Poly (2-ethyl-2-oxazoline)-based amphiphilic diblock copolymer has the potential to form promising membrane materials for water purification due to the thermal stability and good solubility in aqueous solution and also for gas separation because of the presence of polar amide group along the polymer backbone. Moreover, their self-assembly into micelles renders them candidate materials as nanocarriers for drug delivery applications. In this study, a novel well-defined linear PEtOx-based amphiphilic diblock copolymer with a hydrophobic fluoropolymer, i.e., PVDF, have been successfully synthesized by implementing a synthesis methodology that involves the following four steps. In the first step, poly (2-ethyl-2-oxazoline) (PEtOx) was synthesized via living cationic ring-opening polymerization (LCROP) of 2-ethyl-2-oxazoline (EtOx) monomer. The “living” nature of LCROP allows the desirable termination to occur by using the proper termination agent, namely, water, to achieve the polymer with a terminal hydroxyl group, i.e., PEtOx-OH. The hydroxyl end group in PEtOx-OH was converted to PEtOx-Br using 2-bromopropionyl bromide via an esterification reaction. In the third step, the PEtOx-Br macro-CTA was subsequently reacted with potassium ethyl xanthate to insert the necessary RAFT agent via nucleophilic substitution reaction to obtain PEtOx-Xanthate. It s worth mentioning that this step is vital for the sequential addition of the second block via the RAFT polymerization reaction of fluorinated monomer, i.e., VDF, to finally obtain the well-defined amphiphilic diblock copolymer with variable controlled chain lengths. Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR) and Fourier Transform Infrared Spectroscopy (FT-IR) confirmed the structure of the macroinitiator and final copolymer, respectively. Size Exclusion Chromatography (SEC) determined the number-average molecular weight (Mn) and the polydispersity index (PDI) of the obtained copolymer. Furthermore, the polymorphism of the diblock copolymer characterized by X-Ray Diffraction (XRD) indicated that the copolymer displays the electroactive α-phase. The resultant amphiphilic diblock copolymer exhibits spherical micelles morphology, as confirmed by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). Moreover, Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) investigated the thermal decomposition behavior of the copolymer and determined the glass transition temperature (Tg ≈ 70 °C), melting temperature (Tm ≈ 160-170 °C), and crystallization temperature (Tc ≈ 135-143 °C) of the diblock copolymer, respectively.

L'objectif principal de ce travail de thèse étant la préparation de nanovecteurs biocompatibles, nous avons mis au point des systèmes catalytiques exempts de métal pour polymériser les différents monomères préparés dérivés de l’acide diméthylmalique. En présence de ces systèmes catalytiques, la polymérisation anionique par ouverture de cycle (aROP) se déroule de manière contrôlée avec une cinétique plus rapide que celle réalisée en présence d’autres organo-catalyseurs déjà décrit dans la littérature. Nous avons ainsi synthétisé trois homopolymères hydrophobes et deux familles de copolymères di-blocs amphiphiles ayant différentes balances hydrophiles/hydrophobes. Des nanoparticules (NPs) ont été préparées par nanoprécipitation à partir des homopolymères hydrophobes et des copolymères à blocs amphiphiles. La taille des NPs varie entre 30 et 170 nm avec de faibles dispersités (PDI ≤ 0,23) et ayant une très bonne stabilité à 4°C et à 37°C. Des études de cytotoxicité in vitro sur la lignée cellulaire d'hépatome HepaRG ont mis en évidence que toutes les NPs ont une faible toxicité à des concentrations inférieures à 3 μM. En parallèle, une sonde fluorescente, le DiR, a été encapsulée dans les NPs lors de la nanoprécipitation sans affecter les caractéristiques et la stabilité des NPs correspondantes. Enfin, des études in vitro utilisant ces NPs chargées en DiR ont montré que ces dernières étaient effectivement captées par les cellules HepaRG avec différents pourcentages de captation. / The main objective of this PhD thesis being the preparation of biocompatible nanovectors, we have set up metal-free catalytic systems to polymerize various prepared monomers derived from dimethylmalic acid. Using such catalytic systems, the anionic ring opening polymerization (aROP) proceeds in a controlled manner with faster kinetics compared to the organo-catalysts already reported in the literature. Three hydrophobic homopolymers and two families of amphiphilic block copolymers with different hydrophilic/hydrophobic balances have been therefore synthesized. Nanoparticles (NPs) have been prepared by nanoprecipitation of these hydrophobic homopolymers and amphiphilic block copolymers. The size of the NPs ranges from 30 to 170 nm with low dispersity values (PDI ≤ 0.23) and high stability at 4°C and 37°C. In vitro cytotoxicity studies on HepaRG hepatoma cell line have highlighted that all the NPs have low toxicity at concentrations lower than 3μM. In parallel, NPs were loaded with the fluorescent probe DiR without altering the characteristics and the stability of the corresponding DiR loaded NPs. Finally, in vitro studies using NPs loaded with DiR have shown that HepaRG cells effectively uptake the NPs in different percentages of uptake.

