Extending conjugation in 2-dimensions: Synthesis and characterization of multidentate monomers Over the past decade pi-conjugated organic polymers have attracted considerable attention because of their desirable characteristics similar to plastics (e.g., mechanical flexibility, simplicity and low-cost processing, etc.) as well as their interesting electronic/optical properties. The potential use of these materials in molecular electronics provides impetus for the development of new and modified pi-conjugated polymers. To that end, we propose to increase the dimensionality of pi-conjugation through formation of a two dimensional polymer. The synthesis of tri- and tetra-dentate monomers, which were designed for their predicted ability to form continuous conjugated sheets via surface confined polymerization, will be presented. / Conjugaison de élargissement dans 2 dimensions : Synthèse et caractérisation des monomers multidentate Pendant la décennie passée, les polymères organiques pi-conjugués ont attiré une attention considérable en raison de leurs caractéristiques souhaitables semblables aux plastiques (par exemple, flexibilité mécanique, simplicité, et traitement peu coûteux, etc.) en plus de leurs propriétés électroniques/optiques intéressantes. L'utilisation potentielle de ces matériaux dans l'électronique moléculaire fournit l'impulsion pour le développement du nouveau et modifié polymères pi-conjugués. À cet effet, nous proposons d'augmenter la dimensionnalité du pi-conjugaison par la formation d'un polymère bidimensionnel. La synthèse des tri- et tétra-dentelés monomères, qui ont été conçus pour que leur capacité prévue forme les feuilles conjuguées continues par l'intermédiaire de la polymérisation confinée extérieure, sera présentée.

The synthesis of two nitrogen containing aromatic boronic acids was accomplished in the premise that the interaction between B and N would grant hydrolytic resistance to a boronic ester intermediate in the catalysis of an amide formation reaction. One of these catalysts, 2-(dimethylamino)methyl- phenylboronic acid, gave comparable yields to known boronic acids catalysts, despite lacking electron withdrawing groups and furthermore, without the need to remove water. Following NMR investigations of the boronic ester intermediate formed during the reaction, it was found that less of this intermediate was formed due to the presence of the B-N interaction when compared to other boronic acids. It is postulated that this interaction lowers the Lewis acidity of the boron atom, effectively causing lower levels of formation of the desired intermediate. Higher than expected yields are obtained, as a result of the molecule being a bifunctional catalyst and not as a result of increased hydrolytic stability. / La synthèse de deux acides boroniques aryles, qui contiennent une interaction B-N fut accompli; étant donné que cette interaction puisse rendre l'ester de cette acide boronique, produite durant la formation d'un amide, resistant à l'hydrolyse. Une de ces catalyseurs, l'acide boronique 2-(dimethyleamino)methylephenyle, produit un bon rendement dans une de ces réactions sans que l'eau ne soit enlevée. Le rendement est comparable à ceux qui sont obtenus par des acides boroniques connus qui contiennent un groupe qui retire des électrons du système aromatique. Des analyses NMR ont déterminé que l'ester de l'acide boronique se forme moins bien lorsque la molécule contient une interaction B-N. On croit que c'est parce que cette interaction a comme résultat de réduire la capacité de l'atome de bore d'accepter des électrons, devenant ainsi un acide de Lewis moins fort. Le bon rendement lors des réactions de formation est attribué au fait que la molécule est en elle-même, un catalyseur bi fonctionnel.

Although chemists often exploit the high stereo selectivity of hydrolytic enzymes to produce pure enantiomers, the difficulty in selecting the best hydrolase from hundreds of commercial hydrolases and microorganisms remains a major deterrent to their wider use. Moreover, the emerging ability to create large libraries of recombinant enzymes demands fast and simple selection methods. The current method of selection is time-consuming because it requires carrying out small-scale reactions and measuring enantiomeric purity. This thesis focuses on the development of methods to speed up this selection process. / We first report the development of empirical substrate models for Aspergillus niger lipase (ANL) to predict which enantiomer of a racemate reacts faster. For secondary alcohols, a rule based upon the size of the substituents at the stereocentre of a substrate previously proposed for other lipases and esterases works for ANL. Surprisingly, a rule based upon charge rather than size of the substituents can predict the preferred enantiomer of alpha-amino acids. These qualitative rules aid in the design of new synthetic applications of ANL. / Next, we report the development of a spectropholometric assay to accurately but rapidly measure the enantioselectivity of a hydrolase towards a target substrate without measuring enantiomeric purity called "quick E". The initial rates of hydrolysis of each enantiomer of a substrate are separately measured relative to a reference compound. The ratio of the two relative rates yields the enantioselectivity. We first developed this method for chromogenic esters. Next, to extend quick E to non-chromogenic esters, we developed a pH indicator assay to quantitatively detect ester hydrolysis. We optimized this method for screening in 96-well plates for speed. / Finally, we apply these spectrophotometric assays to solve a synthetic problem. Dioxolane nucleosides are powerful pharmacological agents used in the treatment of HIV and hepatitis-B virus but their syntheses require expensive and tedious silica gel chromatography to separate mixtures of diastereomers. Using the quick E method, we rapidly identify two hydrolases that produce the desired dioxolane diastereorner in good yield and excellent diastereomeric excess (>98%). / Overall, our screening methods are simpler to perform than traditional methods and require significantly less substrate and hydrolase (mug quantities per measurement) without compromising sensitivity and quantitativeness.

