Thesis (Ph. D.)--School of Chemistry and Biochemistry, Georgia Institute of Technology, 2004. Directed by Suzanne B. Shuker. / Includes bibliographical references.

Orientador: Carmen Veríssima Ferreira / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-16T13:47:52Z (GMT). No. of bitstreams: 1 Ferreira_PaulaAnastacia_D.pdf: 2451128 bytes, checksum: a13caa2510a3ac1dca624878d50fafab (MD5) Previous issue date: 2010 / Resumo: A eficiência do tratamento da leucemia sob vários aspectos, mesmo com os avanços farmacotecnológicos, ainda permanece como desafio para a medicina. Diante desse fator, maiores informações sobre a base molecular da leucemia e o desenvolvimento de agentes que atuem de forma alvo-específico, apresentem poucos efeitos colaterais e possam impedir o escape das células tumorais à indução de morte são extremamente desejáveis. No presente trabalho, foram abordados 2 aspectos: indução de morte das células leucêmicas por calix[6]areno, flavonóides e diterpeno lactona e contribuição da proteína tirosina fosfatase de baixo massa molecular (LMWPTP) para a resistência de células leucêmicas. As linhagens K562, Lucena-1 (resistente) e HL60 foram utilizadas como modelos no estudo. Calix[6]areno apresentou o mesmo nível de toxicidade para as duas linhagens celulares, mostrando valores de IC50 na faixa de 1-5 µM para K562 e 5-10 µM para Lucena-1. Calix[6]areno induziu vias apoptóticas como demonstrado pelo aumento da razão Bax/Bcl-2 e clivagem de PARP. A proteína tirosina fosfatase PTEN foi ativada pelo Calix[6]areno, fato relacionado com a diminuição da sobrevivência e proliferação. O Calix[6]areno aumentou a expressão de algumas enzimas antioxidantes e não afetou a atividade da proteína associada com o fenótipo de resistência, P-Glicoproteína. As células Lucena-1, que apresentam alta expressão da P-Glicoproteína, também apresentam altos níveis da LMWPTP. Observamos que quando esta enzima foi silenciada, a resposta frente a quimioterápicos das células leucêmicas se tornou mais eficiente. Por outro lado, o aumento da expressão da LMWPTP em células não resistentes provocou insensibilidade das mesmas à vincristina. Nossos dados sugerem que a LMWPTP contribui com o fenótipo resistente através da ativação das quinases Src e BCR-ABL. Outro aspecto investigado neste trabalho foi a indução da diferenciação e apoptose por compostos naturais. Quercetina e a apigenina apresentaram os dois efeitos desejados a um agente quimioterápico, ou seja, expressiva indução da diferenciação das células e também apoptose. Estes efeitos foram dependentes do tempo e modulação do estado redox celular. / Abstract: Leukemia therapy efficiency, under several aspects, even with the progress of pharmacotechnology, remains as a challenge in medicine. According to this, new information about the molecular basis of leukemia and development of agents that act on specific target, present low side-effects and prevent cancer cells escaping from death induction, are extremely desirable. In this work 2 aspects were evaluated: death induction of leukemia cells by calix[6]arene, flavonoids and diterpene lactone and the contribution of the low molecular weight protein tyrosine phosphatase (LMWPTP) for leukemia cells resistance. K562, Lucena-1 and HL60 cells were used as models in this study. Calix[6]arene presented the same level of toxicity on K562 and Lucena-1 cells, displaying an IC50 value ranging 1-5 µM to K562 cells and 5-10 µM to Lucena-1 cells. Calix[6]arene induce apoptosis signaling on both K562 and Lucena cells as molecularly demonstrated by the increased Bax/Bcl-2 ratio and PARP cleavage. Protein tyrosine phosphatase PTEN from leukemia cells became more active in the presence of calix[6]arene, which is related to a decrease of survival and proliferation. Calix[6]arene enhanced the expression of antioxidant enzymes and did not affect P-Glycoprotein activity. Lucena cells, which present high expression of P-Glycoprotein also contain high level of LMWPTP. Interestingly, when this phosphatase was silenced the leukemia cells response appeared to be more efficient towards chemotherapics. On the other hand, overexpression of this enzyme in K562 (non resistant cells) provoked insensitivity to vincristine. Our findings suggest that LMWPTP contributes with the resistance phenotype by supporting the activation status of Src and BCR-ABL kinases. Another aspect examined in this study was the induction of differentiation and apoptosis by natural compounds. Quercetin and apigenin displayed both desired effects of chemotherapics: induction of differentiation and apoptosis. These effects were time- and cellular redox status dependent. / Doutorado / Bioquimica / Doutor em Biologia Funcional e Molecular

