A Steiner triple system of order v, denoted STS(v), is said to be tricyclic if it admits an automorphism whose disjoint cyclic decomposition consists of three cycles. In this thesis we give necessary and sufficient conditions for the existence of a tricyclic STS(v) when one of the cycles is of length one. In this case, the STS(v) will contain a subsystem which admits an automorphism consisting of a fixed point and a single cycle. The subsystem is said to be 1-rotational.

A series of bicyclic peptides have been designed and synthesized to provide ammonium ion complexation sites via hydrogen bonding in a tetrahedral geometry. Molecular modeling dynamics and electrostatics studies indicate that target compounds 1d-6d may provide better selectivity for ammonium ions over potassium ions than the ammonium ionophore currently used for blood analysis applications, nonactin. Attempts to synthesize 1d, cyclo(L-Glu1�D-Val2�L-Ala3�D-Lys4�D-Val5�L-Val6)-cyclo-(1ã-4å), were unsuccessful due to poor solubility of the synthetic intermediates. This led to the design of 2d-6d in which specific amino acid residues were chosen to provide higher solubility. Compound 2d, cyclo(L-Glu1�D-Ala2�D-Ala3�L-Lys4�D-Ala5�L-Ala6)-cyclo-(1ã-4å), was successfully synthesized, but was also too insoluble for characterization or testing in an ion selective electrode (ISE) sensor format. Compound 6d, cyclo(L-Glu1�D-Leu2�Aib3�L-Lys4�D-Leu5�D-Ala6)-cyclo-(1ã-4å), was successfully synthesized and characterized. When 6d was incorporated into an ISE sensor and tested as an ammonium ionophore, results indicated that the bicyclic peptide lacked solubility in the ISE membrane. A 13C-NMR study has been initiated in order to evaluate selectivity of 6d for ammonium over potassium and sodium cations in solution. Preliminary results with the potassium ionophore valinomycin as a control have been completed.

Ce travail de doctorat porte sur la synthèse et utilisation de bicyclolactones glycidiques, de façon à accéder des dérivés de sucres contenant un système carbonylé α,β-insaturé. Trois types de bicyclolactones ont été étudiés: butenolides liés à des cycles furanose, butenolides fusionnés à des cycles pyranose, comprenant S- et NH-analogues et carboxyméthyle glycosides lactones (CMGLs). La méthodologie de synthèse de butenolides sur motif sucre est basée sur l’oléfination de Wittig de 3 ou 5-cétosucres et lactonisation intramoléculaire spontanée de gamma-hydroxyesters α,β-insaturés intermédiaires. Pour la synthèse des systèmes fusionnés, des furano-3-uloses protégés ont été convertis en 3-C-(éthoxycarbonyl)méthylène furanoses. Une hydrolyse acide finale permet la transestérification intramoléculaire et aussi l’isomérization du cycle en forme pyranose. Des précurseurs 5-S et 5-aminofuranosidiques ont conduit à des analogues thiosucres ou à des dérivés glycidiques ayant une fonction amide et un système carbonylé α,β-insaturé, respectivement. Les CMGLs ont été converties en 3-enopyranosid-2-uloses par l’ouverture de la lactone avec une amine et oxydation/élimination du 2-hydroxy pyranoside tri-O-acétylé obtenu. L’oléfination de Wittig subséquente a conduit aux diènes conjugués pyranosidiques ramifiés en C-2. Les glycosides contenant un groupement propargyle ont permis de préparer des 1,2,3-triazoles par ‘click’ chemistry. Quelques molécules ont été soumises à évaluation antimicrobienne et les énulosides de (N-dodécylcarbamoyl)méthyle ont montré les meilleures activités. Le composé le plus actif est l’énuloside-α qui a montré un très fort effet contre des espèces de Bacillus et une forte activité contre Enterococcus faecalis et Penicillium aurantiogriseum. Les diènepyranosides ont révélé une activité forte et sélective contre E. faecalis. Les dérivés triazolés n'ont montré aucune activité. Parmi les composés bioactifs, trois sont avérés peu toxiques chez les cellules eucaryotes. / This PhD work was focused on the synthesis and the uses of carbohydrate bicyclic lactones for the access to sugar derivatives comprising an alpha, beta-unsaturated carbonyl function. Three types of bicyclic lactones were investigated: furanose C-C-Iinked butenolides, pyranose-fused butenolides, including S-or NH-analogues and carboxymethyl glycoside lactones (CMGLs). The synthetic methodology for butenolide containing-sugars was based on the Wittig olefination of 3- or 5-keto sugars and spontaneous intramolecular lactonization of the intermediate gamma-hydroxy axy alpha,beta-unsaturated esters. In the case of the fused systems, protected furanos-3-uloses were converted into 3-C-(ethoxycarbonyl)methylene furanoses. Further acid hydrolysis elicited both intramolecular transesterification and isomerization to the pyranose ring. Introduction of a sulfur or a nitrogen function at C-5 of the furanose precursors led to thiosugar analogues or to carbohydrate derivatives comprising both an amide function and an alpha,beta-unsaturated system, respectively. CMGLs were converted into 3-enopyranosid-2-uloses by a sequence involving opening of the lactone moiety by amines and oxidation/elimination of the resulting tri-0-acetylated 2-hydroxy pyranosides. Further Wittig olefination afforded 2-C-branched-chain conjugated dienepyranosides. Glycosides bearing a propargyl moiety were engaged in "click" chemistry reactions leading to 1,2,3-triazoles. Some of the new molecules were submitted to antimicrobial evaluation and (N-dodecylcarbamoyl)methyl enulosides proved to display the best efficacy. The most active one was the a-enuloside which showed very strong effect towards Bacillus species and strong activity against Enterococcus faecalis and the fungal pathogen Penicillium aurantiogriseum. Dienepyranosides exhibited a strong activity selectively towards E. faecalis. Triazole derivatives were virtually ineffective. Three of the bioactive compounds showed low acute toxicity in eukaryotic cells.

