The Pd(0) catalyzed coupling reaction of o-dibromobenzene with acetylenes afforded bis acetylenic compounds which were used as precursors for the synthesis of 10, 11, 12, 13, 18 and 20-membered ring systems. / The 10-membered benzo-oxadiyne ring 29 is a model compound of the core of antitumor antibiotic calichemicin $ bf{ gamma sp1 sb1}$. Molecular modeling calculations on 29 indicated the possibility of two conformers. / A method for the conversion of aryl carboxylic acids to their iodides has been developed. / Intermediates were prepared as model compounds towards the synthesis of the antitumor antibiotic neocarzinostatin.

A new approach to the ribosyl-ribitol unit of the capsular polysaccharide of Haemophilus influenzae type b (Hib) was developed. Oligomers (n = 1-5) of the polysaccharide attached to a ribose spacer were synthesized. These compounds have potential use as a synthetic vaccine component for immunization against Hib meningitis. / An attempt to synthesize fragments of Escherichia coli K100 bacteria polysaccharide which is cross-reactive with the Hib polysaccharide was made. / In connection with the synthesis of Goniothalenol, a new protecting group, the $p,p sp prime$-dinitrobenzhydryl ether was developed. The formation and removal of this protecting group was described.

In order to investigate the role played by the aromatic moiety of Aromatic Peptide Nucleic Acids (APNAs) in their ability to hybridize with RNA and DNA, as well as improve the solubility of APNA oligomers in aqueous solutions, a new generation of heterocyclic monomers were designed. APNA monomers, where the nucleobase can be thymine, cytosine adenine or guanine, with backbones contain thiophene and pyridine moieties were synthesized. Suitably protected APNA-APNA and PNA-APNA dimers were also synthesized as building blocks for the solid phase synthesis of APNA-PNA chimeras and APNA homopolymers. Due to the instability of the pyridine-containing APNA oligomers to the harsh acidic conditions required to cleave oligomers from the MBHA resin, a new protocol was developed for the synthesis of these molecules on the trityl chloride resin. Oligomers of PNA and APNA-PNA chimeras were successfully synthesized on this solid support, and cleaved from the resin using mild acidic conditions.

The following thesis describes two stereoselective carbon-carbon bond forming processes---the aldol reaction and its one-carbon homologue, the homoaldol reaction. The first chapter describes our efforts to increase the stereoselectivity of a catalytic homoaldol reaction. This methodology features a second generation Binol titanium (IV) fluoride catalyst capable of opening a silyloxycyclopropane ring to form discrete homoenolates. These homoenolates react with a variety of aldehydes to form 1,4-hydroxy carbonyl compounds. The catalyst was prepared by a literature method and has improved the stereoselectivity of this reaction compared to the first generation Binol titanium (IV) triflate catalyst. A variety of substituted Binol ligands were studied to determine the effect of steric and electronic modifications on reaction selectivity. / In the second chapter, a general method for the asymmetric synthesis of alpha,alpha-disubstituted-beta-hydroxy carbonyl compounds is described. This methodology relies on the stereoselective formation of acyclic alpha,alpha-disubstituted amide enolates. These enolates were prepared using methodology developed in the Gleason laboratory. Transmetallation of the initially formed lithium enolate was necessary to achieve high relative and absolute product stereocontrol. The E- and Z-enolate isomers were investigated. The Z-enolate reacted with high stereocontrol, whereas the E-enolate was not able to provide the anti isomer selectively. An X-ray crystal structure confirmed the absolute configuration of the product.

Allyl propargyl ethers undergo cobalt-mediated cycloisomerization reactions to form dihydrofurans in good yield and with excellent diastereoselectivity. The reaction is proposed to proceed by way of an allylic C-H activation and a formal 5-endo-dig cyclization. The reaction works with a range of allylpropargyl ether substrates. / 1,6-Enynes and allyl propargyl ethers undergo a cobalt-catalyzed formal 5-endo-dig cyclization to form vinyl cyclopentenes and dihydrofurans, respectively. The use of equimolar amounts of dicobalt octacarbonyl and trimethyl phosphite affords optimum yields and improved selectivity for cycloisomerization vs. alkene isomerization. / The utility of the cycloisomerization reaction is exemplified through the synthesis of the bis-tetrahydrofuran core of the annonaceous acetogenins. A key feature of the approach centers on the cycloisomerization reaction for the installation of two of the four stereocenters found in the THF-subunit. / An approach towards the total synthesis of Stolonoxide C is described. The mono-THF subunit is synthesized from the corresponding cobalt catalyzed cycloisomerization of an appropriate allylpropargyl ether.