Au cours de ces travaux de thèse, la synthèse de différents calix[8]arènes et complexes calixarèniques mono- et bimétalliques a été réalisée, en vue de préparer des nanoparticules par radiolyse. Les différentes étapes de synthèse ont été optimisées et différentes fonctionnalisations ont été testées pour améliorer la solubilité et le greffage des calixarènes à la surface des nanoparticules. Les nanoparticules métalliques obtenues à partir de sels d’argent et/ou d’or et stabilisées par les calix[8]arènes dans l’éthanol sont sphériques, très petites et très homogènes en taille (inférieures à 5 nm). Les analyses HAADF/STEM-EDX réalisées sur les nanoparticules Au-Ag ont permis de mettre en évidence le caractère bimétallique de ces nanoparticules et la présence de très petits agrégats de tailles inférieures à 1 nm. Les nanoparticules d’argent synthétisées ont montré leur efficacité en catalyse de réduction de composés nitrés. Ces résultats montrent l’efficacité des calixarènes pour stabiliser de très petites nanoparticules, tout en permettant une activité catalytique. Des nanoparticules mono- et bimétalliques (Au et Au-Ag) ont également été obtenues à partir des complexes calixarèniques par voie radiolytique. Cette voie de synthèse a permis d’augmenter la quantité de métal dans le milieu sans accroître la taille des nanoparticules formées, qui reste de l’ordre de 3-4 nm. Cette particularité peut être liée à la présence d’échanges rapides entre des clusters formés entre les calixarènes et les complexes métalliques précurseurs, mis en évidence par RMN. Toutefois, cette étude mérite d’être poursuivie. / During this thesis, the synthesis of different calix[8]arenes and mono- and bimetallic calixarenic complexes was performed in order to produce nanoparticles by radiolysis. The different steps of the synthesis were optimized and different functionalizations were tested to improve the solubility and the anchoring at the nanoparticles surface. Metallic nanoparticles were generated from silver and/or gold salts and stabilized by calix[8]arenes in ethanol. The obtained spherical nanoparticles were very small (less than 5 nm) and homogeneous in size. HAADF/STEM-EDS analyses performed on Au-Ag nanoparticles revealed their bimetallic character and the presence of very small aggregates of less than 1 nm. Catalyticefficiency of the silver nanoparticles was tested through nitreous compound reduction.These results show the calixarenes efficiency to stabilize small nanoparticles while allowing the catalytic activity. Mono- and bimetallic nanoparticles (Au and Au-Ag) were also synthesized by radiolysis from the calixarenic complexes. This synthetic pathway allowed the increase of the amount of metal used during the synthesis without increasing the size of the obtained nanoparticles (3-4 nm). This particularity can be related to fast exchange phenomena between clusters formed by the calixarenes and the metallic precursors complexes, that were shown by NMR spectroscopy. However, this NMR study needs to be pursued.

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Calixarenes, particularly calix[4]arenes, continue to attract considerable attention in synthetic chemistry, notably as platforms for designing sophisticated molecular cages and claw-like ligands. Incorporation of phosphorus containing fragments into the calix[4]arene framework gives rise to new class of phosphorus ligands, called “calixphosphines”, a class of molecules that combine a catalytic center (a transition metal) and a molecular receptor. This area of research has been growing rapidly in recent years. This thesis deals with the synthesis and a systematic study of conformational aspects of phosphorus functionalized calix[4]arene ligands and their palladium complexes. Several phosphorus functionalized calix[4]arene ligands and their (allyl) palladium complexes have been synthesized. The new compounds have been characterized by elemental analysis, NMR and IR spectroscopic data. The molecular structures of some representative compounds have been confirmed by single crystal X-ray diffraction studies. Chapter 1 provides a brief overview of phosphorus functionalized calix[4]arenes and their transition metal chemistry with emphasis on aspects related to the theme of the present study. The scope and aim of the present investigation is outlined at the end of this chapter. Chapter 2 presents the results obtained in the present investigation and a discussion of these results, especially spectroscopic and X-ray crystallographic data. The highlights of the present investigation and possible future directions are summarized at the end of this chapter. Chapter 3 contains relevant details of the experimental procedures for the synthesis of calix[4]arene phosphite ligands and their palladium complexes. Spectroscopic and analytical data of these compounds are also given in this chapter. The details of single crystal diffraction studies are included at the end of this chapter. The references to the literature are compiled at the end of the thesis and are indicated in the text by appropriate numbers appearing as superscripts. The compounds synthesized in the present study are represented by bold arabic numerals. The abbreviations employed in this thesis are those generally used in Chemical Abstracts.

