L'epicocconone est un produit naturel tricyclique, de la famille des azaphilones, isolé en 2003 d'un champignon Epicoccum nigrum. Ce composé se lie de façon covalente aux amines, conduisant à la formation d'une énamine fluorescente. Cette réaction, réversible en fonction du pH, fait de ce composé un excellent marqueur de protéines pour la détection sur gels d'électrophorèse compatible avec une analyse de spectrométrie de masse. La synthèse de ce produit naturel a été débutée au sein de notre laboratoire en s'appuyant sur les travaux réalisés précédemment et mettant en jeu une étape clé de désaromatisation oxydante à l'aide d'iode hypervalent. Une étude méthodologique de réaction clé a permis de comparer l'efficacité et la diastéréosélectivité de l'oxydation effectuée par l'iode (III) ou l'iode (V). / Epicocconone is a tricyclic natural product of the azaphilone family, isolated from the fungus Epicoccum nigrum. This compound covalently binds to primary amines, leading to a protein conjugate which is highly fluorescent. This reaction, reversible according to the pH, make this compound an excellent protein stain compatible with mass spectrometry analysis. The synthesis of this natural product has been started in our laboratory based on the previous work in involves a key oxidative dearomatization using hypervalent iodine. Methodological studies of this key reaction allowed us to compare the efficiency and diastereoselectivity of iodine (III) and iodine (V) mediated oxidations.

Les tétrahydropyrazines et les morpholines sont des hétérocycles à six chaînons comportant deux hétéroatomes en position 1,4. Les objectifs de cette thèse ont été la mise au point de nouvelles méthodes pour leur synthèse. Des tétrahydropyrazines orthogonalement protégée ont ainsi été synthétisées à partir des diamines correspondantes, grâce à l’utilisation de triméthylsilyl-benziodoxolone (TMS-EBX) comme donneur d’alcyne. Ce dérivé d’iode hypervalent s’est par ailleurs révélé être un agent alcynylant chimiosélectif des sulfonamides par rapport aux carbamates. Une approche synthétique différente a été utilisée pour le synthèse des morpholines. En s’appuyant sur les précédents résultats obtenus au laboratoire, une hétérocyclisation catalysée au Fe(III) a été mise au point. En présence d’une quantité catalytique de FeCl3.6H2O, des morpholines 2,6- et 3,5-disubstituées ont été obtenues avec de bons rendements et des diastéréosélectivités toujours en faveur des composés cis. Afin d’améliorer cette méthode pour la rendre encore plus éco-compatible, une méthode monotope a été ensuite développée, menant, à l’aide d’une catalyse séquentielle Pd(0)/Fe(III), à une diversité de morpholines à partir de vinyloxiranes et d’amino-alcools facilement synthétisables. Le changement des substrats de départ permet de faire varier la substitution des morpholines finales sans avoir à modifier les conditions réactionnelles. L’obtention majoritaire des composés de configuration relative cis a été rationalisés à partir des stabilités supposées des différents diastéréoisomères et un mécanisme hypothétique est présenté. / Tetrahydropyrazines and morpholines are six-membered heterocycles including two heteroatoms in positions 1 and 4. The objectives of this thesis were to develop new methods for their synthesis. Orthogonnaly protected tetrahydropyrazines were thus synthesized from the corresponding diamines, thank to the use of trimethylsilyl-benziodoxolone (TMS-EBX) as an alkyne donnor. This hypervalent iodine derivative was also found to be an efficient and chemoselective alkynylating agent of sulfonamides versus carbamates. A different synthetic approach was used for the synthesis of morpholines. Relying on previous results obtained in the laboratory, an iron(III)-catalyzed heterocylization was developped. In the presence of a catalytic amount of FeCl3.6H2O, 2,6- and 3,5-disubstituted morpholines were obtained with good yields and diastereoselectivities in favor of the cis compounds. To improve this method and make it more environnementally friendly, a one-pot method was next designed, leading, with a sequential Pd(0)/Fe(III)-catalyzed process, to a diversity of morpholines from readily available vinyloxiranes and amino-alcohols. A simple switch in the starting materials gives diverse morpholines without any change in the reaction conditions. The cis-compound predominance was rationnalized from the putative stabilities of different diastereoisomeres and a hypothetical mechanism is proposed.

