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Zugl.: Berlin, Freie Univ., Diss., 2009

Dans ce mémoire, nous étudions deux voies d’accès possibles à des analogues cyclobutaniques du GABA. Les deux voies que nous explorons font appel à des photocycloadditions de l’éthylène sur des dihydropyridinones ou bien sur des pyrrolones. Dans le premier chapitre constituant l’introduction, nous évoquerons la place des aminoacides dans la chimie peptidomimétique. Après une brève description des structures primaire, secondaire et tertiaire des enchaînements d’aminoacides, nous étudierons plus particulièrement les oligomères dans lesquels la structure primaire comporte une contrainte apportée par un cycle dans la chaîne principale. Dans le deuxième chapitre, nous présenterons notre stratégie de synthèse des dihydropyridinones à partir des azabicyclo[3.1.0]hexanols. Puis, pour obtenir un plus large éventail de dihydropyridinones, nous étudierons la faisabilité de notre méthode pour la synthèse de dihydropyridinones N-α’-substituées. Dans le troisième chapitre, nous développerons les réactivités particulières des dihydropyridinones d’une part, en milieu oxydant et d’autre part en photochimie et nous en conclurons que la dihydropyridinone issue de la phénylglycine ne constitue par un bon précurseur pour les réactions de photocycoloadditions [2+2]. Dans le quatrième chapitre, nous avons synthétisé des pyrrolones γ-substituées comme substrats alternatifs dans les réactions de photocycloaddition [2+2] avec l’éthylène. Les acides aminés naturels (L-Alanine, L-Valine, L-Leucine, L-Sérine, L-Phénylglycine, L-Phénylalanine) ont été utilisés pour préparer ces différentes pyrrolones. Dans le cinquième chapitre, nous avons donc effectué les photocycloadditions [2+2] de l’éthylène sur ces pyrrolones. Nous avons obtenu les bicyclo[4.2.0]heptanes correspondant dans la plupart des cas. Ces composés pourraient constituer des précurseurs de dérivés cyclobutaniques du GABA. / In this thesis, we study two possible approaches to cyclobutane analogues of GABA. The two paths that we explore rely on photocycloaddition of ethylene with dihydropyridinones or with pyrrolones. In the first chapter is the introduction, we discuss the role of non-natural amino acids in peptidomimetic chemistry. After a brief description of the primary structures, secondary and tertiary amino acid sequences, we study the oligomers in which the primary structure contains a constraint given by a cycle in the main chain. In the second chapter we present our strategy for the synthesis of dihydropyridinones from azabicyclo[3.1.0] hexanol. Then, to obtain a wider range of dihydropyridinones, we will study the feasibility of our method for the synthesis of N- α'-substituted dihydropyridinones. In the third chapter, we will develop the specific reactivities of dihydropyridinones, firstly, in an oxidizing environment and secondly in photochemistry. We conclude that the outcome of dihydropyridinone phenylglycine N-benzyl is not a good precursor for reactions [2 +2] photocycloadditions. In the fourth chapter, we synthesize γ-substituted pyrrolones as alternative substrates in the reactions of [2 +2] photocycloaddition with ethylene. Natural amino acids (L-Alanine, L-Valine, L-Leucine, L-Serine, L-phenylglycine, L-phenylalanine) were used to prepare these different pyrrolones. In the fifth chapter, we study the [2+2] photocycloadditions of ethylene on these pyrrolones. We obtain the bicyclo [4.2.0] heptanes in the cases and these compounds are proposed as precursors of cyclobutane derivatives of GABA.

