No description available.

No description available.

No description available.

Le motif cyclopropanique est présent dans de nombreux composés bioactifs d'origine naturelle ou non-naturelle auxquels il confère une certaine rigidité structurale, qui permet d'augmenter leur biodisponibilité et leur stabilité métabolique. Par ailleurs, l'atome de fluor possède des propriétés particulières dues entre autres à sa forte électronégativité et sa petite taille. Cela permet de modifier les propriétés physico-chimiques des molécules qui le contiennent, telles que l'acidité, la lipophilie ou encore la solubilité. Par conséquent, les cyclopropanes fluorés représentent des motifs intéressants dans la mesure où ils combinent les propriétés des cyclopropanes et celles de l'atome de fluor. Dans ce contexte, nous nous sommes tout d'abord intéressés à la synthèse énantiosélective de cyclopropanes fluorés polyfonctionnalisés à partir d'oléfines fluorées et de composés diazos, par catalyse au rhodium. Pour cela, deux types de composés diazos ont été utilisés : les diaccepteurs et les donneur-accepteurs. Cette méthodologie a été étendue à la synthèse de cyclopropanes chlorés et bromés. Afin de mettre en valeur les composés ainsi obtenus, nous avons ensuite étudié la synthèse de molécules d'intérêt biologique, et plus précisément de mimes d'aminoacides contenant un cyclopropane fluoré. En effet, leur introduction dans des peptides pourrait permettre d'en modifier la conformation et l'interaction avec les récepteurs biologiques. Dans ce cadre, la synthèse d'un mime de proline contenant un cyclopropane fluoré a été développée. Par ailleurs, un mime de leucine contenant un cyclopropane fluoré a été introduit dans la séquence minimum active de la neurotensine et permet d'obtenir une bonne sélectivité pour le récepteur NTS2, ce qui ouvre des perspectives pour le développement de nouveaux analgésiques possédant moins d'effets secondaires. Pour terminer, nous avons examiné la synthèse de composés diazos en flux continu. A l'heure actuelle, ceux-ci sont peu utilisés dans l'industrie car ils présentent une certaine toxicité, une potentielle explosivité et une instabilité qui limite leur stockage. La chimie en flux continu constitue donc une alternative pour les utiliser, puisque leur synthèse, leur purification et leur mise en réaction se fait en continu sur de petites quantités à la fois et ne nécessite pas d'intervention de la part d'un opérateur. Ainsi, les risques présentés par la montée en échelle de la réaction de cyclopropanation précédemment développée sont fortement diminués. / The cyclopropane ring is present in many natural or non-natural bioactive compounds, whose biodisponibility and metabolic stability is increased by its structural rigidity. Besides, the fluorine atom displays singular properties due to its high electronegativity and its small size. This enables to modify the physico-chemical properties of molecules such as acidity, lipophilicity or solubility. As a consequence, fluorinated cyclopropanes represent interesting scaffolds since they combine the properties of cyclopropanes and fluorine atom. In this context, we were interested in the enantioselective synthesis of polyfunctionalized fluorinated cyclopropanes from fluorinated olefins and diazo compounds under rhodium catalysis. For this purpose, two types of diazo compounds were investigated: diacceptor and donor-acceptor. This methodology was further extended to the synthesis of chlorinated and brominated cyclopropanes. To highlight the versatility of these compounds, we then turned our attention to the synthesis of biorelevant targets, and more precisely aminoacids containing a fluorocyclopropane moiety. Indeed, their introduction into peptides could allow to modify their conformation and interactions with biological receptors. In that aim, the synthesis of an analogue of proline containg a fluorocyclopropane was developed. An analogue of leucine containing a fluorocyclopropane was also introduced in the minimum active sequence of neurotensin and shows a good selectivity for the NTS2 receptor. This opens up prospects for the development of new analgesics with less side effects. Finally, we examined the flow synthesis of diazo compounds. Nowadays, diazo compounds are scarcely used in the industry because they exhibit some toxicity, potential explosibility and instability, which restrict their storage. Flow chemistry may constitute an alternative to use them since their synthesis, purification and reaction is continuously made on small quantities at a time and do not require any manipulation from an operator. Hence, the hazards arising from the scale up of the cyclopropanation reaction are highly reduced.

Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: This project entailed the synthesis and characterization of mono- and multi-nuclear rhodium and ruthenium iminopyridyl complexes and their application in the hydroformylation of 1- octene. The multi-nuclear complexes were synthesized in order to investigate whether it could produce catalysts with higher activity than their mononuclear analogues. Four novel iminopyridyl ligands, ranging from mono- to tetra-functional compounds, were synthesized. The synthesis was a two-step process initially involving a Schiff base condensation reaction between 2-pyridinecarboxaldehyde and 4-aminophenol to produce a hydroxy functionalized pyridine-imine. The latter was then subjected to a nucleophilic substitution reaction with an appropriate benzyl bromide derivative to yield the target ligands. All these ligands were isolated in moderate to good yields and characterized using a range of analytical techniques. These ligands, together with the hydroxy functionalized pyridine imine, were then complexed to both Rh(I) and Ru(II) metal precursors, yielding ten novel metal complexes. The characterization of some of the complexes, especially the multi-nuclear complexes, were slightly more difficult due to their low solubility. However, all these complexes could be isolated in good to high yields as stable green-brown (in the case of Rh(I)) and yellow-orange (in the case of Ru(II)) solids. Finally, these complexes were applied as catalyst precursors in the hydroformylation of 1- octene. In the case of the Rh(I) complexes, relatively high activities were observed, with conversions ranging between 50 – 90 % in all cases, when tested at 30 bar, 75 °C and a 0.05 mol% catalyst loading. The activity was found to increase when going from the mono- to the bi-nuclear catalyst. However, solubility in the reaction medium was a major issue for the trinuclear catalyst, as it contributed to the lower activity observed. High chemoselectivity towards aldehydes was observed for all catalysts, which increased with reaction times. During shorter reaction time, linear regioselectivity was also relatively high. This however, decreased with increasing reaction time as the internal octenes formed initially, were converted to branched aldehydes. When the Ru(II) complexes were tested under the same conditions as the Rh(I) complexes, very low activity was observed. Under more stringent conditions (45 bar, 120 °C, 0.5 mol%) the ruthenium catalysts performed relatively well, compared to other complexes in the literature. The same trend in terms of the chemo- and regioselectivity for the Ru(II) complexes were observed. The Rh(I) complexes were far more active than the Ru(II) complexes. / AFRIKAANSE OPSOMMING: Hierdie projek behels die sintese en karakterisering van mono- en multi-kernige rhodium en ruthenium iminopiridiel komplekse en hul toepassing in the hidroformulering van 1-okteen. Die multi-kernige komplekse is gesintetiseer met die doel om vas te stel of hulle katalisatore wat meer aktief is as hul monokernige eweknieë, kan produseer. Vier nuwe iminopiridiel ligande, wat strek vanaf mono- tot tetra-funksionele verbindings, is gesintetiseer. Die sintese was ‘n twee-stap proses wat aanvanklik ‘n Schiff basis kondensasie reaksie tussen 2-piridienaldehied en 4-aminofenol behels, om ‘n fenol gefunksioneerde piridien-imien te vorm. Die laasgenoemde was gevolglik aan ‘n nukleofiliese substitusie reaksie met ‘n gepaste bensiel bromied derivaat onderhewig. Al hierdie ligande is geisoleer in matige tot goeie opbrengste en gekarakteriseer met ‘n reeks analitiese tegnieke. Hierdie ligande, tesame met die fenol gefunksioneerde piridien imien, is dan met Rh(I) en Ru(II) metaal uitgangstowwe gekomplekseer, wat tien nuwe metaal komplekse tot gevolg gehad het. Die karakterisering van sommige van die kompekse, spesifiek die multi-kernige komplekse, was effens moeiliker as gevolg van hul swak oplosbaarheid. Al hierdie komplekse kon egter in goeie tot hoë opbrengste as stabiele groen-bruin (in die geval van Rh(I)) en geel-oranje (in die geval van Ru(II)) vastestowwe geisoleer word. Laastens is die komplekse as katalisator-voorlopers in die hidroformulering van 1-okteen gebruik. In die geval van die Rh(I) komplekse is redelike hoë aktiwiteite waargeneem, met omsettings tussen 50 – 90 % in alle gevalle, wanneer hulle by 30 bar, 75 °C en ‘n katalisator lading van 0.05 mol% getoets is. Die aktiwiteit neem toe vanaf die mono- na die bi-kernige katalisator. Oplosbaarheid in die reaksie medium was egter ‘n probleem vir die tri-kernige katalisator, wat ‘n laer aktiwiteit tot gevolg gehad het. Hoë chemoselektiwiteit na aldehiede is waargeneem vir al die katalisatore en dit neem toe met reaksietyd. Gedurende korter reaksietye was die liniêre regioselektiwiteit ook redelik hoog, maar neem af met toenemende reaksietyd soos die interne okteen wat aanvanklik vorm na vertakte aldehiede omgeskakel word. Toe die Ru(II) komplekse onder dieselfde toestande as die Rh(I) komplekse getoets is, was baie lae aktiwiteite waargeneem. Onder hoër temperatuur en druk (45 bar, 120 °C, 0.5 mol%) toon die ruthenium katalisatore redelik goeie aktiwiteite in vergelyking met ander komplekse wat in die literatuur gerapporteer is. Dieselfde tendense in terme van die chemoen regioselektiwiteit is vir die Ru(II) komplekse waargeneem. Die Rh(I) kompleks was baie meer aktief as die Ru(II) komplekse.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

No description available.