Crystal engineering deals with the design of ordered arrays of molecular building blocks and is of high importance in nanotechnology, electronics and in the pharmaceutical industry. While organic synthesis provides access to a wide range of molecules, control over their intermolecular interactions is the major challenge taken on by crystal engineering. This thesis focuses on the surface self-assembly of carboxylic acids, as a convenient model system to study general factors governing self-assembly. It is a step towards the rational design of materials with desired compositions, morphologies and functionalities.Specifically, this thesis presents a systematic investigation of hydrogen-bonded (H-bonded) assemblies of carboxylic building blocks on surfaces (i.e. 2D crystals), complemented by studies of their assemblies in bulk solid state (i.e. 3D crystals). This work provides new insights into the complex relationship between building block structures, H-bonding synthons and self-assembly outcomes using scanning tunneling microscopy (STM), X-ray diffraction crystallography and quantum-mechanical calculations. Consideration of these insights has resulted in the supramolecular design of novel self-assembled molecular networks (SAMNs), described below.To elucidate the effect of building block structure on self-assembly, architectures formed by cyclic homo-dimers of carboxylic groups (i.e. structures containing the R22(8) synthon) are analyzed. Results are given in the form of case-studies covering formation of H-bonded macrocycles, chains, ladders, rotaxanes, catenanes and various 2D and 3D nets. Similar analyses of other H-bonding carboxylic acid assemblies are used to highlight the most important aspects of the carboxylic group's supramolecular reactivity, as well as the applications thereof.A detailed study of the surface co-assembly of trimesic acid (TMA) with n-alcohols is presented. Investigating this single system allows for the observation of a wide variety of phenomena that were previously only studied separately, and on structurally different systems. This enables relevant comparisons between molecular structure and the many factors governing self-assembly at the liquid-solid interface. The periodicity and fine structure of the TMA-alcohol SAMN is conveniently modulated by varying n-alcohol length and parity, representing an important step towards rational molecular nanopatterning of surfaces using the principles of crystal engineering.Relationships between building block structures and the stability of resulting carboxylic homosynthons (viz. the cyclic dimer R22(8), the trimer R33(12) and the hexamer R66(24)) are established through a combination of empirical observations and quantum-chemical calculations. Thus, formation of specific homosynthons is found to depend strongly upon steric intermolecular interactions, as well as upon the relative packing efficiencies of competing polymorphs. These findings allow explanation of the structure and chiral nature of the self-assembly formed by terthienobenzenetricarboxylic acid (TTBTA). Additionally, the rational design of supramolecular networks formed by the R66(24) homosynthon is demonstrated for the first time, using triethynylbenzenetricarboxylic acid (TEBTA).Finally, porous TMA networks are used as host matrices to control and study the self-assembly of new π-functional guest molecules. Specifically, two semiconducting heterocirculenes (sulflower and selenosulflower) are imaged by STM with sub-molecular resolution, enabling the study of adsorption-desorption dynamics, host-guest interactions, and stable π-π stacking architectures. The latter findings open up the possibility to form multilayers of host-guest architectures with high potential for applications in optoelectronic devices. / L'ingénierie des cristaux de solides moléculaires est un domaine en plein essor, combinant de nombreux aspects de la chimie des matériaux. Il est d'une grande importance pour l'électronique, la nanotechnologie ainsi que pour l'industrie pharmaceutique, ou il y a grand besoin de concevoir des réseaux ordonnés de molécules. Alors que la synthèse organique donne accès à un grand éventail de molécules, le contrôle des interactions intermoléculaires entre celles-ci est le défi pris en charge par l'ingénierie des cristaux. Cette thèse se concentre sur l'auto-assemblage d'acides carboxyliques en surface, en utilisant ce dernier comme modèle pour étudier les facteurs généraux gouvernant l'auto-assemblage. Cette étude constitue une étape vers la conception rationnelle de matériaux ayant des compositions, morphologies et fonctionnalités tels que souhaitées.Plus précisément, cette thèse présente une étude systématique de l'assemblage de certains blocs carboxyliques en surface (i.e. des cristaux 2D), complétée par des études de leurs assemblées à l'état solide (i.e. des cristaux 3D). Ce travail apporte un nouvel éclairage sur la relation complexe entre la structures des blocs, des synthons liées par des ponts hydrogènes et l'auto-assemblage final. Cette étude met en oeuvre la microscopie à effet tunnel (STM), la cristallographie par diffraction des rayons-X et des calculs a base de mécanique quantique. La nouvelle compréhension établie par cette étude a permis d'aboutir à la conception de nouveaux réseaux moléculaires auto-assemblees (SAMNs), décrit ci-dessous.Pour élucider l'effet de la structure des blocs sur l'auto-assemblage, les architectures formées par des homo-dimères de groupes carboxyliques (c'est-a-dire par des structures contenant le synthon R22(8)) sont analysées. Les résultats sont donnés sous la forme d'études de cas, portant sur la formation de macrocycles (liées par des ponts hydrogènes), de chaînes, d'échelles, de rotaxanes, de caténanes et de divers filets en 2D et en 3D. Des analyses similaires d'autres ensembles d'acides carboxyliques sont utilisés pour mettre en évidence les aspects les plus importants de la réactivité supramoléculaire du groupe carboxylique, ainsi que de l'utilité de celle-ci.Une étude détaillée du co-assemblage de l'acide trimésique (TMA) avec des n-alcools est présenté. La recherche complétée sur ce système permet l'observation d'un grand éventail de phénomènes n'ayant été qu'étudiés séparément. Entre autre, cela permet des comparaisons pertinentes entre structure moléculaire et les nombreux facteurs qui régissent l'auto-assemblage à l'interface liquide-solide. La structure fine et la périodicité du SAMN TMA-alcool est modulée simplement, en faisant varier la longueur et la parité des n-alcools. Ceci représente une étape importante vers la nanostructurisation rationnelle des surfaces avec des molécules, en utilisant les principes de l'ingénierie des cristaux.Les relations entre les structures des blocs et la stabilité des homosynthons carboxyliques qui en resultent (à savoir le dimère cyclique R22(8), le trimère R33(12) et l'hexamère R66(24)) sont établies par une combinaison d'observations empiriques et de calculs émanant de la chimie quantique. Ainsi, la formation d'homosynthons spécifiques se trouve à dépendre fortement des interactions stériques intermoléculaires, ainsi que de l'efficacité relative des polymorphes qui résultent de l'assemblage. Ces résultats permettent l'explication de la structure et de la nature chirale de l'auto-assemblage formé par l'acide terthienobenzenetricarboxylic (TTBTA). En outre, la conception rationnelle des réseaux supramoléculaires formés par l'homosynthon R66(24) est démontré pour la première fois, a l'aide de l'acide triethynylbenzenetricarboxylic (TEBTA).Enfin, les réseaux poreux TMA sont utilisées comme matrices d'accueil pour contrôler et étudier l'auto-assemblage de nouvelles molécules π-fonctionnelles.