La situation très préoccupante due aux résistances antimicrobiennes incite les chimistes à concevoir de nouvelles molécules capables de lutter contre ces résistances. Les inhibiteurs de β-lactamases diazabicyclooctanes permettent de préserver l'arsenal thérapeutique actuel en restaurant l’activité des antibiotiques β-lactames. Ainsi, l'avibactam a été très récemment approuvé par la FDA et l'EMA en association avec la ceftazidime (une céphalosporine de 3ème génération) pour le traitement des infections sévères de bactéries Gram négatif. Ces composés se caractérisent par une structure bicyclique présentant un motif N-hydroxyurée cyclique qui est la clé de leur activité. Cependant, les méthodes permettant d’accéder facilement à ce type d'hétérocycles saturés, sont peu nombreuses. Dans le cadre de cette thèse, l'objectif était de développer une nouvelle approche synthétique permettant d’accéder à des analogues de l'avibactam. Pour cela, nous avons développé des cyclisations chimiosélectives, initiées par des réactifs d’iode(III) de N-alkoxyurées insaturées. Trois cyclisations différentes ont été optimisées et étudiées, fournissant des oxazolidinones oximes ou des N-oxyimidazolidinones à partir des mêmes substrats, selon des mécanismes distincts. Les différents modes de cyclisation peuvent être contrôlés grâce à l’association d’un réactif d'iode(III) et d'un sel d'halogénure ou de TEMPO, selon des conditions réactionnelles simples à mettre à œuvre. En parallèle, nous avons également réalisé la synthèse asymétrique d'un intermédiaire monocyclique clé, qui devrait conduire à des analogues de l'avibactam grâce à une nouvelle voie de synthèse utilisant la méthodologie de cyclisation développée. / The current dire situation of antimicrobial resistances urges synthetic chemists to design new molecules that can fight these resistances. Hence, the diazabicyclo-octanes β-lactamase inhibitors are of particular interest, as they can preserve the current therapeutic arsenal by restoring the activity of β-lactam antibiotics. Thus, avibactam was very recently approved by the FDA and the EMA in combination with ceftazidime (a 3rd generation cephalosporin antibiotic) for the treatment of severe Gram-negative bacteria infections. Structurally, these compounds are characterized by a bicyclic framework featuring a cyclic N-hydroxylated urea motif that is key to its activity. Yet, only few methods exist to easily access this singular type of saturated heterocycles. The aim of this project was to develop a new synthetic approach to acces a new range of avibactam analogues. For this, we developed chemoselective iodine(III)-mediated cyclizations of unsaturated N-alkoxyureas. We were able to optimize and study three different cyclizations that proceed through distinct mechanisms to yield oxazolidinone oximes, or N-oxyimidazolidinones from the same substrates. The different modes of cyclization can be triggered using a combination of the iodine(III) and a halide salt or TEMPO, under reaction conditions which are operationally simple and easily tunable. In parallel, we also devised asymmetric synthesis of a key monocyclic intermediate which should yield avibactam analogues, through a new synthetic route that relies on the methodology we developed.