Le marquage isotopique représente un enjeu important dans le domaine de la recherche liée à la santé que ce soit en milieu académique ou industriel. Dans ce cadre, les isotopes du carbone jouent un rôle fondamental pour l’étude des propriétés pharmacocinétiques et pharmacodynamiques des candidats médicaments. L’objectif de cette thèse est de développer des nouvelles méthodologies pour le marquage «late-stage» des candidats médicaments à travers la synthèse d’urées et de carbamates cycliques. Ces entités chimiques, largement présentes dans le monde pharmaceutique, étaient traditionnellement marquées via l’utilisation du phosgène ou du monoxyde de carbone. Ce manuscrit présente de nouvelles méthodes alternatives qui considèrent l’utilisation du CO₂, qui est le réactif de départ pour la synthèse avec le carbone-14 et le carbone-11. C’est pourquoi l’utilisation du CO₂ dans une dernière étape de marquage a retenu notre attention. Cette thèse présente un processus réactionnel séquentiel de Staudinger/aza-Wittig qui a été étudié et amélioré pour une incorporation rapide du CO₂ via la formation d’un intermédiaire isocyanate. Le piégeage intramoléculaire de cette espèce par des alcools ou des amines permet la formation d’urées et de carbamates cycliques d’une grande variété structurelle. Après optimisation, cette séquence a pu être effectuée en une étape, à température ambiante et dans des temps très courts de l’ordre de cinq minutes. Ces conditions optimisées ont permis une application directe à la chimie des isotopes [¹⁴C] et [¹¹C], notamment dans le cadre de collaborations avec le Service Hospitalier Joliot Curie (Orsay) et la Karolinska Institute (Suède) fournissant un outil puissant pour le marquage des candidats-médicaments, et ce avec les deux radio-isotopes. / Radioisotope labeling is a relevant topic for health applications in academy, pharmaceutical and agrochemical industries. In this context, carbon isotopes play a basic role in drug development and ADME and toxicological studies. Traditional synthesis with radiocarbon (¹⁴C), based on lengthy and multistep approaches, have hampered the sustainability of the strategy. The aim of this PhD thesis is the development of new methodologies for the late-stage carbon labeling of drug candidates and specifically of cyclic ureas and carbamates. These chemical entities, widely present in pharma and crop science, were used to be labeled using toxic radioactive reagents such as phosgene and carbon monoxide. As valuable alternative, the employ of CO₂, the most readily available building block for carbon-14 and carbon-11 radioisotopes, has been proposed. Unfortunately, [¹⁴C]CO₂ is a poorly reactive building block that requires strong nucleophiles or harsh conditions for its functionalization. Consequently, the incorporation of the isotope at the very beginning of the synthetic process is required causing, de facto, a dramatic stepwise increase of the radioactive waste production, with a heavy environmental impact. In this thesis, we investigate the use of a sequential Staudinger/aza-Wittig reaction that allows the rapid incorporation of CO₂ to provide the corresponding isocyanate. The cyclic urea and carbamate could be so obtained by intramolecular reaction with an amine or hydroxyl moieties. After optimization, the methodology could be successfully performed one-pot, at room temperature within five minutes, demonstrating also a broad scope reliability. Those conditions allowed a direct translation to [¹⁴C] and [¹¹C] chemistry, in collaboration with the Service Hospitalier Joliot Curie (Orsay) and the Karolinska Institute (Sweden), furnishing a powerful tool for the labeling of drug candidates within both the radioisotopes

Dans ce mémoire, nous étudions deux voies d'accès possibles à des analogues cyclobutaniques du GABA. Les deux voies que nous explorons font appel à des photocycloadditions de l'éthylène sur des dihydropyridinones ou bien sur des pyrrolones. Dans le premier chapitre constituant l'introduction, nous évoquerons la place des aminoacides dans la chimie peptidomimétique. Après une brève description des structures primaire, secondaire et tertiaire des enchaînements d'aminoacides, nous étudierons plus particulièrement les oligomères dans lesquels la structure primaire comporte une contrainte apportée par un cycle dans la chaîne principale. Dans le deuxième chapitre, nous présenterons notre stratégie de synthèse des dihydropyridinones à partir des azabicyclo[3.1.0]hexanols. Puis, pour obtenir un plus large éventail de dihydropyridinones, nous étudierons la faisabilité de notre méthode pour la synthèse de dihydropyridinones N-α'-substituées. Dans le troisième chapitre, nous développerons les réactivités particulières des dihydropyridinones d'une part, en milieu oxydant et d'autre part en photochimie et nous en conclurons que la dihydropyridinone issue de la phénylglycine ne constitue par un bon précurseur pour les réactions de photocycoloadditions [2+2]. Dans le quatrième chapitre, nous avons synthétisé des pyrrolones γ-substituées comme substrats alternatifs dans les réactions de photocycloaddition [2+2] avec l'éthylène. Les acides aminés naturels (L-Alanine, L-Valine, L-Leucine, L-Sérine, L-Phénylglycine, L-Phénylalanine) ont été utilisés pour préparer ces différentes pyrrolones. Dans le cinquième chapitre, nous avons donc effectué les photocycloadditions [2+2] de l'éthylène sur ces pyrrolones. Nous avons obtenu les bicyclo[4.2.0]heptanes correspondant dans la plupart des cas. Ces composés pourraient constituer des précurseurs de dérivés cyclobutaniques du GABA.