Notre recherche se divise en deux parties distinctes. La première est issue d’une collaboration avec le Laboratoire de Chimie Organique et Photochimie de l’ULB des Pr. A. Kirsch-De Mesmaeker et C. Moucheron. Les travaux de ce groupe consistent à utiliser des complexes de Ru(II) polyazaaromatiques comme drogues photoactivables ou comme agents de diagnostic dans des systèmes biologiques. Cependant à cause de leur grande hydrophilie, ces complexes de Ru(II) ne peuvent pas pénétrer les membranes cellulaires, ce qui complique leur utilisation comme drogues photoactivables. <p>Afin d’améliorer cette pénétration cellulaire, deux stratégies ont été développées dans le cadre de cette collaboration. La première consistait en la synthèse et l’étude de deux nouveaux complexes de Ru(II) possédant des N,N-ligands facilement fonctionnalisables :[Ru(TAP)2btz]2+ et [Ru(TAP)2pytz]²+. Les études électrochimiques et photophysiques ont montré que l’état ³MLCT de ces complexes était un excellent agent oxydant. Ces complexes pourraient donc photo-réagir avec une guanine pour former un photo-adduit. Néanmoins, une étude photophysique plus détaillée a montré que l’état excité du complexe [Ru(TAP)2pytz]²+ possédait une durée de vie plus longue que celui du [Ru(TAP)2btz]2+. Par ailleurs, le [Ru(TAP)2pytz]²+ est plus photostable dans l’eau que le [Ru(TAP)2btz]2+. Seul, le complexe de Ru(II) constitué de deux ligands TAP et d’un ligand pytz facilement fonctionnalisable pourrait donc être utilisé pour photo-réagir avec des biomolécules dans l’eau.<p>La deuxième stratégie concernait la synthèse et l’étude de complexes de Ru(II) à partir de ligands dérivés de calix[4 ou 6]arènes. Des stratégies de synthèses originales ont été mises au point pour greffer une unité phen ou pytz sur des calix[4 ou 6]arènes mono-fonctionnalisés. Par la suite, des antennes de reconnaissance cellulaire (sucres) ont été introduites sur les positions phénoliques restantes des calixarènes dans le but d’effectuer une vectorisation ciblée. Pour cela, l’alkylation des positions phénoliques par des groupes azido a été mise au point. Ces groupes azido ont alors été mis en réaction avec des sucres possédant une fonction alcyne afin d’obtenir des ligands multivalents. Après, une réaction de complexation avec les précurseurs métalliques de Ru(II), ces différents ligands ont conduit aux nouveaux complexes calix[4 ou 6]arène-Ru(II) désirés.<p>Les propriétés électrochimiques et photophysiques des différents complexes de Ru(II) ont ensuite été étudiées. L’état ³MLCT des différents complexes est un excellent agent oxydant. Cependant, l’étude des propriétés photophysiques a montré que seul le complexe [(TAP)2Rupytz’(diN3C6)2+ était un candidat potentiel pour photo-réagir avec des biomolécules. En effet, un quenching des durées de vie a été observé pour les complexes de Ru(II) possédant des groupes phénol. Il est probablement provoqué par un transfert d’électron intramoléculaire du phénol vers l’état excité du complexe. Un quenching de luminescence a également été observé avec le complexe [(TAP)2Ruphen’(trisN3C4)2+ qui est probablement dû à un TE intramoléculaire du complexe excité vers le groupe azido. Le complexe multivalent n’a pas pu être étudié dans le cadre de ce travail mais il devrait être intéressant pour photo-réagir avec une biomolécule. <p>La seconde partie de ce travail est le fruit d’une collaboration avec le Laboratoire de Matière Condensée et de Systèmes Electroactifs (équipe des Dr. P. Hapiot et C. Lagrost, UMR 6510, Université de RENNES 1) et avec le Pr. O. Reinaud (Laboratoire de Chimie et Biochimie pharmacologiques et toxicologiques, UMR 8610, Université Paris Descartes). <p>Our research is divided into two distinct parts. The first part was developed in collaboration with the Laboratory of Organic Chemistry and Photochemistry of the Professors Andrée De Mesmaeker and Cécile Moucheron (ULB). The research topic of this group consists in using polyazaaromatic Ru(II) complexes as potential drugs in anti-cancer therapy or as diagnostic agents in biological systems. However, because of their high hydrophilicity, these Ru(II) complexes can not penetrate cell membranes which prevents their use as photoreactive drugs.