Two types of research were carried out in this thesis; the first section is about the development of a new phosphine-based tridentate pincer N-heterocyclic carbene ligand and examination of the catalytic activities of its transition metal compexes including conjugated addition, alkyne-aldehyde addition and Alkyne-Aldehyde-Amine (A-3) coupling reaction. The second section of the thesis is about the methodology development of an A-3 based tandem synthesis of isoindoline derivatives and gold (I) catalyzed cyclization for the synthesis of isoindolo[2,1-a]quinolines derivatives. The aim of these studies is to develop novel catalysts and synthetic methodologies that can approach conventional chemical syntheses in a "greener" manner, therefore substantially gain atom-economy, step-economy and leads to a more sustainable life. / Deux types de recherches ont été accompli dans cette thèse. La première section comporte sur le développement d'un nouveau ligand carbène hétérocyclique et l'analyse de ses complexes formés avec des métaux de transitions et leur efficacité lors des additions conjuguées, d'addition alcyne-alcène et des réactions de couplage entre un alcyne, une aldéhyde et une amine (A-3). La deuxième partie de cette thèse porte sur le développement d'une méthodologie de synthèse de dérivés d'isoindoline utilisant une réaction en tandem dérivés du couplage A-3 et la synthèse de dérivés d' isoindolo[2,1-1]quinolines par cyclisation catalysée par des sels d'or(I). Le but de ces études étant de développer des méthodologies de synthèse et des catalyseurs novateurs pouvant s'appliquer à des synthèses conventionnelles et de ce fait les rendre plus "vertes", en augmentant leur économie d'atomes, économie d'étapes dans une perspective de développement durable.

