The RNA dimer ApA is rapidly cleaved in the presence of lanthanum(III) chloride yielding the products of transesterification and hydrolysis, 2 '-AMP, 3'-AMEP and adenosine. The intermediate 2,3'-cAMP does not accumulate. Under pseudo-first-order conditions (approximately 100-fold excess lanthanum(III) chloride) the half-life for ApA cleavage is only 13 seconds. / The potentiometric titration, pH-rate profile and dependence upon lanthanum(IIII) chloride concentration support a penta-mu-hydroxo dilanthanum species as the active species. The kinetic isotope effect of 1.9 and a one-proton inventory indicate that the 2'-hydroxyl deprotonation is not concerted with the nucleophilic attack. It is proposed that a rapid equilibrium proton transfer occurs between the 2'-hydroxyl and a bridging hydroxo prior to the nucleophilic attack and rate-determining intramolecular general acid catalyzed breakdown of the phosphorane to products. It is proposed that the general acid is a bound water, formed from the protonation of the bridging hydroxo. / Lanthanum(III) ion was found to be among the best of the trivalent lanthanides for promoting ApA cleavage, contrary to literature reports. The proposed lanthanide dimer mechanism, which is consistent with the behavior of the other lanthanides, easily explains this. / The lanthanum(III) dimer was also found to be highly reactive towards the DNA model compound bis(p-nitrophenyl) phosphate and the cyclic nucleotides 3',5'-cAMP and 2',3'-cAMP, providing half-lives of 12s, 9min and 340ms respectively. The results were consistent with a bound mu-hydroxo as the nucleophile. / The results for the ApA and cyclic nucleotides reactions are faster than any reported for synthetic catalysts.

The Lewis acid catalysed tandem Michael-Claisen (4C + 2C) annelation reaction of 1-trimethylsiloxy-1-methoxy-3-phenylthio-1,3-butadiene and 4,4-dimethyl-2-cyclohexen-1-one has been reexamined. The intermediate E and Z Michael adducts were cyclized under basic conditions to give the $ beta$-diketone 3-phenylthio-5,6,4a,8a-tetrahydro-5,5-dimethyl-(4H,7H)-naphthalen-1,8-dione. Angular methylation of this $ beta$-diketone under basic conditions was examined in detail, providing the cis angularly methylated product stereoselectively. / The cis ring junction stereochemistry of the $ beta$-diketone derivative mentioned above has been used advantageously to establish the C$ sb8$ (naphthalene numbering) $ alpha$-hydroxyl stereochemistry required for the forskolin structure. A subsequent enolate oxidation/nucleophilic addition sequence was then used to stereoselectively install the C$ sb1$ and C$ sb2$ (naphthalene numbering) cis $ alpha, alpha$-diol functionality also present in the forskolin structure. Subsequent functional group manipulations then provided 1,2,5,6,7,8,8a-heptahydro-$1 alpha,2 alpha$,4-${ rm trihydroxy}$-8$ alpha$-(tert-butyldimethylsiloxy)-$1 beta(1 sp prime$-${ rm hexynyl}$)-2,5,5,8a$ beta$-tetramethyl-naphthalen-3-one, a highly oxygenated $ alpha$-diketone intermediate for the synthesis of forskolin. / A number of the decalin compounds leading to the $ alpha$-diketone intermediate mentioned above, were tested for antifeedant activity against the spruce budworm (Choristoneura fumiferana). Eleven of these compounds were found to be active and structure-activity relationships were examined.

