Les réactions asymétriques catalysées constituent une approche élégante au problème de l'introduction de centres stéréogène pour la synthèse de molécules complexes. Dans ce contexte, les oxydations sont notables de par la possibilité de créer en une seule étape à la fois le centre asymétrique ainsi que les fonctions dont les réactivités sont à la base des méthodologies de synthèse. La sélectivité d'un catalyseur est le plus souvent contrôlée par sa structure même. Notre groupe étudie les oxydations aérobies asymétriques par activation C-H par des analogues chiraux du N-hydroxyphtalimide (NHPI). Nous avons développé une nouvelle structure de catalyseur comportant un cœur BINOL-maléimide afin de dépasser les limitations intrinsèque des précédentes générations de catalyseurs. La première série n'a pas montré d'énantiosélectivité, cela nous a conduit a synthétiser une deuxième série dont les caractéristiques permettraient d'améliorer l'efficacité de ces catalyseurs d'oxydation aérobie asymétrique. Le développement d'un analogue portant deux iodes nous a conduit à étudier cette structure en tant que cœur de catalyseurs à base d'iode hypervalent. Nous avons analysé trois séries de ces catalyseurs pour l'oxytosylation de cétones prochirales et montré que notre structure est comparable avec celles présentées dans la littérature. / Catalysed asymmetric reactions are an elegant approach towards the synthesis of complex molecules for the controlled introduction of stereocenters. Within this field, oxidations are noteworthy since they allow to create in one step both the stereogenic elements and the moieties whose reactivities are the cornerstone of the methodologies of synthesis. The selectivity of a catalyst is most often controlled by its own structure. Our group has investigated catalysed asymmetric aerobic oxidations by C-H activation through the use of chiral analogues of N-hydroxyphtalimide (NHPI). We have developed a new structure of catalyst based upon a BINOL-fused maleimide core to circumvent the inherent limitations of previous catalysts generations. The first series showed no enantioselectivity and led us to synthesize a second series whose features are expected to improve the overall efficiency of those catalysts for asymmetric aerobic oxidations. The development of an analogue bearing two iodine moieties prompted us to study this structure as a core for chiral hypervalent organo-iodine(lll) catalysts. We have investigated three series of such catalysts for the asymmetric α-oxytosylation of prochiral ketones and showed that our structure is comparable with the ones found in the literature.

Dans cette thèse, nous avons développé et caractérisé un nouveau type de source de mise en phase gazeuse de biomolécules qui repose sur une désorption laser non résonnante sur des microgouttelettes directement sous vide. Ce dispositif nous permettra à terme d’ouvrir une voie d’étude originale pour appréhender les effets des rayonnements ionisants sur des molécules organiques d'un point de vue physique.Nous présenterons en détail ce dispositif avec lequel nous avons réussi à transférer sous vide, de façon non destructive, des biomolécules et des complexes non-covalents dans une gamme de masse de l’ordre du kDa et à les identifier par spectrométrie de masse par temps de vol. Nous montrerons notamment les défis techniques qu’il a fallu relever pour permettre le transfert des microgouttelettes sous vide et comment par simulation du spectromètre, nous sommes parvenus à optimiser fortement les paramètres de collection des espèces moléculaires désorbées et la résolution en masse de notre système, en remplaçant, dans la zone de désorption, l’extraction électrostatique à potentiels retardés par un piège électrostatique quadripolaire. Nous exposerons enfin la façon dont ce dispositif, couplé à une plateforme d'irradiation d'ions simplement chargés possédant une énergie de l'ordre du keV, nous permettra de caractériser à une échelle moléculaire l’endommagement lié à des mécanismes de chimie radicalaire radio-induits. / In this thesis, we have developed and characterized a new type of gas phase source of biomolecules which based on non-resonant laser desorption on microdroplets directly under vacuum. This device will eventually allow us to open an original way to study the effects of ionizing radiation on organic molecules from a physical point of view. We will present in detail this device with which we transfered with sucess under vacuum,in a non-destructively way, biomolecules and non-covalent complexes in a mass range of the order of kDa and we assigned them with time-of-ight mass spectrometry. We will show in particular the technical challenges that we had to overcome in order to allow the transfer of microdroplets under vacuum and how by simulation of the spectrometer, we have been able to highly optimize the collection parameters of the desorbed molecular species and the mass resolution of our system, by replacing, in the desorption zone,delayed extraction by a quadrupole electrostatic trap. Finally, we will describe the way in which this device, coupled to a simply charged ion irradiation platform with an energy of the order of the keV, will enable us to characterizeon a molecular scale the damage due to radio-induced radical chemistry mechanisms.

