Meso 1,9-diketones (six to seven stereocenters)are readily obtained by stepwise or simultaneous two-directional aldol reactions of tetrahydro-4H-thiopyran-4-one with a thiopyran-derived aldehyde. Enantioselective enolizations of these diketones with the lithium amide from (R,R)-bis(1-phenylethyl)amine occur with simultaneous kinetic resolution to give the mono-TMS enol ethers in >90% yields based on recovered starting material (BORSM) and >90% ee. The developed methodology was applied in synthetic studies towards the asymmetric synthesis of denticulatin A.

A series of nickel(II) and Pt(II) complexes supported by the bis(2-diphenylphosphinophenyl)amide ligand, [PNP]¢w have been prepared. In Nickel(II) chemistry, the halide complexes are both air and water stable. The nickel(II) alkyl and aryl derivatives were presented including those in which the alkyl contains

No description available.

The purpose of this investigation was to study the syntheses of enol lactones and to prepare a series of amide derivatives of these compounds.

No description available.

This thesis is divided into two main chapters, which are focused on two separated and uncorrelated research areas. The first part of this thesis is dedicated to the research I carried out in benzyne chemistry and the second part is focused on catalytic C-H bond activation. In the first place, a novel insertion reaction of arynes into the nitrogen-carbonyl σ-bond of amides has been investigated as a rapid and powerful approach for the preparation of valuable ortho-disubstituted arenes. Readily available aromatic amides undergo smooth insertion when treated with O-triflatophenyl silane aryne precursors, producing versatile anthranilic derivatives in good to excellent yields. The process is entirely metal-free and has been expanded to the synthesis of biologically active heterocycles such as acridones and acridines. Secondly, the synthesis of medium-sized ring systems by intramolecular oxidative CH bond coupling has been explored. Despite the abundance of biologically active natural products featuring mediumsized rings, the synthesis of such ring systems using classical synthetic routes faces many challenges and has led to a dearth of medium ring compounds in medicinal chemistry. In contrast to the more facile 5-membered ring synthesis by oxidative C-H coupling, medium ring synthesis has not been previously reported using this approach. The chemistry, which requires zero pre-functionalisation of the substrates, is catalysed by palladium and has been exemplified using heteroaromatic substrates at the core of numerous biologically active molecules. The mechanism of the reaction has also been studied and a catalytic cycle has been proposed.

Cancer is a leading cause of death worldwide, accounting for around 13% of all death [1]. Traditional cancer therapeutics usually require careful selection of one or more intervention, such as surgery, radiotherapy, and chemotherapy, which have made momentous progress, but have ample limitations [2]. The next generation of cancer therapeutics will specifically target processes responsible for the growth and survival of cancer cells. Among the most promising of these molecularly-targeted therapeutics are short interfering RNAs (siRNAs). These siRNAs serve as the effectors of RNA interference, a naturally occurring and highly specific mechanism for regulating gene expression through sequence-specific degradation of messenger RNA. However, the native structure of RNA is plagued with undesirable chemical properties. For example, the sugar-phosphate backbone contains a negative charge which hinders its ability to cross the negatively charged lipid bilayer. Furthermore, the phosphodiester backbone is a substrate for nucleases, which catalytically cleaves the phosphate-oxygen bond, thus degrading the native RNA [3]. As such, there is widespread interest in chemically modifying the backbone of siRNAs in order to overcome some of the inherent problems with its native structure. There have been only two reports that have employed amide-bond linkages as phosphate replacements within siRNAs [4, 5]. In both of these studies, the amide bond containing monomer units were placed at the 3’-overhangs and not within the internal Watson-Crick region of the double stranded siRNA due to the limitation of standard solid-phase oligonucleotide synthesis. In this thesis, we proposed to utilize phosphoramidite chemistry to localize internal amide-bond modifications [6]. A practical synthesis of a peptide nucleic acid unit combined with an RNA nucleoside (PNA-RNA dimer, UaU) is reported [7]. Using this PNA-RNA dimer phosphoramidite allows us to control the site-specific location of the internal amide-bond modification throughout the desired RNA strand. Polyacrylamide gel (PAGE) and mass spectrometry analysis were performed to ensure the formation of full-length modified siRNA molecules. The effects of these modifications were explored with respect to the biophysical and biological properties of the modified siRNAs. The techniques used in this work included hybridization affinity assays (melting temperature), secondary structure determination (circular dichroism), cell-based luciferase assays, and nuclease stability assays. Melting temperature experiment reveals that localizing a UaU dimer unit within the RNA oligonucleotides has an overall destabilizing effect, whereas UaU modifications at the 3’-overhang positions show little change in thermal stability. Circular dichroism experimental results illustrate that all chemically modified siRNAs exhibit the standard A-form helix. In cell-based luciferase assays, we utilized two different target sequences and our results highlight the compatibility of utilizing a neutral amide-bond backbone within siRNAs. Specifically, the internal amide-bond modification is compatible within the RNAi machinery when placed at 3’-overhang position in the sense strand of the double-stranded siRNA. However, poor efficacy is observed when this unit is placed adjacent the Ago 2 cleavage site on the antisense strand. The nuclease stability assays reveal that the introduction of a PNA-RNA dimer at the 3’-end of the siRNA where the exonuclease cleaves the terminal nucleotide, increased markedly the resistance to serum-derived nucleases. To the best of our knowledge, this is the first report that involves amide-bonds as phosphate backbone replacements within the internal regions of siRNAs and thus opens the future possibility for examining and utilizing this modification in studying new structure-function relationships. / UOIT