The development of new strategies and associated reagents that enable previously inaccessible synthetic disconnections is largely attributing to the remarkable progress in exploring new chemical space for drug discovery and innovative complex molecule syntheses. In the Wengryniuk laboratory, we are devoted to discovering new synthetic methodologies that are based on umpolung or reverse polarity, strategies, enabled by Nitrogen-ligated (bis)cationic hypervalent iodine reagents (N-HVIs). I(III) N-HVIs represent an attractive new class of oxidant as they are environmentally benign, highly tunable, and have shown ability in enabling distinguished modes of reactivity. This dissertation focuses on demonstrating the synthetic utility of these N-HVI reagents towards C–O bond formation via a reverse polarity approach.In Chapter 1, a summary of the reactivity and characteristics of hypervalent iodine reagents is provided. Chapter 2 describes a mild and metal-free strategy for alcohol oxidation mediated by I(III) N-HVI reagents. This method demonstrates the first method for chemoselective oxidation of equatorial over axial alcohols and was the first in situ synthesis and application of N-HVIs for a simple one-pot procedure. Chapter 3 discusses a novel strategy for a dual C–H functionalization to access functionalized chroman scaffolds via an umpolung oxygen activation cyclization cascade. Computational studies in collaboration with Prof. Dean Tantillo (UC-Davis) along with experimental probes in our laboratory, support the formation of an umpoled oxygen intermediate as well as competitive direct and spirocyclization pathways for the key C–O bond forming event. The utility of the developed method is demonstrated through a downstream derivatization of the iodonium salt moiety to access C–H, C–X, and C–C substitution via established Pd-catalyzed cross couplings. Total synthesis of (±)-conicol natural product was performed in 8 steps and 23% overall yield, further demonstrating the synthetic utility of the developed method. Key synthetic steps include a smooth construction of the chroman core via N-HVI mediated C–H etherification of a pendant alcohol followed by a late-stage double bond installation. Overall, this dissertation summarizes the current state of research enabled by N-HVI reagents, with a focus on their utility in reverse polarity heteroatom activation strategies, and it serves as a practical guide for future development in the field. / Chemistry

Surgical preparation reduces commensal bacterial load. Currently, no standardized preoperative ocular preparation method in the dog has been reported. Previous studies use culture-based methods to determine commensal bacterial populations. Recent reports suggest that high-throughput sequencing may be superior to culture techniques to determine bacterial communities in the eye and other tissues. The goal of this study was to describe the conjunctival commensal ocular microbiome and bacterial community using DNA sequencing and aerobic cultures of six normal, healthy dogs and investigate the short and long-term effects of an antiseptic protocol on the ocular microbiome. Samples were obtained prior to, immediately following, 24 hours following, and 4 weeks following ocular preparation. The Mississippi State University microbiology laboratory evaluated aerobic cultures, and the Gastrointestinal Laboratory of Texas A&M University performed DNA sequencing. This is the first study to show short and long-term effects of standard ocular surgical preparation on the ocular surface microbiome.

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The development of future electronics depends on the availability of suitable functional materials. Printed electronics, for example, relies on access to highly conductive, inexpensive and printable materials, while strong light absorption and low carrier recombination rates are demanded in photocatalysis industry. Despite all efforts to develop new materials, it still remains a challenge to have all the desirable aspects in a single material. One possible route towards novel functional materials, with improved and unprecedented physical properties, is to form composites of different selected materials. In this work, we report on hydrothermal growth and characterization of graphene/zinc oxide (GR/ZnO) nanocomposites, suited for electronics and photocatalysis application. For conductive purposes, highly Al-doped ZnO nanorods grown on graphene nanoplates (GNPs) prevent the GNPs from agglomerating and promote conductive paths between the GNPs. The effect of the ZnO nanorod morphology and GR dispersity on the nanocomposite conductivity and GR/ZnO nanorod bonding strength were investigated by conductivity measurements and optical spectroscopy. The inspected samples show that growth in high pH solutions promotes a better graphene dispersity, higher doping and enhanced bonding between the GNPs and the ZnO nanorods. Growth in low pH solutions yield samples characterized by a higher conductivity and a reduced number of surface defects. In addition, different GR/ZnO nanocomposites, decorated with plasmonic silver iodide (AgI) nanoparticles, were synthesized and analyzed for solar-driven photocatalysis. The addition of Ag/AgI generates a strong surface plasmon resonance effect involving metallic Ag0, which redshifts the optical absorption maximum into the visible light region enhancing the photocatalytic performance under solar irradiation. A wide range of characterization techniques including, electron microscopy, photoelectron spectroscopy and x-ray diffraction confirm a successful formation of photocatalysts. Our findings show that the novel proposed GR-based nanocomposites can lead to further development of efficient photocatalyst materials with applications in removal of organic pollutants, or for fabrication of large volumes of inexpensive porous conjugated GR-semiconductor composites.