Reductive electron transfer has been successfully utilized to facilitate the first enantioselective desymmetrisation of malonate derivatives. Selective monoreduction of cyclic 1,3-diesters through the combined use of SmI2-Et3N and chiral non-racemic diols has granted rapid access to enantioenriched β-hydroxy acids containing challenging quaternary centres – an abundant motif in many drug molecules. Unique radical anions generated from the single electron reduction of cyclic 1,3-diesters have been exploited in cyclisation cascades. Capture of acyl-type radical anions by both alkene and alkyne acceptors have permitted the construction of complex bicyclic architectures in a single synthetic operation. The reductive cyclisation cascade of lactones has also been demonstrated, using SmI2-H2O to achieve a challenging domino 5-exo-trig/6-exo-trig cyclisation event. This process generates highly decorated carbo[5.4.0]bicyclic scaffolds with complete diastereocontrol.

The first project in this dissertation describes the use of microwave-promoted iminyl radical fragmentations to form functionalized nitriles. Nitrogen-centered radical chemistry is a useful tool to construct valuable C-N bonds commonly found in pharmaceuticals and biologically active molecules. Classically, these reactions require the use of toxic initiators and propagators. Iminyl radical chemistry has been gaining momentum as a means of avoiding these harsh conditions. This project utilizes the fragmentation of cyclic iminyl radicals via irradiation of O-phenyl oxime ethers to produce a synthetically useful nitrile tethered to an alkyl radical in the absence of metal catalysts and redox chemistry. The efficacy of this synthetic method was demonstrated by the diverse functionalization of estrone. We believe this useful chemistry can be a powerful tool when applied to both early and late-stage synthetic endeavors. The latter half of this dissertation focuses on the total synthesis of yaku'amide A, a natural product isolated from a marine sponge. This peptide contains potent anticancer activity and exhibits a novel, unique mode of action. Due to its scarcity in nature, comprehensive biological studies have remained elusive. The structure of yaku'amide A contains complex, unsymmetrical bulky dehydroamino acids such as E- and Z- dehydroisoleucine which pose a synthetic challenge. Despite the efficient strategy developed in our lab, the synthesis remains lengthy. Simpler symmetrical dehydroamino acids dehydrovaline and dehydroethylnorvaline were substituted in place to prepare two analogues of yaku'amide A that closely resemble the conformation of the natural peptide. Activity profile of the simplified analogues showed comparable potency to that of yaku'amide A.

Cette thèse décrit le développement de nouvelles réactions dans le cadre de la chimie radicalaire par transfert de xanthate développée au laboratoire. Nous nous sommes tout particulièrement intéressés à apporter des solutions à l’alkylation formelle de cétones par voie radicalaire. Dans ce cadre, une alkylation bidirectionnelle de cétones non symétriques a été développée à partir de dixanthates. Reposant sur les différences de stabilité des radicaux présents dans le milieu, cette réaction a permis la synthèse de nombreuses cétones formellement dialkylées à partir d’oléfines non activées. La puissance de cette technologie a également été éprouvée dans le cadre de l’alkylation formelle des gem˗α˗dichlorocétones, composés très sensibles aux conditions basiques. Les conditions douces et neutres de réaction ont permis de préparer de nombreux dérivés et d’étudier plus en détails leur réactivité vis-à-vis du réarrangement de Favorskii. Dans un troisième temps, une réaction de vinylation radicalaire a été appliquée à la synthèse de cétones trifluorométhylées. Enfin, le développement de nouvelles réactions à partir des adduits radicalaires est envisagé. / This manuscript is dedicated to the development of new reactions based on xanthate radical transfer reaction, which has been developed in our laboratory. In particular, we were particularly interested in its application to the formal alkylation of ketones. Within this project, we studied a bidirectional alkylation of non-symmetrical ketones from dixanthates derivatives. Based on the difference of stability of the radicals involved in the reaction, this strategy allowed the preparation of various formally dialkylated ketones from unactivated alkenes. This powerful strategy was also applied to the formal alkylation of the highly base˗sensitive gem˗α˗dichloroketones. The mild and neutral conditions employed for the radical addition allowed the preparation of various derivatives. Their reactivities towards a Favorskii rearrangement were as well studied. The scope of a radical vinylation reaction was also extended to the synthesis of various trifluoromethylated ketones and enones. Finally, the development of new reactions from the radical adduct was envisaged.