Hydrolase catalyzed reactions are used for selective chemical catalysis. With directed evolution, rational mutations and molecular modeling the selectivity of these hydrolases can be increased and the origin of selectivity determined. This study investigates four selective hydrolase catalyzed reactions. Using molecular modeling the unusual regioselectivity of Pseudomonas cepacia lipase (PCL) and the selectivity of Candida antarctica B lipase (CAL-B) in nucleoside acylation reactions has been attributed to the binding of the nucleoside base within the active site. The enantio-selectivity of Pseudomonas fluorescens esterase (PFE) has been improved using a rational approach to directed evolution and models to explain the origin of improved mutants has been produced. The enantioselectivity of the beta-lactam ring opening reaction by CAL-B has been attributed to unfavorable steric interaction of the substrate with Ile189 and a model has been proposed for an alcohol bridge between the catalytic histidine (His224) and the lactam amine. Finally, high acetyl selectivity of ThermoGen esterase E018b has been demonstrated and reaction conditions optimized.

Alkylation of carbonyl compounds with diorganozinc, organozinc halides and organoaluminium reagents has been conducted in ionic liquids. Systems studied included solvents such as N-butylpyridinium tetrafluoroborate, 1-butyl-3-methylimidazolium tetrafluoroborate and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate. Interestingly, reactivities of organometallics towards ionic liquids were revealed, yielding the imidazolylidene zinc complex formation in the case of alkylation with diethylzinc. Thus, different ways of ionic liquid preparations and purification methods were studied. The reaction between diethylzinc and aldehyde proceeded cleanly with high yield. This is in contrast to the reaction in aqueous media where diethylzinc is hydrolyzed readily, or in conventional volatile organic solvents where the addition of diethylzinc to aldehyde is generally sluggish and gives a low yield. / Generation of organozinc reagents in situ in carrying out other zinc mediated alkylation reactions has also been attempted. Preliminary success of the in situ preparation of ethylzinc and isopropylzinc halide has been achieved in ionic liquid. / Besides, we have demonstrated that the trialkylaluminium reagents could be used to alkylate carbonyl compounds giving dimethylaluminium alkoxides as the major reaction products. And it is believed that triorganoaluminium reagents react with carbonyl compounds in both solventless and ionic liquid conditions involving the first order four-center transition state.

The design of enantioselective transition metal catalyzed reactions is an important area of chemical research. The purpose of this study was to develop a new method to incorporate chirality into transition metal catalysis via ion pairing interactions. This has led to the development of the first enantioselective transition metal catalyzed reaction using a chiral counteranion as the sole source of asymmetry. / In chapter two, the synthesis of a chiral bis(1,1'-bi-2-naphtholato)borate anion is described. This anion can be incorporated into cationic copper(I) complexes via anion exchange, which has allowed its effect on the copper(I) catalyzed aziridination and cyclopropanation reactions to be examined. In the cyclopropanation reaction, it was found that changing the chirality of the counteranion in the presence of (R,R)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline), a chiral ligand, results in a change in the enantioselectivity of the cyclopropanes formed by over 30%. The influence of the chiral counteranion in the absence of a chiral ligand was also explored. / Chapter three describes the use of the copper(I) bis((R)-1,1' -bi-2-naphtholato) borate salt as a chiral NMR shift reagent. The coordination of the (R) and (S) enantiomers of 2,2'-bis(di-p-tolyl-phosphino)-1,1 '-binaphthyl (tol-BINAP) to copper(I) bis((R)-1,1' -bi-2-naphtholato) borate in CD2Cl2 results in well resolved 1H NMR (400 MHz) resonances for the two enantiomers. Examination of standard solutions of 2,2'-bis(di-p-tolyl-phosphino)-1,1 '-binaphthyl demonstrate that the copper complex can be used as an effective NMR shift reagent over a wide range of enantiomeric compositions. / In chapters four and five, the synthesis of a new class of peptide-based chiral counteranions, and their incorporation into copper(I) catalysts via ion exchange, is described. Studies on the copper(I) catalyzed cyclopropanation of styrene with ethyl diazoacetate demonstrate that ion-pairing with these anions can provide a novel method to incorporate a copper cation into a chiral alpha-amino acid environment for asymmetric catalysis. (Abstract shortened by UMI.)