A kinetic study on the thermal decomposition of 2,2-dichloro-3-(9-fluorenyl) episulfide (28) was investigated in detail. Solid evidence as to the nature of the desulfurization process is given. A two-term rate equation is derived to account for the overall rate changes. Both a unimolecular and bimolecular ionic mechanism involving the concatenation of sulfur atoms was proposed to account for the observed kinetic behaviour. An extended study in 15 different solvents at different temperatures showed the desulfurization is ionic in nature. Activation parameters were calculated and rationalized with respect to differences in solvation of the ground and transition states. A linear isokinetic relationship was found indicating a similar mechanism of decomposition in these solvents. Rates of reaction were also found to be linearly correlated with dielectric constant as well as the $ pi sp *$ scale of Kamlet and Taft. A solvent isotope effect was found to exist and the rate of desulfurization is decreased in the presence of acetic acid. A radical mechanism is discounted from a rate study in the presence of radical inhibitors. / Several new disubstituted 9-fluorenones were prepared for the first time using Meyers methodology. These and other mono and disubstituted fluorenones were employed in an effort to synthesize a variety of novel stable thiiranes. Only three thiiranes were prepared in this manner. The X-ray crystal structures of 2,2-dichloro-3,3-diphenyl episulfide (110) and 2,2-dichloro-3-dibenzosuberonyl episulfide (123) were also obtained for the first time. / Thiirane 28 as well as sodium cyanodithioformate (139) were investigated as possible precursors to diatomic sulfur but no evidence of this interesting intermediate was detected. The chlorination of tetramethylthiuram disulfide, however, in the presence of 1,3-dienes, afforded products consistent with the trapping of diatomic sulfur. (Abstract shortened by UMI.) ftn*Please refer to the dissertation for diagram.

Tandem reactions are multiple reactions occurring simultaneously in one-pot, where the product of each reaction is the substrate for the next. The hallmark of tandem reactions is a considerable increase in molecular complexity resulting from a single synthetic step. As this represents a substantial gain in efficiency and step-economy, all tandem reaction methodology represents a more sustainable, “Greener,” approach to preparing more complex organic molecules from simple precursors. The aim of this study was to expand the two-step tandem reaction, aldehyde-alkyne-amine coupling, to include two to three additional intermolecular steps. The goal of green chemistry is for the means to justify the end, but for a proof a principle the end should also justify the means. We chose dipropargyl amines and isoindolines due to their well documented importance as synthetic precursors and biologically active compounds. We outline the development of methodology for the preparation of dipropargyl amines (Chapter 2) and isoindolines (Chapter 3) starting from simple amines, alkynes, and aldehydes in one-pot and a single synthetic operation. / Les réactions tandem sont des réactions multiples qui se produisent de façon consécutive dans un seul milieu réactionnel. Le produit de chaque réaction est en fait un réactif pour la réaction suivante. Par le biais des réactions tandem, il est possible d'accéder à des molécules complexes en une seule étape synthétique. Comme elle représente un gain significatif en termes d'efficacité et d'économie synthétique, ce type de réaction représente une approche environnementalement durable pour la préparation de molécules complexes à partir de simples précurseurs.Le but de cette thèse consiste à augmenter la complexité de la réaction tandem entre les aldéhydes, les alcynes et les amines et d'y ajouter d'autres réactifs pour augmenter le nombre d'étapes synthétiques. Le but ultime de la chimie pour le développement durable est pour les moyens de justifier la fin. Par contre, comme preuve de principe, la fin doit aussi justifier les moyens. Nous avons choisi de synthétiser des amines dipropargyliques et des isoindolines en raison de leur importance bien documentée comme précurseurs synthétiques et comme composés biologiquement actifs. La méthodologie pour la préparation des amines dipropargyliques est développée dans le Chapitre 2 alors que la synthèse des isoindolines à partir d'aldéhydes, d'alcynes et d'amines simples (dans un seul milieu réactionnel et en une étape synthétique) est développée dans le Chapitre 3.