L’incorporation de groupements pharmacologiquement intéressants pendant la dernière étape de synthese d’une cible thérapeutique potentielle permet une exploration rapide et efficace de son espace chimique. En particulier, les cycles hétéroaromatiques sont des structures clefs en chimie médicinale et agrochimie et un grand nombre d’études ont porté sur leur modification tardive. La chimie radicalaire des xanthates est apparue comme étant particulièrement adaptée à cette stratégie, grâce à sa grande tolérance de groupements fonctionnels. La fonctionnalisation d’hétéroaryles par l’intermédiaire des xanthates a permis l’introduction de groupements tertiaires et secondaires sur des motifs hétéroaromatiques simples, ainsi que sur des composes plus complexes telles que des principes actifs de médicaments et produits phytosanitaires commerciaux. / The late introduction of pharmacologically relevant groups before evaluating the biological properties of potent targets enables a faster and efficient exploration of their chemical space. This has been particularly studied and applied on heteroaromatic rings which are key scaffolds in medicinal and agrochemical research. In this context, the radical chemistry of xanthates has emerged as an useful tool, thanks to its high functional group compatibility. The xanthate-mediated addition of tertiary and secondary alkyl radicals to heteroarenes enables the easy functionalization of heteroaromatic rings as well as more decorated structures, such as marketed drugs or agrochemicals.

<p>Radical polymers bearing open-shell moieties at their pendant sites offer potential advantages in processing, stability, and optoelectronic properties compared to conventional doped conjugated polymers. The rapid development of radical-containing polymers has occurred across various applications in energy storage devices and electronic systems. However, significant gaps still exist in understanding the key structure-property-function relationships governing charge transport phenomena in these materials. Most reported radical conductors primarily rely on (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) radicals, which raises fundamental questions about the ultimate limits of charge transport capabilities and the impact of radical chemistry choice on material deficiencies. Moreover, an understanding gap persists when it comes to connecting the computable electronic features of individual units and the charge transport behavior of these materials in condensed phases. This dissertation seeks to address these gaps by developing a molecular understanding of charge transport in radical-bearing materials through a combined computational and experimental approach.</p> <p><br></p> <p>The initial stage of this dissertation investigated the impact of dimeric orientations and interactions on charge transport by conducting a density functional theory (DFT) study on a diverse set of open-shell chemistries relevant to radical conductors. The results revealed the anomalously high reorganization energies of the TEMPO radical due to strong spin-localization, which may result in inefficient charge transfer. Additionally, a significant mismatch was identified between dimeric conformations favored by intermolecular interactions and those maximizing charge transfer. This study provided new insights into the impact of steric hindrance and spin delocalization on elementary charge transfer steps and suggests opportunities for exploiting directing interactions to enhance charge transport in these materials.</p> <p><br></p> <p>Building upon these findings, we established a direct relationship between the molecular architecture and intrinsic charge transport properties. To accomplish this, single-molecule characterization methods (i.e., break junction techniques) were implemented to study the nanoscale charge transport properties of radical-containing oligomeric nonconjugated molecules. Temperature-dependent measurements and molecular modeling revealed that the presence of radicals improves tunneling at the nanoscale. Integrating open-shell moieties into nonconjugated molecular structures significantly enhances charge transport, thereby characterizing charge transport through radicals at the individual level and opening new avenues for implementing molecular engineering in the field of nanoelectronics.</p> <p><br></p> <p>To further connect the electronic properties of repeat units with the condensed-phase charge transport behavior of radical polymers, a quantum chemical study was carried out to explicitly evaluate the interplay between polymer design, open-shell chemistries, and intramolecular charge transport. After comprehensive conformational sampling of the configurational space of radical polymers, we determined their anticipated intrachain charge transport values by utilizing graph-based transport metrics. We show that charge transport in radical polymers primarily hinges on the choice of radical chemistry, which in turn affects the optimal selection of backbone chemistry and spacer group to ensure proper radical alignment and prevent undesired trap states. These findings highlight the potential for a substantial synthetic exploration in radical polymers for radical conductors.</p> <p><br></p> <p>In summary, this dissertation provides compelling evidence of radical-mediated charge transport and suggests potential design guidelines to enhance the charge transfer behavior of radical-containing polymer materials. Furthermore, these findings inform future research directions in fine-tuning molecular engineering and modular design to enable the development of radical-based materials and their end-use applications in organic electronics.</p>