Despite their promising biological activity, peptides have a number of unfavorable properties that hinder their ability to be drugs. Namely, peptides have poor bioavailability due to the proteases in the body that break them down. Also, peptides can often be substrates for numerous enzymes, therefore their selectivity can be quite poor. With this in mind, we aimed to design a series of constrained peptidomimetics designed to mimic dipeptide, while at the same time introducing conformational restraint in an attempt to improve selectivity, and they were designed without peptide bonds that could be cleaved by the body's proteases. In addition, these peptidomimetics were designed to be synthesized inexpensively and efficiently. The dipeptide-like linkages were designed to be introduced modularly and chemical handles were built into the design of molecule so that further functionalization would be simple. In this way, the molecule not only can act as a dipeptide mimetic but as a potential drug discovery platform for combinatorial chemistry. With this platform or scaffold, functional groups can easily be deployed in order to probe the geometric and electronic space of enzymes or receptors. During the process of the synthesis of these drug scaffolds we discovered we could increase the diastereoselectivty of the venerable Diels-Alder reaction by running the reaction in less solvophobic solvents. / Malgré leurs activités biologiques intéressantes, les peptides ont certaines propriétés peu favorables à leur conversion en médicaments. Pour exemple, les peptides sont rarement biodisponibles en raison des protéases présentes dans les milieux biologiques. Ces proteases les découpent en fragments plus petits qui peuvent a leur tour présenter diverses activités biologiques. De plus, les peptides peuvent se lier à diverses enzymes et récepteurs, réduisant ainsi leur sélectivité pour une protéine cible donnée. Dans ce contexte, nous avons conçu une série de peptidomimétiques susceptibles de mimer des dipeptides naturels. L'incorporation de contraintes géométriques nous permet d'envisager une meilleure sélectivité pour une cible donnée alors que la réduction du nombre de liaisons amides devrait réduire leur protéolyse. La conception de ces molécules s'est également faite dans le contexte d'une accessibilité synthétique. La synthèse et la structure de ces molécules nous permettra une grande modularité alors que les groupements fonctionnels autour du cœur bicyclique pourront être utilisés comme autant de points d'ancrage pour l'introduction de diversité chimique et structurale. Ainsi, ces molécules peuvent agir à titre de mimes de dipeptides mais aussi comme plateforme en synthèse combinatoire. Dans ce dernier cas, divers groupes fonctionnels peuvent être attachés sur les deux points d'ancrage. Au cours du développement de la voie synthetique, nous avons mis a jour le lien entre la diastéréosélectivité de la réaction de cycloaddition intramoléculaire de Diels-Alder et la solvophobicité des solvants de réaction.