New methods were developed for the regioselective synthesis of new classes of cellulose derivatives with properties that could help improve the delivery of pharmaceutical drugs within the human body. The specific synthetic targets of this research were regioselectively carboxylated and regioselectively aminated cellulose derivatives. While different avenues to the carboxylated cellulose were ultimately explored without success, a new method for the synthesis of selectively <i>O</i>-acylated 6-amino-6-deoxy-cellulose esters was devised. A key reaction that enabled the synthesis of the new cellulose derivatives described in this dissertation was the one-pot conversion of microcrystalline cellulose to 6-bromo-6-deoxy-cellulose esters. This reaction resulted in the highly selective displacement of the primary hydroxyl groups attached to the 6-carbon (<i>C</i>-6) on each anhydroglucose unit (AGU) in cellulose with bromide, with little or no bromination occurring at carbons 2 and 3 (<i>C</i>-2 and <i>C</i>-3). The brominated cellulose was then completely esterified by adding acetic, propionoic, or butyric acid anhydride to the reaction solution. The reaction products were readily soluble in many common organic solvents, including acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and chloroform. It was shown that the bromides could be converted to iodides under Finkelstein reaction conditions. The presence of halides at <i>C</i>-6 allows a variety of new functional groups to be regioselectively introduced to cellulose via nucleophilic substitution. In one case, the 6-bromo-6-deoxy-cellulose esters were reacted with sodium cyanide to produce regioselectively synthesized cellulose nitriles. These compounds were synthesized with the idea that they could be converted to regioselectively carboxylated cellulose derivatives as an alternative pathway to the rhodium-catalyzed carbonyl insertion reactions also attempted in this research. However, the cellulose nitriles were highly susceptible to alkaline degradation, and conversion to the carboxylated cellulose was not achieved. The 6-bromo-6-deoxy-cellulose esters were also reacted with sodium azide to successfully produce 6-azido-6-deoxy-cellulose esters. The azide groups were then reduced to amines using the Staudinger reaction. This very mild and selective reaction allowed the conversion of the azides to amines in the presence of the ester groups still attached to the cellulose backbone. Such derivatives could have properties useful for a range of biomedical applications, including the delivery of anionic drugs. / Ph. D.