Manganese(III) acetate mediated radical cyclisations provide a mild and powerful tool in the construction of complex bicyclic systems. This thesis focuses on the formation of a number of alkenyl substituted [3.3.0]-bicyclic γ-lactones utilising a manganese(III) acetate/copper(II) triflate induced radical cyclisation. The methodology was then applied to a short catalytic and enantioselective synthesis of (+)-aphanamol I and related natural products. Chapter 1 presents a summary of the theories and methodology which will be utilised in this work. In particular, a key focus will revolve around oxidative radical cyclisations and how manganese(III) acetate has become a vital oxidant in such areas. Chapter 2 details a catalytic and asymmetric total synthesis of (+)-aphanamol I. Following an overview of the natural product and its previous total synthesis, a racemic and asymmetric total synthesis is presented which utilises a manganese(III) acetate mediated radical cyclisation and a Claisen ring expansion as key steps. Chapter 3 reports the synthesis and subsequent cyclisation of a wide range of dienyl malonate substrates. Variation of the γ-substituent is first explored, demonstrating the effect that substituent size has on the diastereoselectivity of the cyclisation. Following this, the synthesis of [2.3.0]-,[4.3.0]- and [5.3.0]- bicyclic γ-lactones are investigated. Chapter 4 describes studies towards the total synthesis of a dolabellane natural product. Investigations into substrate synthesis which can be used in a RCM will be presented. Full experimental details and spectral data, with select NMR spectra are also provided.

Les systèmes plastiques à usage unique sont destinés aux industries biopharmaceutiques et biotechnologiques. Ils sont composés de polymères et sont appréciés pour leurs propriétés barrières au gaz et à la vapeur d’eau assurant une préservation des solutions contenues dans ces systèmes. Ces dispositifs présentent de nombreux avantages pour les industriels : ils permettent d’éviter un nettoyage des cuves en inox et ainsi de limiter des risques de contamination croisée. En vue de leur utilisation, ces dispositifs sont stérilisés par irradiation γ. Le but de cette étude est de mettre en évidence l'impact de la stérilisation γ sur certains polymères et sur certains antioxydants utilisés dans la fabrication des polymères. Plusieurs échantillons sont analysés avant et après la stérilisation en utilisant différentes doses de rayonnement γ et au cours du temps (vieillissements naturels). Les modifications de structure des polymères γ-irradiés (EVA, PE et EVOH) ont été caractérisées par diverses méthodes analytiques : IRTF, spectroscopie Raman, RPE, chromatographie… Les résultats sont traités en utilisant des méthodes chimiométriques, comme l’ACP (Analyse en Composantes Principales), l’AComDim (ANOVA Common Dimensions) et SIMPLISMA (Simple-to-use interactive self-modeling mixture analysis). L’ACP a permis de mettre en évidence l’impact de la dose d’irradiation sur le polymère. L’AComDim a conduit à identifier les facteurs responsables de l’évolution des structures (la dose γ, les temps et l’interaction dose γ × temps), alors que les différents lots n’induisent pas de déviation. Enfin, la méthode de résolution de courbe SIMPLISMA a été appliquée pour l’étude du cœur du matériau. / The single use plastic systems are designed for biopharmaceutical and biotechnology industries. They are principally made of polymers and they are very appreciated for their barrier properties to gas and water vapor ensuring preservation of the solutions contained in these single-use systems. These devices have many advantages for industrial: they avoid cleaning stainless steel tanks and thus limit the risk of cross-contamination. In view of their future use, these devices are sterilized by γ-irradiation. The purpose of this study is to highlight the impact of γ sterilization on some polymers and on some antioxidants used in the manufacture of polymers. The samples are analyzed before and after sterilization using different γ-doses and over time (natural ageing). The structural modifications of γ-irradiated polymers (EVA, EVOH and PE) were characterized by various analytical methods: FTIR, Raman spectroscopy, ESR, chromatography… Some results are analyzed using chemometric methods such as PCA (Principal Component Analysis), AComDim (ANOVA Common Dimensions), and SIMPLISMA (Simple-to-use interactive self-modeling mixture analysis). The PCA allowed to highlight the impact of the irradiation dose on the polymer. The AComDim method led to the identification of the factors contributing to the evolution of structures (γ-dose, ageing and γ × ageing interaction), whereas the several lots do not involve variation. Finally, the curve resolution method, SIMPLISMA, was applied to the study of the core of the material.

