. These immobilized ligands produced moderate extraction results with a number of metal ions from aqueous solution. / AFRIKAANSE OPSOMMING: Hierdie studie behels die sintetisering van 2 nuwe ligande en die immobilisering daarvan, te same met 2 kroon eters, op vier verskillende silika substrate. Die geïmobiliseerde ligande is gebruik vir die ekstraksie van verskillende metaal - en metaloied ione uit water. Die ekstraksie kapasiteit van die onderskeie geïmobiliseerde ligande is vergelyk om te bepaal of die substrate ‘n uitwerking op die ekstraksie vermoeë van die ligande het. Herwinnings eksperimente is uitgevoer deur die verplasing van die geadsordeerde metaal ione deur middel van reprotonasie van die ligande. Twee nuwe azamakrosikliese basis ligande, 1,4,7-tris-[(S)-2-hidroksipropiel]-1,4,7-tri-azasiklodekaan (THTD) en 1,4,8-tris-[(S)-2-hidroksipropiel]-1,4,8-tri-azasikloundekaan (THTUD), is gesintetiseer. Vormings konstante data dui daarop dat THTD en THTUD uiters stabiele komplekse met Cd2+ vorm wat hierdie ligande dus geskik behoort te maak vir die ekstraksie van Cd2+. Die twee ligande toon ook ‘n mindere mate van simmetrie as gevolg van die verskillende lengtes van die koolstof brûe tussen die stikstof atome. Hierdie eienskap verskaf aan die ligande die moontlikheid om beide vyf- en sesledige ringe vorm tydens kompleksering met die metaal ione. Die ligande is ten volle gekarakteriseer deur middel van KMR-metings, massa-spekstroskopie en element analise. Karakterisering van die silika substrate [Si gel (60 Å), MCM-41, SBA-15, and HMS] sluit in BET, lae hoek X-straaldiffraksie en FTIR. MCM-41 het die grootste oppervlakte, gevolg deur SBA-15, Si gel (60 Å) en HMS. Ten spyte van die feit dat MCM-41 die grootste oppervlakte het, was dit egter nie die beste subtraat om te gebruik nie. Die interne areas van die uiters groot porie-oppervlaktes van MCM-41 is nie toeganklik vir immobilisering nie a.g.v. die uiter klein porie-openinge. Si gel (60 Å) en HMS het die kleinste oppervlak areas. Si gel (60 Å) is ‘n baie beter substraat om te gebruik as HMS, en selfs ook beter as MCM-41 aangesien die totale oppervlakte van die Si gel (60 Å) gebruik kan word. Die mees ongeskikte substrate was SBA-15 en HMS. Die alreeds klein oppervlak areas word verder “verklein” a.g.v. die klein porie openinge wat die interne oppervlekte van die porieë ontoegangklik maak. ‘n Verbinder, 3-Glysidieloksipropiel-trimetoksisilaan (glymo) is gebruik om die ligande op die silika substrate te immobiliseer. Vaste toestand KMR en FTIR analise het bevestig dat die verbinder suksesvol geïmmobiliseer is op die onderskeie silika substrate. Die geïmmobiliseerde aza makrosikliese ligande is ten volle gekarakteriseer deur vaste toestand KMR en FTIR. Die termiese stabiliteit is bepaal d.m.v GTA en die geïmmobiliseerde ligande is stabiel tot 250ºC. Die basis ligande 15-kroon-5 an 18-kroon-6 is uiters geskik vir die ekstraksie van Sr2+ en UO22+. Om hierdie kroon eters te immobiliseer, is (2-aninometiel)-15-kroon-5 en (2-aninometiel)-18-kroon-6 gebruik. Die amino groep dien as anker vir die immobilisering. Twee metodes van immobilisering op silika is gebruik: 1) direkte immobilisering op die substraat en 2) immobilisering d.m.v. die glymo verbinder. Die immobilisering is bevestig en die ligand-substraat funksionel groep is gekarakteriseer d.m.v. vaste toestand KMR en FTIR. Die termiese stabiliteit van die geïmmobiliseerde kroon eters is bepaal d.m.v. GTA en is stabiel tot 200ºC. Ekstraksie eksperimente is uitgevoer by 25ºC en atmosferiese druk. Die ekstraksies is uitgevoer by pH waardes van 4.5 en 5.9. Die adsorpsie kapasiteit van die geïmmobiliseerde ligande is bepaal d.m.v. IGP analise. Soos verwag is die ekstraksie by pH 5.9 beter as by pH 4.5. Cr6+ ekstrksie was die hoogste met al die die ligande geïmmobiliseerd op die onderskeie substrate. Si gel (60 Å) was die beste substraat om te gebruik. Die ekstraksie kapasiteit van al die metaal ione het verbeter met die toevoeging van ‘n verbinder, behalwe vir UO22+. Beter ekstraksie van die UO22+ is verkry met die gebruik van die kroon eters wat direk op die substrate geïmmobiliseer is, eerder as met ‘n verbinder toegevoeg. Herwinning van die metaal ione en die ligande is probeer deur standard filtrasie. Na die filtrasie is die geïmmobiliseerde ligande en substrate met water gewas. Die filtreerpapier en ligande is met HNO3 behandel, maar van die metaal ione het egter op die filtreer papier agter gebly en die IGP resultate het ‘n hoër herwinning getoon as wat tydens die ekstraksie verkry is. Hierdie aspek sal weer in die toekoms ondersoek moet word. Die ligande is suksesvol gesintetiseer en geïmmobiliseer. Hierdie geïmmobiliseerde ligande toon gemiddelde ekstraksie resultate met ‘n aantal metaal ione uit waterige medium by ‘n pH van 5.9.