The interest in molecular electronics began in the 1970s with the work of Aviram and Ratner, who proposed that a donor-acceptor dyad, specifically TTF–sigma–TCNQ molecule (TTF–tetrathiafulvalene, sigma–nonconjugated bridge and TCNQ– tetracyanoquinodimethane), can resemble the electric properties of a p-n junction, acting as a unimolecular diode. The reason of such behaviour lies in asymmetrically distributed electronic levels, and very low HOMO-LUMO gap (0.3 eV) that was imposed for the model molecule. Up to date, numerous donor-acceptor dyads were investigated as candidates for molecular rectifiers, which included some D–sigma–A dyads with weak or moderate donor and acceptor moieties, numerous D–sigma–A and also molecules without obvious asymmetry in the electronic structure. However, neither the original TTF–sigma–TCNQ molecule nor any other molecule with similar HOMO–LUMO gap have been studied in molecular electronics applications, which was due to synthetic unavailability of such molecules.In this thesis we present molecular design, synthesis as well as characterization of series of Donor-Acceptor dyads with different combinations of well studied electroactive moieties (TTF-sigma-fluorene, nEDOT-3CNQ, nEDOT-NDI). Herein we describe our progress towards the main synthetic challenge in the field of molecular rectifiers – coupling together strong donor and strong acceptor molecules. To achieve this we employed different synthetic strategies, namely, use of intermediates with moderated redox properties and highly reactive derivatives to avoid formation of charge-transfer complexes between donor and acceptor as well as utilization of the donor-acceptor complexation which results their in covalent binding. The synthetic design includes two types of approaches allowing binding the dyad molecules to electrode surface: (1) amphiphilic structure which enables deposition of molecular monolayers via Langmuir-Blodgett technique and (2) thiol/disulfide functionality suitable for covalent grafting of molecules to metals. Characterization of such monolayers by different spectroscopic and electrochemical techniques as well as analysis of the alignment and packing of the molecules within the films as well as monolayers stability is discussed. Finally, we describe fabrication of Electrode/Organic monolayer/Electrode junctions and discuss results of the charge transport measurements of the synthesized donor-acceptor dyads. / L'intérêt pour l'électronique moléculaire a commencé dans les années 70, avec la découverte d'Aviram et de Ratner. Ils ont proposé une dyade donneur-accepteur telle que la molécule TTF–sigma–TCNQ (TTF–tetrathiafulvalene, liaisons sigma isolées et TCNQ– tetracyanoquinodimethane) qui pourrait fonctionner comme une jonction p-n, jouant le rôle d'une diode unimoléculaire. Ce phénomène est dû à une distribution asymétrique des niveaux électroniques, ainsi qu'au très faible écart HOMO-LUMO (0.3 eV) de cette molécule.Jusqu'à présent, un grand nombre de dyades donneur-accepteur ont été étudiées comme candidates pour la synthèse de redresseurs moléculaires. Ceux-ci incluent certaines dyades D–sigma–A avec des groupes donneur et accepteur faibles ou modérés, de nombreux dyades D–sigma–A, ainsi que des molécules ayant une forte asymétrie dans leur structure électronique.Dans cette thèse, nous présentons la conception moléculaire, la synthèse et la caractérisation d'une série de donneur-accepteurs avec de différentes combinaisons de groupes connus comme étant électroactifs (TTF-sigma-fluorene, nEDOT-3CNQ, nEDOT-NDI). Nous décrivons les progrès que nous avons apportés au domaine complexe de redresseurs moléculaires par l'entremise du couplage de puissant donneurs et accepteurs. Pour réussir cela, nous avons employé différentes stratégies dont: l'utilisation d'intermédiaires avec des propriétés oxido-réductives modérées et des dérivés très réactifs pour empêcher la formation de complexes à transfert de charge ainsi que de se servir de ces mêmes complexe pour obtenir des liaisons covalentes.La synthèse utilisée explore deux approches qui permettent la liaison des dyades à la surface de l'électrode: (1) l'utilisation de structures amphiphiles permettant la déposition de monocouches moléculaires par la technique Langmuir-Blodgett et (2) l'utilisation de groupes de thiol et dedisulfure permettant la liaison covalente des molécules avec des métaux. La caractérisation de ces monocouches a été fait à l'aide de techniques spectroscopiques et électrochimiques.L'analyse de la densité, l'ordre des molécules dans les films et leur stabilité a aussi été étudié. Finalement, nous décrivons la fabrication de jonctions électrode/monocouche organique/électrode et nous discutons les résultats des mesures de transport de charges des dyades donneur-accepteur synthétises.

Amphiphilic copolymers of hydrophobic Disperse Red 1 acrylate (DR1A) and hydrophilic acrylic acid (AA) were dissolved in THF and a H2O/THF co-solvent series. The thermal cis-trans isomerization behavior of the azo groups was measured by means of flash photolysis to investigate self-assembled structure in solution. The rate constants observed for the azo-containing polymers permit an estimation of how the thermal isomerization is influenced by both polymer and solution properties. In pure THF the relaxation can be analyzed by a monoexponential decay. In aqueous-organic solutions all poly(DRlA-co-AA) samples show a slow isomerization process due to inhibited mobility of the azo groups, preceded by a faster isomerization process for unaggregated azo groups. In such cases, the relaxation of the cz's-isomer was fit to a biexponential function which clearly demonstrates two distinct local chromophore environments. The spectroscopic results of this study suggest that weakly aggregated states of the amphiphilic polymers in an aqueous-organic solution can be readily studied through isomerization spectroscopy to estimate the fractions of aggregated groups involved and their local environment.