<p>In order to enhance the cellular uptake, two strategies have been developed in the frame of this collaboration. The first one has consisted in the synthesis and study of two new Ru(II) complexes from N,N-ligands that can be readily functionalized: [Ru(TAP)2btz]2+ and [Ru(TAP)2pytz]²+. The photophysical and electrochemical studies have shown that both complexes behave as excellent oxidizing agents in their ³MLCT state. Thus, these complexes could photo-react with a guanine to form a photo-adduct. However, a more detailed examination of the photophysical parameters has shown that the excited state lifetimes of the complex [Ru(TAP)2pytz]²+ is longer than that of [Ru(TAP)2btz]2+. Moreover, the [Ru(TAP)2pytz]²+ is more photostable in water than the [Ru(TAP)2btz]2+. So, the Ru(II) complex obtained by the combination of two TAP ligands and one functionalized pytz ligand is an attractive photoreagent for biomolecules.<p>The second strategy has involved the synthesis and study of Ru(II) complexes from ligands based on calix[4 or 6]arenes. Original strategies have been developed to graft one phen or pytz unit on mono-functionalized calix[4 or 6]arenes. Subsequently, cellular recognition subunits (sugars) were introduced on the phenolic positions of calixarenes in order to perform a targeted vectorization. For this, the alkylation of phenolic positions by azido groups has been developed. These azido groups were then reacted with alkyne-glycoside to obtain multivalent ligands. After a complexation reaction with Ru(II) precursors, these ligands have led to new calix [4 or 6] arene-Ru(II) complexes. <p>Then, the photophysical and electrochemical properties of the different Ru(II) complexes were studied. The various complexes are sufficiently oxydizing in their ³MLCT. However, the study of their photophysical properties has shown that only the complex [(TAP)2Rupytz'(diN3C6)2+ could be a potential candidate to photo-react with biomolecules. Indeed, a quenching of lifetimes has been observed for the Ru(II) complexes with phenolic groups. It is probably due to an intramolecular electron transfer from the phenolic groups to the excited state of the complex. A luminescence quenching was also observed with the complex [(TAP)2Ruphen'(trisN3C4)]2+ probably because of an intramolecular electron transfer from the excited complex to the azido group. The multivalent complex has not been studied but it should be a valuable candidate to photo-react with a biomolecule. <p>The second part of this work is the result of a collaboration with the Laboratory of Condensed Matter and Electroactive Systems (Doctors Philippe Hapiot and Corinne Lagrost team, UMR 6510, Université de Rennes 1) and With the Professor Olivia Reinaud (Laboratory of Chimie et Biochimie pharmacologiques et toxicologiques, UMR 8610, Université Paris Descartes). / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Thesis (MSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Dithiadiazolyl heterocyclic radicals form part of an ever-growing research field in the quest for organic magnets and conducting materials due to the lone electron located within the heterocyclic ring. These compounds could potentially be used as electrical current conductors and transistors which may be developed into a molecular switch or other types of molecular devices. This thesis describes the successful synthesis of three nitrile functionalised calix[4]arenes, mono-, distal- and tetra-, as bulky scaffolds to be used as precursors in the synthesis of dithiadiazolyl functionalised calix[4]arenes. The crystal structures of these three nitriles are reported herein for the first time. Dithiadiazolyls tend to dimerise in the solid state, thus by selecting a calix[4]arene as a bulky R-group, it was hoped to inhibit dimerisation. Furthermore, synthesis of the radicals on different positions of the calix[4]arene may also inhibit dimerisation in the solid state. The typical reaction in the synthesis of dithiadiazolyls involves the reaction between a nitrile and lithium bis(trimethylsilyl)amide followed by the formation of the dithiadiazolylium chloride salt by the addition of sulfur dichloride. The salt is subsequently reduced giving the desired dithiadiazolyl. However, the addition of lithium bis(trimethylsilyl)amide to mono-nitrile calix[4]arene in the synthesis of the mono-dithiadiazolyl functionalised calix[4]arene was unsuccessful. To investigate the incompatible nature of the electrophile and