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Peptides are a promising class of therapeutic candidates due to their high specificity and affinity for cellular protein targets. However, peptides are susceptible to protease degradation and are typically not cell-permeable. In efforts to design more effective peptide drug discovery systems, investigators have discovered that incorporation of non-canonical amino acids (ncAAs) and macrocyclization overcome these limitations, making peptides more drug-like. In this work, we exploit the promiscuity of wild-type aminoacyl-tRNA synthetases (aaRSs) to ‘mischarge’ ncAAs onto tRNA and ribosomally incorporate them into peptides using a cell-free translation system. We have demonstrated the ability to incorporate five ncAAs into a single peptide with near-wild type yield and fidelity. We also demonstrated the in situ incorporation of ncAAs containing azide and alkyne functionalities, enabling the use of CuAAC (click chemistry) to generate triazole-bridged cyclic peptides. When combined with bisalkylation of peptides containing two cysteines via an α,α’-dibromo-m-xylene linker, we created bicyclic peptides which are structurally similar to the highly bioactive knotted peptide natural products. Biological display methods, such as mRNA display, are powerful peptide discovery tools based on their ability to generate libraries of >1014 unique peptides. We combined our ability to incorporate ncAAs with our bicyclization technique adapted for use with mRNA display to create knotted peptide library scaffolds. We performed side-by-side monocyclic and bicyclic in vitro selections against a model protein (streptavidin). Both selections resulted in peptides with mid-nM affinity, and the bicyclic selection yielded a peptide with remarkable protease resistance. We used a new library that enables the generation of a diverse collection of linear, monocyclic and bicyclic scaffolds in one pot, increasing the likelihood of target-ligand conformational alignment. We performed a second selection against streptavidin and revealed a nearly unanimous preference for linear peptides containing an HPQ motif, a known streptavidin-binding sequence. However, when we used these libraries for in vitro selection against a biological target, DNA repair protein XRCC4, we did not observe convergence. In summary, we have developed a novel technique for production of bicyclic peptide libraries. These highly-constrained protease-stable scaffolds can be used as platforms to identify high affinity, drug-like ligands using mRNA display.

The aim of this work was studying of the coordination properties of TACN macrocyclic derivatives with aminophosphinate pendant arms. Two ligands were prepared, one with two pendant arms NODPam and one with three pendant arms NOTPam. Because of degradation of ligand NODPam during its synthesis, only the ligand NOTPam was studied further. Acid-base properties of ligand and termodynamic stability of aluminium and gallium complexes were studied. Formation and disociation studies were performed with the complexes. Coordination of fluoride ions to aluminium complex was studied using ion selective fluoride electrode. Finally coordination of complex AlFx with ligand NOTPam was studied using 19F and 27Al NMR spectroscopy. Selected experiments were made also with ligand NOTA. Key words: macrocyclic complexes, positron emission tomography, phosphinic acids

The aim of this thesis was to prepare monoamide of macrocycle H3NOTA, which was prepared by multiple step synthesis. Ligand was characterized by NMR, MS and X-ray difraction analysis. Acid-base properties were studied by potentiometric titrations. Four protonation constants pKa`s were found and these protonation constants are lower than pKa`s of H3NOTA. Coordination properties with selected metal ions from the first row of transition metal, metal ions of biological interest and with lithium ions were investigated by potentiometric titration. Stability constants show that monoethylamide derivative of macrocycle H3NOTA forms complexes with lower stability than diethylamide derivative of macrocycle H3NOTA. Stability constants for complexes which contains amide group are lower than for H3NOTA complexes. Kinetics of Ga3+ complexation was investigated at different pH by 71 Ga NMR. The rate constants of and half-lives of complexation were determined at pH = 1. The rate constant was higher and the half-life of complexation was shorter than for H3NOTA ligand. Key words: macrocyclic complexes, thermodynamic stability, formation kinetics, radiopharmaceutical