Polysaccharides are one of the most abundant and diverse families of natural polymers, and have an incredibly wide range of natural functions including structural reinforcement, energy storage, aqueous rheology modification, and communication and identity. Application of native polysaccharides like cellulose as sustainable materials is limited by some inherent drawbacks such as insolubility in common solvents including water, and poor dimensional stability. To increase their functionality and utility, researchers have sought to tailor the chemical and physical properties of cellulose and other polysaccharides using a variety of chemical modification techniques, resulting in a number of important, useful commercial derivatives. Because of their greater biocompatibility and biodegradability, and low immunogenicity, naturally derived cationic polymers including cationic polysaccharide derivatives are very attractive candidates for biomedical applications, due to the fact that they are capable of binding with anionic biomolecules, such as nucleic acids and certain proteins, via electrostatic interactions. However, there are relatively few practical synthetic methods reported for their preparation. We demonstrated a useful and efficient strategy for cationic polysaccharide salt preparation by reaction of 6-bromo-6-deoxypolysaccharides such as 6-bromo-6-deoxycellulose esters with pyridine or 1-methylimidazole exclusively at the C-6 position, resulting in high degrees of substitution (DSs). These permanently cationic polysaccharide derivatives have been demonstrated to dissolve readily in water, and bind strongly with a hydrophilic and anionic surface. Availability of these cationic polysaccharides will facilitate structure-property relationship studies for biomedical uses including drug delivery and bioelectronics applications. We also extended the chemistry, reacting 6-imidazolo-6-deoxycellulose with propane sultone, leading to a new synthetic pathway to zwitterionic cellulose derivatives. In addition to cationic and zwitterionic derivatives, we found a simple, efficient route to carboxyl-containing polysaccharide derivatives from curdlan esters via regioselective ring-opening reactions catalyzed by triphenylphosphine (Ph3P) under mild conditions. Curdlan, a polysaccharide used by the food industry and in biomedical applications, was employed as starting material for preparing these carboxyl-containing derivatives by a reaction sequence of bromination, azide displacement and ring-opening reaction with cyclic anhydrides, affording high conversions. These modification techniques have been demonstrated to display essentially complete regio- and chemo-selectivity at C-6. These novel polysaccharide-based materials starting from abundant and inexpensive curdlan are promising for some applications such as amorphous solid dispersion (ASD) oral drug delivery. / Ph. D. / Polysaccharides are chains of natural sugars. They constitute one of the most abundant and diverse families of natural polymers (polymers are chains of small molecules, and polysaccharides are a class of polymers), and in nature polysaccharides play an incredibly wide range of functions such as structural reinforcement, energy storage, changing the viscosity of solutions of things in water, and communication. Cellulose, a polymer comprising long chains of linked glucose molecules, may be the most abundant natural polysaccharide on earth. Application of native cellulose as a sustainable material is limited by its inability to dissolve in water or commonly used organic solvents, poor dimensional stability, inability to melt and flow when heated, and the fact that it degrades when exposed to the environment. In order to increase its functionality and utility, a number of research groups have tried to tailor the chemical and physical properties of things made from cellulose (cellulose “derivatives”) using various chemical modification techniques, resulting in some important, useful commercial cellulose derivatives. The Edgar group, in the recent years has developed a series of new techniques to synthesize various cellulose derivatives for effective oral drug delivery. We have demonstrated that these cellulose derivatives are capable of preventing drugs from forming insoluble crystals, meanwhile protecting the drugs from the harsh environment of the stomach. As a result, these formulations based on cellulose derivatives enhance the solubility of drugs in the digestive tract, and the ability of the drug to permeate to the blood stream, thereby enhance distribution to the parts of the body where it is needed, is enhanced as well. Cellulose- and other polysaccharide-based polyelectrolytes are very attractive candidates for biomedical and therapeutical applications. However, currently, the set of commercially available cellulose derivatives is limited in number and diversity, and contains no positively charged derivatives. This dissertation focuses on the development of new ways to make charged polysaccharide derivatives using chemical modification of cellulose, cellulose esters, and other polysaccharides. Unlike conventional methods which require harsh reaction conditions or metal catalysts, the new approaches in this dissertation offer simple and efficient ways to make a wide variety of charged derivatives of cellulose or other polysaccharides under mild conditions. Availability of these polysaccharide-based charged polymers will help us design more useful, economical materials for biomedical, pharmaceutical, and other applications including gene or drug delivery, oral delivery of potent and selective protein drugs, agricultural applications, and coatings.

Es wird gezeigt, wie das Zusammentreffen hervorragender Wissenschaftler mit breitem Wissen und Fähigkeiten zur interdisziplinären Kooperation im letzten Jahrzehnt vor der Machtergreifung der Nationalsozialisten zu einer Glanzzeit naturwissenschaftlicher Forschung an der Freiburger Universität führte. / It is demonstrated, how the coincidence of excellent scientists with broad knowledge und ability for interdisciplinary cooperation led to a height of scientific research at the Freiburg University.

Es wird gezeigt, wie das Zusammentreffen hervorragender Wissenschaftler mit breitem Wissen und Fähigkeiten zur interdisziplinären Kooperation im letzten Jahrzehnt vor der Machtergreifung der Nationalsozialisten zu einer Glanzzeit naturwissenschaftlicher Forschung an der Freiburger Universität führte. / It is demonstrated, how the coincidence of excellent scientists with broad knowledge und ability for interdisciplinary cooperation led to a height of scientific research at the Freiburg University.

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