nucleophile, computational and physical experiments were conducted on the mono-nitrile calix[4]arene derivative. These avenues were pursued to determine whether the unreactive nature of the nitrile in this case is due to electronic effects. Changes in the reaction conditions (i.e. temperature, solvent and the equivalents of nucleophile) were all varied, but this proved to be unsuccessful. Computationally, through charge calculations, it was determined that the electronic properties of the nitrile were similar to that of nitrile examples known to work in the literature. Therefore, it was established that steric effects of the calix[4]arene are playing a critical role in the unreactive nature of the nitrile. There are two non-degenerate LUMO orbitals for the nitrile as one is conjugated and the other is planar (LUMO + 1) to the aromatic system. It has been established that nucleophilic attack through the lowest energy LUMO would result in a high energy transition state due to the loss of conjugation and attack through the higher energy LUMO + 1 would result in a lower energy transition state. However, this was not possible due to the steric conditions surrounding its position relative to the nitrile. The results obtained from this study were, therefore, able to confirm that the normally suitable reaction procedure seems to be limited to less sterically encumbered nitriles. / AFRIKAANSE OPSOMMING: Dithiadiazolyl heterosikliese radikale vorm deel van 'n steeds groeiende navorsingsveld in die soeke na organiese magnete en material met geleidingsvermoë as gevolg van die ongepaarde elektron wat binne in die heterosikliese ring geleë is. Hierdie verbindings kan moontlik gebruik word as elektriese stroom geleiers en transistors wat tot 'n molekulêre skakelaar of ander tipe molekulêre toestelle ontwikkel kan word. Hierdie tesis beskryf die suksesvolle sintese van drie nitriel gefunksionaliseerde calix[4]arene, mono-, distale- en tetra-, as lywige steiers om as voorgangers in die sintese van dithiadiazolyl gefunksionaliseerde calix[4]arene gebruik te word. Die kristal strukture van hierdie drie nitriele is hier in vir die eerste keer gerapporteer. Dithiadiazolyls is geneig om te dimeriseer in die vaste toestand. Daarom is die redenasie agter die keuse van die calix[4]arene as 'n lywige R-groep, as dimeriseering te inhibeer. Sintese van die radikale op verskillende posisies van die calix[4]arene kan dimeriseering in die vaste toestand inhibeer. Die tipiese reaksie in die sintese van dithiadiazolyls behels die reaksie tussen 'n nitriel en litium bis(trimetielsiliel)amied gevolg deur die vorming van die dithiadiazolylium chloried sout deur die byvoeging van swaeldichloried. Die sout is dan gereduseer om die gewenste dithiadiazolyl te vorm. Die toevoeging van litium bis(trimethielsiliel)amied mono-nitriel calix[4]arene in die sintese van die mono-dithiadiazolyl calix[4]arene was egter onsuksesvol. Om die oënskynlik onverenigbare aard van die electrofiel en nukleofiel te ondersoek, is rekenaar-berekeninge en fisiese eksperimente uitgevoer op die mono-nitriel calix[4]arene afgeleide. Hierdie twee maniere is gevolg om te bepaal of die onreaktiewe aard van die nitriel in hierdie geval as gevolg van elektroniese effekte is. Wysigings in die reaksie omstandighede (d.w.s. temperatuur, oplosmiddel en die ekwivalente van nukleofiel) is gemaak, maar dit was onsuksesvol. Deur middle van ladings-berekeninge, is dit bepaal dat die elektroniese eienskappe van die nitriel soortgelyk is aan dié van nitriel voorbeelde wat in die literatuur geraporteer is. Daarom is dit vasgestel dat die steriese effekte van die calix[4]arene 'n kritieke rol in die onreaktiewe aard van die nitrile speel. Daar is nie-ontaarde LUMO orbitale vir die nitriel soos 'n mens is vervoeg en die ander is planêr (LUMO + 1) na die aromatiese stelsel. Daar is vasgestel dat nukleofieliese aanval deur die laagste energie LUMO sal lei tot 'n hoë energie oorgangstoestand as gevolg van die verlies van konjugasie. Aanval deur die hoër energie LUMO + 1 sou lei tot 'n laer energie oorgangstoestand. Dit was egter nie moontlik nie, as gevolg van die steries toestande rondom die orbital se posisie met betrekking tot die nitriel. Die resultate van hierdie studie bevestig, dus, dat die gewone reaksie proses beperk is tot minder steries verhinderde nitriele.