Les nuages représentent un milieu multiphasique complexe et réactif. Une grande partie de composés chimiques atmosphériques de la phase particulaire ou gazeuse se dissout dans les gouttelettes de nuage où peuvent subir des transformations chimiques, photochimiques et microbiologiques. L'eau de nuage a été échantillonnée à la station du puy de Dôme et caractérisée par des mesures physico-chimiques. La première partie de mon travail de thèse est focalisée sur la réactivité de l’eau du nuage. La formation d’espèces réactives, le radical hydroxyle, est étudiée par photolyse directe de sources inorganiques et photolyses nano-pulsée et sa vitesse de formation a été corrélée à la concentration de sources. Les propriétés spectroscopiques et la dégradation d'un composé modèle, l'acide tartronique, ont été étudiés. Les expériences faite par irradiation continue (photolyse directe et induite par le radical hydroxyle) et par photolyse pulsée ont permis de comprendre la réactivité de ce composé dans le milieu nuageux. La deuxième partie de mon travail est focalisée sur la caractérisation et la réactivité de la matière organique dans la phase aqueuse des nuages. La détection et la quantification de tryptophane par spectroscopie de fluorescence et l'étude de sa réactivité ainsi que la détection et quantification d‘acides aminés représente une partie importante de ce travail. Les acides aminés ont été détectés pour la première fois dans l'eau de nuage grâce à l'utilisation d'une méthode chromatographique de dérivation et détection par fluorescence. Ce travail à démontré que les acides aminés peuvent représenter entre 4 et 21 % de la concentration en carbone de la matière organique dissoute dans le nuage. La réactivité des acides aminés avec le radical hydroxyle a été comparée avec celle des acides carboxyliques et de la matière organique dissoute. Ce résultat montre clairement que le rôle des acides aminés comme piège de radicaux hydroxyles ne peut plus être négligé. / Clouds represent a multiphase complex and reactive medium in which gases, liquid particles and aerosols are in continuous interaction. A large fraction of atmospheric chemical compounds present in the particulate and gaseous phases can be transferred to the cloud droplets where can undergo chemical, photochemical and microbiological transformations. Cloud waters were sampled at the puy de Dôme station. The first part of my PhD work is focused on the photoreactivity of cloud water. Formation of a reactive species such as hydroxyl radical, by direct photolysis of inorganic sources was investigated, as well as the correlation between the concentration of sources and the hydroxyl radical formation rate. The spectroscopic proprieties and fate of tartronic acid, were investigated under cloud water conditions. Moreover, photochemical experiments were performed using continuous irradiation (direct and hydroxyl radical mediated photolysis) and nanosecond flash photolysis in order to assess the reactivity of this compound in cloud aqueous phase. The second part of my work is centered on the characterization of organic matter in clouds. Two studies are presented: i) Detection and quantification of tryptophan by fluorescence spectroscopy and the assessment of its reactivity; ii) detection and quantification of amino acids. Amino acids are detected for the first time in cloud water using a derivatization method and this work show that they represent the 9% of the dissolved organic matter in cloud. Their reactivity with hydroxyl radical was compared to the reactivity of carboxylic acids and dissolved organic matter. These results clearly demonstrate that amino acids represent a major sink of hydroxyl radicals in cloud water.