Sequential kinetic resolutions proceed via two or more enantioselective steps. An optimum sequential kinetic resolution has, first, equal specificity for both substrates: starting material and intermediate product. Hence, in the porcine liver esterase (PLE)-catalyzed hydrolysis of trans-1,2-diacetoxycyclohexane rac-1, a significant increase in the enantiomeric purity of the final product was observed when the rates of hydrolysis of 1-diacetate and 1-monoacetate were equalized by using a biphasic system buffer-organic solvent where the fast reacting diacetate was partially extracted to the organic phase. The resulting enantiomeric purity was increased from 58 in buffer to 94% ee in two-phase conditions where both steps are partly rate-determining. The second criterion for an optimal resolution is high enantioselectivity for both steps (E$ sb1$ and E$ sb2$) so that the maximum overall enantioselectivity, E$ sb{ rm T(max)}$, given approximately by (1 + (E$ sb1$ $ times$ E$ sb2)$) /2, is as large as possible. / Enantiomers of the following C$ sb2$-symmetric compounds were also separated by sequential resolution: trans-1,2-cyclohexanediol, trans-2,3-butanediol, trans-2,4-pentanediol, trans-2,5-hexanediol and trans-1,2-cyclopentanediol. / Finally, high enantiomeric purities were measured with a methodology employing enzymes to concentrate the minor enantiomer.

Aminoglycosides are broad spectrum antibiotics that act by binding to 16S rRNA of bacteria. The wide spread of aminoglycoside resistance threatens the use of these important medicines. Two general approaches can be used to address the aminoglycoside resistance problem. One is to derive the existing aminoglycoside antibiotics; the other is to develop inhibitors blocking resistance pathways.We developed a novel methodology to regio- and chemo-selectively derivatize unprotected aminoglycosides at the N-6' position, and used this method to prepare a series of amide-linked aminoglycoside-CoA bisubstrate analogs. These analogs are the first reported nanomolar inhibitors of AAC(6')-Ii, an aminoglycoside resistance-causing enzyme. They have been proved useful as mechanistic and structural probes to investigate the molecular mechanism of the catalysis by AAC(6')-Ii.Although the aminoglycoside-CoA bisubstrates are nanomolar inhibitors of AAC(6')-Ii, they are not active in cells due to their size and negative charges. A series of truncated aminoglycoside-CoA bisubstrates were next synthesized. These derivatives were used to determine key structure-activity relationships. One analog is discovered active against resistant strain in cells.Bisubstrate inhibitors containing sulfonamide, sulfone and sulfoxide linkers were synthesized and used as mechanistic probes to study mechanism of AAC(6')-Ii. Our results support the suggestion that AAC(6')-Ii may catalyze acetyltransfer without stabilization of the tetrahedral intermediate. Surprisingly, sulfide oxidation of the amide-linked bisubstrate dramatically improved inhibition of AAC(6')-Ii.Bisubstrates with linkers containing phosphoryl group (P=O) were proposed and synthesized, the biological results are under investigation. These molecules will facilitate investigations of the potential stabilization of the tetrahedral intermediate by the enzyme. Our efforts in this project also improved our chemical knowledge of phosphorus chemi / Les aminoglycosides sont des antibiotiques à large spectre. Ils agissent en se fixant à l'ARN ribosomal 16S des bactéries et perturbent la synthèse protéique. L'extension rapide du phénomène de résistance aux aminoglycosides menace cependant leur efficacité. Parmi les différents mécanismes de résistance aux aminoglycosides, le plus important est la production d'enzymes inactivant l'antibiotique. Trois types d'enzymes impliquées dans ce mécanisme ont été identifiés, à savoir les aminoglycoside-N-acétyltransférases (AACs), les aminoglycoside-O-phosphoryltransférases (APHs) et les aminoglycoside-O-nucléotidyltransférases (ANTs). Deux approches peuvent être envisagées pour combattre ou contourner le phénomène de résistance. La première consiste à créer de nouveaux antibiotiques en modifiant des antibiotiques existant. L’autre implique le développement d'inhibiteurs capables de bloquer la résistance. Une nouvelle méthodologie pour la dérivatisation régio- et chimio-sélective d'aminoglycosides non protégés à la position N-6' a été développée. Cette méthode a ensuite été appliquée à la synthèse d'une série de bisubstrats aminoglycoside-coenzyme A. Ces analogues se sont avérés être de puissants inhibiteurs (resistance d'inhibition de l'ordre de la nanomole) de l'enzyme aminoglycoside 6'-N acétyltransférase Ii (AAC(6')-Ii), impliquée dans la résistance à de nombreux antibiotiques aminoglycosides. Plus particulièrement, ces molécules ont pu être co-cristallisées avec AAC(6')-Ii par nos collaborateurs, qui n'étaient à ce jour jamais parvenus à cristalliser cette enzyme avec un aminoglycoside. Les structures 3D ainsi obtenues ont permis d'obtenir de précieuses informations sur le site de fixation des aminoglycosides. Une deuxième génération d’inhibiteurs de l'AAC(6')-Ii a ensuite été synthétisée. Elle consistait en une série d'analogues tronqués de la première génération d'inhibiteurs. Ces ana