The synthesis of highly substituted tropones is a very difficult task due to the lack of available synthetic methods. A one pot strategy for formation of cycloheptadiene acetal using a conjugate addition followed by cross coupling and divinylcyclopropane rearrangement was explored. Oxidation of the expected product under acidic condition would in theory afford the desired tropones. Addition of vinyl cuprates to a cyclopropenone acetal was successfully developed. Also, in a model system, the subsequent Pd(PPh3)4 catalyzed cross-coupling reaction between a cyclopropyl cuprate and a vinyl iodide was successful. However, in the desired system, cross- coupling between vinylcyclopropyl cuprates and the substituted vinyl iodide necessary for CP-225,917 synthesis could not be achieved. In a second project, synthesis of hybrid molecules combining a functional unit of retinoic acid analogs with a functional unit for histone deacetylase activity are presented. Retinoic acid analogs were synthesized via condensation of tetrahydro- tetramethylnaphthalene carboxylic acid with aromatic amines possessing Zn binding functional groups. Additional hybrids were prepared by a metal catalyzed cross coupling strategy. These hybrid molecules were assessed by collaborators and found to be fully bifunctional molecules. One structure, a hydroxamic acid analog of known retinoid TTNN, proved to be particularly effective against several retinoid resistant cancer cell lines. / La synthèse de tropones hautement substituées est une tâche particulièrement difficile dû au manque de méthodes de synthèse appropriées. Nous avons exploré une stratégie pour la formation d'un acétal cycloheptadiène en une étape, à partir d'une addition conjuguée, suivie par un couplage croisé et d'un réarrangement de cyclopropane divinylique. Une oxydation sous conditions acides du produit attendu pourrait générer des tropones multisubstituées. L'addition conjuguée de vinyl cuprate sur un acétal de cyclopropénone a été développée avec succès. De plus, dans un système modèle et grâce à la catalyse par le Pd(PPh3)¬4, le couplage croisé entre un cyclopropyl cuprate et un iodure de vinyle a été réussi. Par contre, le couplage nécessaire pour la synthèse de la molécule CP-225,917, soit une réaction entre des iodures de vinyle substitués et des vinylcyclopropyl cuprates, n'a pu être réalisé. Un second projet comportant la synthèse de molécules hybrides est présenté. Ces hybrides combinent des groupements fonctionnels d'analogues connus de l'acide rétinoïque avec des groupements fonctionnels possédant une activité sur les histones déacétylases. Les analogues de l'acide rétinoïque ont été créés grâce à la condensation d'acides carboxyliques tétrahydrotétraméthylnaphthalène avec des amines aromatiques possédant des groupements fonctionnels capables de se lier au zinc. D'autres hybrides ont été préparés via une stratégie de couplage croisé à l'aide de catalyseur métallique. Ces hybrides furent testés par des collaborateurs et leur activité bifonctionnelle a été prouvée. Une molécule en particulier, un acide hydroxamique analogue du rétinoïde TTNN, a démontré une efficacité notable contre plusieurs lignées cellulaires cancéreuses résistantes aux rétinoïdes.

Antisense oligonucleotides (AON) offer a rational approach for drug design. The specificity of AONs towards a complementary messenger RNA (mRNA) target via Watson and Crick base pairing as well as their ease of synthesis render this technology very attractive. RNase H-degradation of mRNA via formation of a AON/mRNA hybrid is crucial to mainstream antisense technologies. Numerous studies have demonstrated the importance of the AON's structure and conformational flexibility for efficient induction of RNase H activity. However the precise mode of action and substrate specificity of the RNase H are not fully understood at present. Our Laboratory recently discovered that incorporation of flexible acyclic linkers (e.g. butanediol, 2'-seco-RNA) significantly amplifies enzyme activity. Unfortunatly incorporation of such linkers was accompanied by a drop in the thermal stability of the AON/RNA hybrids. This prompted us to incorporate a less flexible linker such as a peptide nucleic acid, with the hope to maintain similar enzymatic activity while increasing the duplex thermal stability. / This thesis highlights the synthesis of the 5'-amino nucleoside analogue required for the incorporation of the peptide nucleic acid in both 2'-fluoroarabinonucleic acid (2'F-ANA) and DNA. Circular dichroism experiments afforded information on the hybrid conformation in solution, whereas UV thermal melting studies provided a measure of the thermal stability of such hybrid duplexes. Finally, ability of various linker modified AON/RNA hybrids to activate the RNase H enzyme was evaluated in parallel with the corresponding native unmodified DNA/RNA hybrids. / Incorporation of a PNA residue within DNA or 2'-FANA did not afford improvement in neither thermal stability nor enzymatic cleavage (except for homopolymeric sequences vs DNA) as compared to control or butyl-sequences.

A new method of drug discovery, the pseudo-dynamic combinatorial library, is described. The technique involves expanding on the dynamic combinatorial library method, where a reversible synthetic reaction is carried out in the presence of a target. In the pseudo-dynamic combinatorial library, this reversible reaction is separated into two irreversible steps. The independent control of the two steps leads to superior selectivity in the screening process. A model system based on peptidic inhibitors of carbonic anhydrase was developed and studied. The synthesis of a series of new carbonic anhydrase inhibitors is described. Amino acids with sulfonamide and sulfamide functional groups, which are known to bind to carbonic anhydrase, were prepared. The synthesis of a series of active esters attached to solid support are described. The tetrafluorophenyl esters are shown to be ideal for amide bond formation in aqueous media. The properties of this class of active esters were investigated. Initial studies on a static library screening method are reported. The design and results of a series of dynamic combinatorial library experiments are described.