The synthesis of cyclic allenes with eight or less skeletal C-atoms, known as highly strained organic compounds, has for the past decades attracted increasing interest. The first part of study describes an investigation aimed at the incorporation of an allene unit into a natural compound, being &amp / #945 / -pinene, by using &amp / #946 / -elimination method. The two double-bond isomers 310 and 299b were synthesized as key compounds. Treatment of 310 with t-BuOK resulted in the formation of ketone 308 and diene 313. For the formation of 308, the cyclic allene 300 was proposed as an intermediate. Treatment of 299b, with t-BuOK gave arise to the diene 313 and the dimerization product 322. On the basis of density-functional-theory (DFT) calculations on the allene 300 and the alkyne 320, the formation of the latter as the intermediate was excluded. In the second part of study, the stability of endo-carbene 304 was investigated. Previous studies indicated, during the formation of intermediate 264, no exo-carbene 330 structure could be optimized in its free carbene form. At this point, we were curious about the stability of endo-cyclopropylidene 304 not discussed before in literature. First, addition of bromofluorocarbene to anti-7-ethylbenzonorbornadiene (352) was aimed to isolate the endo-adduct 302b. However, no carbene addition reaction was observed caused by pyramidalization on double bond respect to the methoxy derivative, 363b. Therefore, the bromine was introduced to C-7 carbon atom. Treatment of 302a with MeLi in the presence of furan, gave furan adduct 306a confirmed the formation of allene 305a as a reactive intermediate. Theoretical calculations showed endo-carbene 304a was optimized in the free carbene form . However, it readily isomerizes to allene 305a afforded furan adduct 306a.

The development of the interrupted Nazarov cyclization of allenyl vinyl ketones is presented. The intermediate oxyallyl cation, derived from an allenyl vinyl ketone, may be trapped efficiently by a divergent array of nucleophilic species generating functionalized cyclopent-2-enone products. Allenyl vinyl ketones are also a versatile source of cyclic molecules via a tandem reaction sequence terminated via reaction with acyclic dienes, cyclic dienes, aza-heterocycles, electron-rich alkenes, or styrenes by the formation of an additional ring by a [4 + 3] and/or [3 + 2] cyclization or by the formation of one additional carbon-carbon bond. The bicyclic compounds generated by these processes are densely substituted, and would be difficult to access as succinctly in other ways. The products of these interrupted Nazarov reactions generally reflect excellent regio- and stereoselectivity in the trapping reaction. In some instances, equilibrating conditions were shown to enhance the proportion of one product at the expense of another or to provide a different carbon skeleton. This process appears fairly general, and can be conducted with unsubstituted or alkyl, aromatic, or heteroaromatic allenyl vinyl ketones. The exceptional affinity of allenyl vinyl ketones to undergo interrupted Nazarov reactions is likely a result of the increased longevity of the intermediate oxyallyl cation, due in part to the increased resonance stabilization provided by the allene unit. The high regioselectivity noted in the trapping process was computationally and experimentally confirmed to be a result of a localization of the positive charge in the intermediate oxyallyl cation. The application of this recently developed methodology towards the synthesis of the natural product (+)-roseadione is also described. The tandem Nazarov/[4 + 3] cascade of allenyl vinyl ketones provides a unique manner in which to access the tricyclic core of this cyclooctanoid natural product, a molecule which, to date, has never been synthesized.