The synthesis of nucleosides (28a) and (28b) is described.* / The best procedure consisted of a five step synthesis from 5-methyluridine. Simultaneous protection of the 3'- and 5' -hydroxyl groups of 5-methyluridine with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane-1,3-diyl gave nucleoside (11). Base protection of nucleoside (11 ) with (trimethylsilyl)ethoxymethyl chloride provided product ( 24). It was transformed to its allyl ether (23) by reaction with allyl bromide and silver (11) oxide. Oxidation of ( 23) with N-methylmorpholine N-oxide and osmium tetroxide, followed by sodium metaperiodate afforded aldehyde (27). Desilylation of aldehyde (27) gave the desired nucleosides (28a) and (28b).* / 1H-NMR analysis of the diacetylated forms of the nucleosides indicated that both acetates at the newly formed anomeric center were in an axial conformation, and that structures and conformations (28a) and (28b) are a good representation for the two isomeric diols.* / Dimerization of nucleosides (28a) and (28b) are to be explored.* / *Please refer to dissertation for diagrams.

A method to synthesize a diastereomeric mixture of 2',5 '-phophorothioate A(psG) dimers in solution was developed. The sulfurizing reagent "EDITH" allowed for the synthesis of the diastereomeric mixture of dimers with minimal formation of oxidized side products. The separation of the two isomers was carried out using silica gel flash chromatography to afford the stereoisomerically pure Rp and S p dimers. The orthogonal solution-phase coupling of the individual dimers to the appropriately protected monomers allowed for the creation of the corresponding branched trimers bearing vicinal 2',5'-phophorothioate and 3',5'-phosphodiester linkages. / Conversely, a convergent solid-phase strategy applicable to the synthesis of branched oligonucleotides was employed to construct a symmetrical branched phosphodiester trimer, A(pG)pG, using an adenosine bisphosphoramidite synthon. This compound served as a positive control substrate, relative to both the Sp and Rp-phophorothioate V-trimers, in the investigation of the stereochemical requirements of the yeast debranching enzyme (yDBR) at the 2',5'-phosphodiester linkage. (Abstract shortened by UMI.)

The objective of this study is to investigate the potential use of transition metal carbonyl complexes for the sequential insertion of CO and imines, with the ultimate goal of developing an imine/CO co-polymerization catalyst. / The reactivity of (CO)4CoMe with Tol(H)C=NMe has been investigated and evidence of imine insertion into the Co(I)-acyl bond of (CO)4Co(COMe) is observed by 1H-NMR. Attempts to generate the postulated product of Tol(H)C=NMe insertion into (CO)4Co(COMe) by addition of (CO)4Co- to Tol(H)CN(Me)COPh+Cl - led to decomposition. / The reaction of (CO)5MnR (R = Me, Ph) with imines Tol(H)C=NR '(R' = Me, Bz, Ph) yielded ortho-metallated products (CO)4Mn[2,5-C6H3(CH=NR' )(CH3)]. The reaction of (CO)5MnMe, Tol(H)C=NMe, and AlCl3 afford (CO)4Mn[CH(Tol)N(Me)C(O)Me] ( 51). Attempts to generate a CO/imine insertion product by the addition of (CO)5Mn- to Tol(H)CN(Me)COPh+Cl - yielded the new complex (CO)4Mn[C(O)CH(Tol)N(Me)C(O)Ph] (54), incorporating an inserted CO into the Mn-R bond. The x-ray crystal structure of (54), and (PPh3)(CO)3Mn[CH(Tol)N(Me)C(O)Ph] (61) were obtained and are discussed.