Cyclopropyl-containing substrates have been frequently utilized as "probes" for the detection of SET pathways in organic and biorganic systems. These reactions are based on the cyclorpropylcarbinyl → homoallyl rearrangement, which is fast and essentially irreversible. The implicit assumption in such studies is that if a "radical" species is produced, it will undergo ring opening. We have found that there are two important factors to consider in the design of SET probes: 1) ring strain, the thermodynamic driving force for the rearrangement, and 2) resonance energy, which may help or hinder rearrangement, depending on the specific system. Delocalization of spin and charge were found to be important factors pertaining to substituent effects on the rates of radical anion rearrangements. Previous studies from our lab have centered on highly conjugated phenyl cyclopropyl ketones. This work considers a series of compounds varying in their conjugative components from a highly conjugated spiro[2.5]octa-4,7-dien-6-one and derivatives to simple aliphatic ketones. Utilizing cyclic, linear sweep voltammetry, and preparative electrolysis techniques, it was discovered that all substrates yielded ring opened products with rates and selectivities that will prove useful and informative in the design of mechanistic probes based on the cyclorpropylcarbinyl → homoallyl rearrangement. Rates of homogeneous electron transfer from a series of hydrocarbon mediators to substrates were measured using homogeneous catalysis techniques. Standard reduction potentials and reorganization energies of substrates were derived using Marcus theory. Conjugative interactions with the cyclopropyl group are discussed. / Ph. D.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第24432号 / 理博第4931号 / 新制||理||1704(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 若宮 淳志, 教授 畠山 琢次 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

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Polysaccharides are complex biopolymers that play essential roles in the biological systems including energy storage, structural support, lubrication, and signal transduction. Despite their importance, the synthesis of polysaccharides has proven to be very challenging due to the presence of multiple hydroxyl groups and difficulty in controlling the stereochemical outcome of glycosylation reactions. As a conventional chemical method to synthesize polysaccharides, ring-opening polymerization of anhydrosugars enables the synthesis of stereoregular α-(1→6)-linked polysaccharides, but is less effective in preparing polysaccharides with other linkages. Enzymatic polymerizations have also been explored, however, these methods typically require expensive monomers, and suffer from a narrow scope of enzymes and small scale of reactions. The limited approaches to polysaccharides have inspired chemists to synthesize polysaccharide mimetics with achiral linkages that can be constructed efficiently. Poly-amido-saccharides (PASs) are a new type of saccharide polymers in which the O-glycosidic linkages in natural polysaccharides are replaced with (1→2)-amide linkages. With saccharide moieties inter-connected by amide bonds, PASs exhibit characteristics of both polysaccharides and polypeptides, such as possessing pyranose-backbones and lots of hydroxyl groups, and adopting a left-handed helical conformation. However, due to lack of sufficient terminal saccharide residues, previously synthesized glucose and galactose PASs display weak interactions with carbohydrate binding lectins and receptors, limiting their applications in biomedical and pharmaceutical fields. Herein, the design and synthesis of PASs with novel structures and properties is described. By pre-installing the stereochemistry in the monomer, Altrose PASs (Alt-PASs) with β-(1→2)-amide linkages are prepared via ring-opening polymerization of an altrose-based β-lactam followed by debenzylation. Circular dichroism shows that Alt-PASs adopt a right-handed helical conformation in aqueous solution. Via the polymerization of disaccharide-based β-lactams, two PASs with either 4-O-α-D-glucose branches (Mal-PASs) or 6-O-β-D-glucose branches (Gen-PASs) are obtained. Biological studies reveal that Mal-PASs are multivalent ligands to lectin Concanavalin A, while Gen-PASs activate RAW 264.7 macrophage cells by enhancing the secretion of TNF-α and NO. The anionic ring-opening polymerization of sugar-based β-lactams is a useful method to synthesize well-defined polysaccharide mimetics, and this method expands the current repertory of approaches available to complex saccharide polymers with biological activities. / 2021-02-15T00:00:00Z