Novel chimeric oligonucleotides containing L-alpha-dC monomeric units linked in the 3'3' → 5 '5' orientation have been synthesized and binding studies were performed. Thermal denaturation studies done on 7-mer sequences containing either an internal 3'3' L-alpha-dC-5'5' insert or a 3'3'-D-alpha-dC-5 '5' insert in the same position, with their complementary sequence, showed a comparable destabilization of DeltaT m = 6°C and 7°C, respectively in physiological buffer. / A 19-mer sequence, complementary to a sequence near the beginning of the 5'LTR region of HIV-1 genomic mRNA, containing six alternating 3'3'-L-alpha-dC-5 '5' inserts was synthesized. Binding studies showed that this novel oligonucleotide formed stable duplexes with both its DNA and RNA targets, DeltaTm = 4°C and 8°C respectively. / Similarly, an 18-mer, also complementary to a sequence near the beginning of the 5'LTR region of HIV-1 genomic mRNA containing a terminal 3'3'-L-alpha-dC-5 '5' unit was synthesized. Binding studies demonstrated that the duplex formed showed minimal destabilization. Inhibition studies done in the presence of this modified oligonucleotide showed that the amount of (-) strong stop DNA synthesized was decreased in comparison to when the inhibition studies where done in the presence of an unmodified AON. However, due to the presence of two 5'-hydroxyl groups, this modified oligonucleotide did not serve as a substrate for the priming reaction. / The novel synthesis, as well as the characterization, of N 3-functionalized 2-beta-deoxycytidine phosphoramidite are also described.

The reactivities of two dinuclear metals complexes with bridging hydroxides for hydrolyzing phosphrite diesters have been examined. / The second-order rate constants ($ rm k sp prime sb{hyd}/M sp{-1} s sp{-1}$) for the hydroxidecatalysed hydrolysis of bridging aryl methyl phosphates in di-$ mu$-hydroxodinuclear cobalt(III) complex ($ rm Co sb2( lbrack 9 rbrack aneN sb3) sb2(OH) sb2(OP(O)(OMe)(OAr) rbrack sp{3+}$ ( (9) aneN$ sb3$ = 1,4,7-triazacyclononane) and the corresponding free aryl methyl phosphates (25$ sp circ$C and 0.1 M ionic strength) obey the following Bronsted equations: eqalign{ rm log k sp prime sb{hyd} (free diester) = -0.70 pK sb{ rm a}-0.66 & quad rm(R = 0.996) cr rm log k sp prime sb{hyd} (bridging diester) = -1.40 pK sb{ rm a} + 14.4 & quad rm (R = 0.999) cr} hese linear free energy relationships suggest that the di-$ mu$-hydroxodinuclear cobalt(III) complex, irrespective of the leaving groups hydrolyzes the bridging phosphate diesters by the same mechanism. They also indicate that the complex provides greater rate-acceleration for hydrolyzing phosphate diesters with good leaving groups than with poor ones. / La(III) cooperates with hydroxide in hydrolyzing bis(4-nitrophenyl) phosphate (BNPP). The close agreement between the titration data and the pH-rate profile indicates that the active core of the catalyst is a dinuclear La(III) complex bridged by five hydroxide ions La$ rm sb2(OH) sb5 sp+.$ The mechanism proposed for $ rm La sb2(OH) sb5 sp+$-promoted hydrolysis of BNPP involves double Lewis acid activation and intramolecular nucleophilic catalysis of the bridging hydroxide.