The accomplishment of the γ-alkylation reaction from β-keto esters of tropinone and the enantioselective aziridine formation from nortropinone is first reported. This opened two new paths to develop tropinone enolate chemistry. One is indirect α-alkylation of tropinone, another is the nucleophilic attack from α-C enolate to the nitrogen atom.<p>Seven interesting chiral amines have been synthesized and applied into the enolate chemistry of two interesting precursors of synthesis of natural products: 1,4- cyclohexanedione monoethylene ketal and tropinone.<p>The aldol reaction between the lithium enolate of 1,4-cyclohexanedione monoethylene ketal and benzaldehyde demonstrated the high diastereoselectivity (up to 98% de) and the moderate to high enantioselectivity (up to 75% ee) induced by those chiral lithium amides. On the other hand, high diastereoselectivity (up to 100% de) and the low enantioselectivity were obtained from the aldol reaction of tropinone enolate with benzaldehyde differentiated by chiral lithium amides with extra electron donor atoms.<p>An analysis method to determine enantioselectivity from racemic α-hydroxytropinone was developed. That will, no doubt, benefit the further enantioselective α-hydroxylation reaction of tropinone.

The purpose of this project was to investigate if retention of polar compounds that are given to treat tuberculosis, diabetes, inflammatory bowel disease and childhood leukemia could be obtained with HILIC separation. By varying different parameters for different types of columns the compounds were analyzed with the aim of finding guidelines for future method optimizations. To perform these analyzes three different columns were tested – ZIC-HILIC (silica-based with zwitterions), ZIC-pHILIC (polymer-based with zwitterions) and XBridge Amide (amide functions). The results were evaluated with selected quality measures. The parameters being varied were pH, temperature, flow rate, type of buffer and ionic strength. In addition, comparisons between isocratic and gradient separations were performed.   Over 1 000 analyzes were conducted in which retention of 16 of total 18 substances were successfully obtained with HILIC. The columns that generated the best results in terms of greatest number of identified compounds were ZIC-HILIC and XBridge Amide. ZIC-pHILIC offered a wide pH range but generally gave inferior chromatography. The influence of the different parameters on the results has not been investigated in sufficient scope. This means that no specific methods for the different drug groups can be reported.

La présence d'amides dans l'environnement et leurs effets néfastes sur la santé a suscité le développement d'une méthode d'analyse globale des amides (R-CO-NH₂). Cette méthode est basée sur la chromatographie liquide à haute performance à phase inverse dotée respectivement d'un détecteur UV et fluorescence (HPLC-UV/FLUO). Ceci a nécessité la transformation des amides en dérivés amides susceptibles d'êtres détectés en UV et fluorescence. Lors de la présente étude, le réactif le chlorure de dansyle (DNS-Cl) a été utilisé pour la dérivatisation des amides. Le groupement sulfonyle du DNS-Cl réagit avec le groupement NH₂ des amides primaires pour former des produits dérivés aromatiques fluorescents. Les dérivés standards DNS-amides ne sont pas disponibles commercialement, ce qui a nécessité le développement d'une méthode de préparation des dérivés standards de trois classes d'amides primaires un amide aromatique, un amide aliphatique insaturé et deux amides aliphatiques saturés (benzamide, acrylamide, acétamide et propionamide). Le rendement moyen obtenu est de 55 % non optimisé. Les dérivés standards DNS-amides obtenus ont été d'abord caractérisés par infrarouge (IR) et la résonance magnétique nucléaire du proton (¹H) et du carbone 13 (¹³C) et par la suite analysés par le couplage HPLC-UV/FLUO. Les longueurs d'onde (λ) d'absorption, d'excitation et d'émission (déterminées par le spectrofluorimètre) employées lors de cette étude sont respectivement de 254 nm, 345 nm et de 535 nm. Les valeurs des limites de détection obtenues pour les quatre amides étudiés (benzamide, acrylamide, acétamide et propionamide) par HPLC-UV sont respectivement de 0,02 ppm, 0,02 ppm, 0,03 ppm et 0,03 ppm et celles obtenus par HPLC-FLUO sont respectivement de 0,01 ppm, 0,04 ppm, 0,004 ppm et 0,003 ppm. L'étude montre que le couplage HPLC-UV/FLUO permet d'avoir une bonne sensibilité et que la technique HPLC-FLUO est plus sélective que la technique HPLC-UV. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Amides, Benzamide, Acrylamide, Acétamide, Propionamide, Analyse globale, HPLC-UV/FLUO.