<p dir="ltr">Ring strain is the driving force for numerous ring-opening reactions of three- and four-membered heterocycles. By comparison, five-membered heterocycles lack this thermodynamic driving force. As a result, only a few methods exist for the ring-opening of five-membered heterocycles using transition metal catalysts. For unstrained and unactivated 2,5-dihydrofurans this is achieved via a β-O elimination process, wherein, gaining selectivity over a competing β-H elimination is challenging. We report a novel strategy for the asymmetric ring-opening of 2,5-dihydrofurans with dichloroalkenes utilizing an earth-abundant cobalt catalyst. We propose that the dichloroalkenes form reactive vinylidene intermediates with the chiral catalyst, followed by a [2+2] cycloaddition with the heterocyclic alkene. This cobaltacyclobutane exclusively undergoes an outer-sphere β-O elimination assisted by zinc halide. Alternative inner-sphere β-O and β-H elimination pathways are inaccessible from this four-membered metallacycle. This is followed by a transmetallation step to form a zinc metallacycle, which subsequently gives rise to homoallylic alcohols, upon quenching, with high diastero- and enantioselectivity. Additionally, the organozinc intermediate can be trapped in situ by various electrophiles for further derivatizations. DFT model predicts the origin of the high diastereo- as well as enantioselectivity observed in the reaction.</p><p dir="ltr">Furthermore, the cobaltacyclobutane intermediate serves as a dynamic platform, facilitating access to a diverse array of products depending on the alkene partners employed. Utilizing chiral allylic alcohols as alkene partners leads to the translation of stereochemical information enabling the stereospecific synthesis of both <i>E</i>- and <i>Z</i>-isomers of alkenes. Alkenes are important motifs found in various natural products and bioactive compounds. A catalytic approach for the precise control of the alkene geometry is highly valuable since the stereochemistry of alkenes plays a pivotal role in determining the properties of molecules. Our strategy provides access to organozinc dienes which could be functionalized further to form highly substituted 1,4-skipped dienes. Additionally, meso-diols can undergo a desymmetrizing β-O elimination from the cobaltacyclobutane intermediate yielding chiral cyclopentenols with contiguous stereocenters</p>

Genom ringöppningssampolymerisation av utvalda epoxider och anhydrider möjliggjordes en enkel strategi för att syntetisera funktionella sampolymerer. Sampolymererna hade förmågan att bilda tvärbundna material, och var dessutom benägna för både hydrolytisk och enzymatisk nedbrytning. Användning av organokatalysatorn PPNCl gjorde det möjligt att bilda sampolymerer genom alternerande ringöppning av epoxider och anhydrider. Utbytet var högt, och polymererna nådde molekylvikter i intervallet 0,7–7,6 kg mol-1. De omättade bindningarna i sampolymerernas sidokedjor gav dem förmågan att bilda tvärbundna nätverk. Graden av tvärbindning dikterades av sampolymerernas molekylära struktur och molekylvikt. De termiska egenskaperna hos sampolymererna reglerades genom att variera anhydriden, där strukturella skillnader mellan de valda anhydriderna hade en inverkan Tg och T5%. Tvärbindningsreaktionen resulterade i en ökning av både Tg och T5% i förhållande till de ursprungliga linjära sampolymererna. De klyvbara estergrupperna i sampolymerkedjorna gjorde det möjligt för sampolymererna att genomgå både hydrolytisk och enzymatisk nedbrytning. De nedbrutna sampolymererna påvisade en förändring i molekylvikt och dispersitet, samt en ökad viktminskning. De nedbrutna tvärbundna materialen visade på större svällning och lägre gelinnehåll än de initiala värdena före nedbrytning. Dessa resultat ger en ökad förståelse kring hur strukturen hos epoxid/anhydrid-baserade sampolyestrar påverkar deras egenskaper, så som förmågan att bilda tvärbundna material samt deras nedbrytbarhet. Förhoppningen är att denna studie ska gynna utvecklingen av nya material inom denna klass av polyestrar, och vara till hjälp för att förutse deras potentiella tillämpningar. / The ring-opening copolymerization of selected epoxides and anhydrides enabled a simple strategy to synthesize functional copolymers with the ability to form crosslinked materials and prone to hydrolytic and enzymatic degradation pathways. The synthesis utilized PPNCl as an organocatalyst and allowed the formation of copolymer chains by alternating ring-opening of epoxides and anhydrides in high yield and molar mass in the range of 0.7-7.6 kg mol-1. The pendant unsaturated bonds in the copolymer chains endowed the copolymers with the ability to form crosslinking networks. The degree of crosslinking was dictated by the molecular structure and molar mass of the copolymers. The thermal properties of the copolymers were regulated by varying the anhydrides, the difference in the structure of each anhydride influence the Tg and T5%. Crosslinking reaction indeed increased the Tg and T5% from the native copolymers. The presence of ester as cleavable groups in the copolymer chains allowed the copolymers to undergo hydrolytic and enzymatic degradation. The degraded copolymers showed a change in molar mass and dispersity and increased mass loss. The degraded crosslinked materials showed higher swelling ratio and lower gel content than the initial values before degradation. These results deliver a better understanding of the structure-property relationships, the ability to form crosslinked materials, and the degradation behavior of epoxides/anhydrides-based copolyesters. They should favor the design of new materials belonging to this class of polyesters and to envisage their potential applications.

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