The first part of study describes an investigation aimed at the incorporation of an allene unit into a natural compound, being alpha-pinene, by using Doering-Moore-Skatteboel method. DFT computations show that both allene product and insertion product can be isolated if the reaction of methyllithium with 3,3-dibromo-2,7,7-trimethyl-tricyclo[4.1.1.02,4]octane is carried out at either low or high temperatures. One insertion product resulting from the intramolecular C-H insertion at the bridge and three allene dimers were isolated when this reaction was carried out at room temperature. In the second part of study, exo- and endo-cyclopropylidene incorporated into benzonorbornadiene were investigated by using theoretical and experimental methods. Theoretical calculations show that the endo-carbene would be stable and undergo some kind of insertion and addition reactions. On the contrary, the exo-carbene is not stable and isomerizes to the corresponding allene structure during the optimization process. For this purpose, the reaction of dibromocarbene and dichlorocarbene with 7-methoxybenzonorbornadiene was achieved to afford gem-dibromocyclopropane and gem-dichlorocyclopropane adducts, respectively. However, they suffer stereoelectronically-controlled ring opening under the reaction conditions to give the ring-expanded allylic dihalides, respectively. On the other hand, gem-bromofluorocyclopropane, obtained by the treatment of 7-methoxybenzonorbornadiene with bromofluorocarbene, provided one of the four possible [2+4] allene adducts upon treatment with MeLi in furan. The exact structure of the adduct has been elucidated on the basis of NMR spectral data. This result confirms the formation of the bicyclic allene as an reactive intermediate. No products were isolated derived from the endo-carbene.

Ce travail de thèse décrit la synthèse d’iminosucres bicycliques comportant un carbone quaternaire en jonction de cycle à partir de cétonitrones polyalcoxylées. Dans un premier temps, nous nous sommes intéressés à l’étude de l’addition nucléophile d’a-diazoesters sur des nitrones. Des β-N-hydroxyamino α-diazoesters ont ainsi été obtenus avec succès en employant le bis(triméthylsilyl)amidure de lithium comme base dans le THF à -78 °C. Le traitement de ces hydroxylamines par différents catalyseurs métalliques a conduit à la formation de cétonitrones inédites par migration 1,2 d’hydrure. Le triflate d’argent et le tétrakis acétonitrile hexafluorophosphate de cuivre ont été les catalyseurs les plus performants et ont permis de préparer dix nouvelles cétonitrones cycliques α-alcoxyméthylcarbonylées. Leur réactivité vis-à-vis de divers dipolarophiles a été explorée. Les cycloadduits résultant de la réaction de ces cétonitrones avec l’alcool allylique et l’alcool homoallylique ont été convertis en pyrrolizidines et en indolizidines par réduction de la liaison N-O en employant le molybdène hexacarbonyle. Des modifications fonctionnelles (réduction de la fonction ester et hydrogénolyse des éthers benzyliques) ont permis d’accéder à six nouveaux iminosucres bicycliques comportant un carbone quaternaire en jonction de cycle. L’évaluation biologique de ces molécules en tant qu’inhibiteurs de glycosidases a révélé que parmi elles, deux indolizidines étaient des inhibiteurs puissants et sélectifs d’α-glucosidases. / This manuscript reports the synthesis of bicyclic iminosugars bearing a quaternary carbon at their ring junction from polyalkoxylated ketonitrones. Firstly we have studied the nucleophilic addition of α-diazoesters to nitrones. The expected β-N-hydroxyamino α-diazoesters were successfully obtained by using lithium bis(trimethylsilyl)amide as base in THF at -78 °C. Treatment of these hydroxylamines with different metal catalyst induced 1,2-hydride shift and lead to unprecedented ketonitrones. To promote this transformation, silver triflate and tetrakis acetonitrile copper hexafluorophosphate were the most effective catalyst and ten new α-alkoxymethylcarbonyl cyclic ketonitrones were prepared. Their reactivity as 1,3-dipoles in cycloaddition reactions with various dipolarophiles was investigated. Cycloadducts obtained from the reaction between these ketonitrones and allyl alcohol or homoallyl alcohol were coverted into the corresponding pyrrolizidines or indolizidines by a molybdenum-catalyzed N-O bond cleavage. Subsequent modifications (ester reduction and benzylic ethers hydrogenolysis) gave acess to six new bicyclic iminosugars which are substituted at their ring junction. Among these molecules, the inhibitory activity evaluation revealed two potent and selective inhibitors of α-glucosidases.