Thesis (PhD)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: The use of chiral oxazoline directed lithiation provides a highly diastereoselective (up to >99% de) route to meta functionalised inherently chiral calixarenes. This methodology can be used on both the butylated and debutylated calixarene systems and is tolerant of a wide range of different electrophillic quenches allowing access to a structurally diverse range of inherently chiral metafunctionalised calixarenes. The oxazoline directing group can be removed via hydrolysis, generating a range of functionalised calixarene carboxylic acids in high ee. We also demonstrate that the use of derivative alkyllithiums such as cyclopentyl lithium can provide significantly enhanced diastereoselectivity over the conventional organolithiums such as sec-butyl lithium, when employed in ortholithiation reactions of this nature. The differences in diastereoselectivity associated with the different alkyllithiums can be tied, in certain cases, to the steric bulkiness associated with the individual reagents. In this regard we have found that the use of the so called Tolman angle or cone angle approach allows quantification of the relative steric bulk of the alkyllithium. We also detail that the oxazoline directing group provides a hitherto unknown ability to be diastereoselectively tuned through the choice of the ligand system in the ortholithiation reaction. In this regard the development of a series of diglyme based ligands have proved to provide a highly diastereoselective means of inverting the chirality from that which the use of the conventional TMEDA ligand is able to generate (up to –92% de). The use of diglyme ligands to invert the sense of chirality is also shown to occur on the ferrocenyloxazoline system and presents an apparently general and hitherto unknown facet of asymmetric oxazoline directed ortholithiation. This diglyme induced inversion has been shown to be controlled through a secondary nitrogen coordinated mechanism that is able to operate with chiral oxazolines. / AFRIKAANSE OPSOMMING: Die gebruik van chirale oksasoliengerigte litiëring verskaf ’n hoogs diastereoselektiewe (tot en met >99% do) roete om metagefunksionaliseerde, inherente chirale calixareen produkte te sintetiseer. Deur gebruik te maak van verskillende elektrofiele kan die metodologie toegepas word op beide gebutileerde en de-gebutileerde calixareen sisteme om ’n reeks uiteenlopende inherente chirale, meta-gefunksionaliseerde calixareen produkte te vorm. Die oksasolien groep kan daarna verwyder word deur hidroliese om ’n reeks gefunksionaliseerde calixareenkarboksielsure te vorm in baie hoë eo. Ons het ook gedemonstreer dat die gebruik van afgeleide alkiel-litiums, soos siklopentiel-litium, kan bydrae tot aansienlik verhoogde diastereoselektiwiteit as dit vergelyk word met meer algemene organolitiums soos sekbutiellitium, tydens ortolitiëring reaksies van hierdie natuur. Die verskille in diastereoselektiwiteit kan verbind word, in sekere gevalle, tot die steriese bonkigheid van die individuele reagense. Deur gebruik te maak van die sogenaamde Tolmanhoeke of die koniesehoek benadering is dit moontlik om die relatiewe steriese bonkighied van alkiellitiums te kwantifiseer. Daar was ook bepaal dat die oksasoliengroep die ongekende vermoë besit om die diastereoselektiwiteit van die produk te stem deur die keuse van verskillende ligand sisteme tydens die ortolitiëring reaksie. Daar was bepaal dat die chiralitiet van die produkte omgekeer kan word op ’n hoogs diastereoselektiewe manier, deur gebruik te maak van ’n reeks ontwikkelde diglymegebaseerde ligande, indien dit vergelyk word met die produkte wat deur die konvensionele TMEDA gegenereer was (tot en met –92% do). Die gebruik van diglyme ligande was ook getoets op ferroseenoksasolien sisteme en dit was bevind dat dieselfde omkering in chiraliteit ook plaasvind wat aanleiding kan gee tot 'n oënskynlik algemene en tot nou toe onbekende faset van asimmetriese oksasoliengerigte orto-litiëring. Dit is bepaal dat hierdie diglyme geïnduseerde omkering in chiraliteit beheer word deur middel van 'n sekondêre stikstofgekoördineerde meganisme, wat in staat is om saam te werk met chirale oksasoliene.