No description available.

Highly stereo- and regioselective rhodium-catalysed carbometallations of ynamides using organometallic reagents have been disclosed. The scope of the process was explored, and investigations revealed that Rh(cod)(acac) acts as an effective precatalyst for carbometallation of ynamides using a range of organozinc reagents. A plausible mechanism has been suggested where an alkenylzinc intermediate is formed. This species has been exploited in further transformations with electrophiles and in cross-coupling reactions, thus providing access to multisubstituted enamides in a stereo- and regioselective manner. It was also possible to carry out the carbometallation of ynamides using organoboron reagents by using [Rh(cod)(MeCN)2]BF4 as a precatalyst. This complementary protocol allowed the introduction of a greater diversity of substituents, including those carrying sensitive functional groups. Mechanistic studies, including deuterium labelling, suggested that an alkenylrhodium intermediate was produced during the course of the reaction. With a set of optimised conditions, this species was successfully used in a tandem carbometallation– conjugate addition (or annulation) reaction with bifunctional arylboron reagents. The 2-amidoindene products were obtained in good yields and high regioselectivities. Preliminary studies on the development of an asymmetric variant of this transformation have been undertaken and the initial results have been reported. In addition, highly enantioselective dihydroxylation of the enamide substrates prepared from the developed rhodium-catalysed carbometallations of ynamides was readily accomplished using commercially available AD-mix- . This novel procedure provides an access to a wide range of chiral products that might be difficult to access using existing methods. Finally, as a further exemplification of asymmetric enamide dihydroxylation, this method was applied to a concise total synthesis of the antifugal natural product (+)-Tanikolide.

Distinctive fine-structure due to ³⁵Cl/³⁷Cl isotopologue and isotopomer effects is resolved at high magnetic fields for ¹⁹⁵Pt and ¹⁰³Rh NMR signals, resulting in a unique NMR “finger-print”, with which it is possible to uniquely identify all chlorido containing Pt(IV) and Rh(III) complexes. In this study, these isotope shifts are computed from first principles in order to provide a solid theoretical framework for the empirical observations. Use is made of DFT to calculate the ³⁵/³⁷Cl and ¹⁶/¹⁸O induced isotope shifts in the ¹⁹⁵Pt NMR spectra of [Pt³⁵Cl₆]²⁻ and [Pt³⁷Cl₆]²⁻, for the [Pt³⁵Cl n ³⁷Cl₅₋ n(H₂O)]⁻ (n=0-5), cis-Pt³⁵Cln³⁷Cl₍₄₋n₎(H₂O)₂ (n=0-4), and fac-[Pt³⁵Cl n³⁷Cl₍₃₋ n₎(H₂O)₃]⁺ (n=0-3) series. The computational protocol is extended to calculate the ³⁵/³⁷Cl and ¹⁶/¹⁸O induced isotope shifts in [Pt³⁵Cl n³⁷Cl₍₅₋ n₎(OH)]²⁻ (n=0-5), cis- [Pt³⁵Cln³⁷Cl₍₄₋ n₎(OH)₂]²⁻ (n=0-4), fac-[Pt³⁵Cln³⁷Cl₍₃₋ n₎(OH)₃] ²⁻ (n=0-3), cis- [Pt³⁵Cl n³⁷Cl₂₋n(OH)₄]²⁻ (n=0-2) and [Pt³⁵Cl n³⁷Cl₍₁₋ n₎(OH)₅]²⁻ (n=0-1). For Rh(III), the ³⁵Cl/³⁷Cl isotope shifts in the ¹⁰³Rh NMR spectra of [Rh³⁵Cl n³⁷Cl₅₋ n(H₂O)] ²⁻ (n=0-5), cis-[Rh³⁵Cl n³⁷Cl₍₄₋ n₎(H₂O)₂]⁻ (n=0-4), and fac-Rh³⁵Cl n³⁷Cl₍₃₋ n₎(H₂O)₃ (n=0-3) were calculated. The ¹⁹⁵Pt and ¹⁰³Rh NMR chemical shifts computed for these species reproduce the order of magnitude of the observed effect reasonably well, up to ca. 1 ppm. In most cases, general trends are also captured qualitatively, thus providing the first theoretical basis for the origin of subtle isotope shifts in ¹⁹⁵Pt NMR spectra. Neither simple polarizable continuum models nor small, microsolvated complexes lead to improved isotope shifts for the series investigated, however, valuable insight into the degree of solvent interaction was gained. Using the polarized continuum model to calculate shielding/bond-length derivatives together with gas-phase zero-point corrections to estimate shieldings, it was shown that the contraction of the coordination sphere in the hydroxide complexes cause the Pt-Cl bonds to become magnetically equivalent, justifying why their isotopomers aren't resolved. In this study, theoretical modelling of structural effects on NMR parameters extends to the smallest scale, distance changes of a few femtometers upon isotopic substitution.