Development of nanochemical tools targeting receptors in the tumor microenvironment Targeting the receptors in the tumor microenvironment is crucial for the future development of targeted therapies, precision medicine and immunotherapy of cancer. The options available now are, however, limited by the availability of specific ligands. The advances in the field strongly rely on the use of antibodies and genetic modifications of immune cells. Availability of small molecules targeting the receptors of interest would allow further development of alternative strategies as well as deepen our understanding of the underlying mechanisms of cancer development, progression and clearance. In the search for new small-molecule ligands and their use for receptor targeting, the prostate-specific membrane antigen (PSMA) and the immune receptors CD3 and CD64 were selected as model targets. The selected method - the phage display of bicyclic peptides - utilizes chemical modification of the displayed three-cysteine peptides to achieve their cyclization and formation of bicycles. The panning of a peptide library displayed on the phages and probed with PSMA revealed a reproducibly-selected amino acid sequence. Interestingly, the phage clone carrying this sequence was a specific binder of PSMA, but the synthesized peptide alone...

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La synthèse énantiosélective de la (+)-ambruticine S, un produit naturel antifongique a été effectuée au sein de notre groupe. Trois approches ont été développées pour la synthèse du fragment lactone (cycle A). Ces trois voies d’accès au cycle A ont pour intermédiaire commun le methyl α-D-glycopyranoside déjà porteur du diol requis et disponible commercialement à bon prix. Une désoxygénation de l’hydroxyle en C-4 et l’homologation d’un carbone de la chaine latérale en C-6 ont permis l’obtention du cycle lactonique A. Le deuxième projet est une collaboration entre le groupe Hanessian et ISIS Pharmaceuticals afin de développer de nouveaux oligonucléosides antisens. Les nucléosides antisens [4.3.0]-bicycliques cis et trans ont été synthétisés avec succès à partir d’un monosaccharide naturel commun, L-arabinose, porteur des stéréocentres requis. Un réaction clé d’allylation de Sakurai a permis d’obtenir les diastéréoisomères cis et trans dans des conditions de contrôle de type Felkin-Ahn et de contrôle par chélation respectivement. Les composés bicycliques finaux cibles ont été obtenus par une réaction d’aldol intramoléculaire catalyzéé par la proline, par métathèse de fermeture de cycle et par l’application de la méthode de Vorbrüggen pour la synthèse de nucléosides. / An enantioselective synthesis of the antifungal natural product (+)-ambruticin S has been accomplished in our group. For the synthesis of a ring A lactone fragment, three approaches were developed. They all started from commercially available and inexpensive methyl α-D-glycopyranoside, which already possesses the required diol unit. A deletion of the hydroxyl group at C-4 and a one-carbon homologation of the C-6 side chain furnished the ring A lactone. The second project is an ongoing collaboration between the Hanessian group and ISIS pharmaceuticals to develop new antisense oligonucleosides. The cis- and trans-[4.3.0]bicyclic antisense nucleosides were successfully synthesized from a common natural monosaccharide, L-arabinose, which bears the required stereocenters. A key Sakurai allylation led to the cis- and trans diastereomers under Felkin-Ahn and chelation-controlled conditions respectively. The final bicyclic targets were achieved by a practical proline-catalyzed intramolecular aldol reaction and ring-closing metathesis (RCM) strategy, and application of the Vorbrüggen method for nucleoside synthesis.