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Calixarenes are large cyclic molecules that have a distinctive bowl-shaped geometry. The nonplanar nature of these molecules means that, by selectively functionalizing the calixarene on one side of the symmetry plane, one introduces inherent chirality. As with other varieties of chirality, this asymmetry can be utilised to impart stereoselectivity to the formation of new bonds through asymmetric catalysis. The evaluation of inherently chiral calixarenes has been hindered thus far by the difficulty in obtaining enantiomerically pure samples. Using a recently developed stereoselective methodology, incorporating chiral oxazoline directed ortholithiation, the synthesis of a series of upper-rim meta-substituted inherently chiral calixarenes is described. With the use of this methodology, the desired calixarene ligands are synthesised in high diastereoselectivity (from 75% de to >99% de). The inherently chiral meta-substituted bidentate thioether-oxazoline calixarenes synthesised were subsequently investigated as asymmetric ligands for palladium catalysed allylic alkylation. The debutylated series of calixarenes showed good catalytic efficiency, achieving high levels of conversion (>90% isolated yield). A rate enhancement relative to a planar model system was observed. Moderate levels of enantioselectivity (31% ee to 89% ee) were achieved. The influence of the central chirality of the chiral oxazoline was determined to be the predominant stereoselective effect. Increasing the steric bulk on this chiral carbon resulted in a significant increase in the stereoselectivity. Inherent chirality was found to have a subtle but significant effect. Increasing the steric bulk on the calixarene bowl, through the use of analogous tert-butylated calixarene, had an adverse effect on the catalytic efficiency. These ligands formed unstable complexes that decomposed before any appreciable yield of the desired product could be formed. / AFRIKAANSE OPSOMMING: Calixarene is groot sikliese molekule met 'n kenmerkende bak-vormige meetkunde. Die nie-planêre aard van hierdie molekules beteken dat selektiewe functionaliseering van die calixareen op een kant van die simmetrievlak vorm 'n inherente chirale molekuul. Soos met ander soorte van chiraliteit, hierdie asymmetrie kan gebruik word om stereoselektiwiteit aan die vorming van nuwe bindings aan te dra, deur middel van asimmetriese katalise. Die evaluering van inherente chirale calixarene dusver is verhinder deur probleme in die verkryging van enantiomeerisesuiwer monsters. Met behulp van 'n onlangse ontwikkelde stereoselektief metodologie, waarin ‘n chirale oksasolien gerig ortolitiëring, die sintese van 'n reeks van boonste rand meta-gefunksionaliseerde inherent chirale calixarene word beskryf. Met die gebruik van hierdie metodologie, word die verlangde calixareen ligande gesintetiseer in hoë diastereoselektiwiteit (van 75% to t 99% do). Die inherente chirale meta-gefunktionaliseerde tio-eter oksasolien calixarene gesintetiseer is daarna as asimmetriese ligande vir palladium-gekataliseerde allyliese alkilering ondersoek. Die gedebutieleerde reeks van calixarene het goeie katalitiese effektiwiteit getoon, met die bereiking van hoë vlakke van omsetting (> 90% geïsoleerde opbrengs). ‘n Tempoverbetering relatief tot 'n planêre modelstelsel is waargeneem. Gematige vlakke van enantioselektiwiteit (31% eo tot 89% eo) is behaal. Die invloed van die sentrale chiraliteit van die chirale oksasolien is bepaal as die oorheersende stereoselektiewe effek. Die verhoging van die steriese massa op hierdie chirale koolstof het gelei tot 'n beduidende toename in die stereoselektiwiteit. Inherente chiraliteit is gevind om 'n subtiele, maar betekenisvolle uitwerking te hê. Die verhoging van die steriese grootmaat op die calixarene bak, deur die gebruik van analoog tert-butieleerde calixarene, het 'n nadelige uitwerking op die katalitiese effektiwiteit. Hierdie ligande vorm onstabiel komplekse dat ontbind voordat enige aansienlike opbrengs van die verlangde produk kan gevorm word.