Development of new eco-compatible reactions : applications in synthesis of bioactive molecules

La leucémie myéloïde chronique (LMC) est une affection hématologique maligne caractérisée par l’apparition dans la moelle osseuse et le sang, d’un nombre important de globules blancs dont certains sont immatures. A l’heure actuelle, le principal traitement est l’Imatinib, commercialisé sous le nom de Glivec®. Ce traitement conduit, chez certains patients, à l'émergence de souches résistantes, ce qui complique la thérapeutique et nécessite un large panel de molécules actives pour contourner les mécanismes de résistance. Par conséquent, la recherche de nouvelles molécules bioactives agissant sur de nouvelles cibles biologiques reste toujours un défi important et d’actualité. Au cours de ce projet de thèse, nous nous sommes intéressés au développement de nouveaux procédés de synthèse pour accéder et découvrir de nouvelles molécules bioactives, en série nucléosidique, pour contourner les mécanismes de résistances dans des modèles de LMC. Nous avons tout d’abord développé une nouvelle méthode de synthèse propre et efficace de nouveaux analogues de C-nucléosides en utilisant une catalyse par le fer. Nous avons ensuite réalisé plusieurs modifications post-synthétiques pour accéder à de nouveaux C-nucléosides hautement fonctionnalisés, en particulier les analogues de la thiophènefurine. Nous avons également développé un nouveau procédé de synthèse d’une famille de O-glycosides, en combinant l’activation par les ultrasons à la catalyse par le fer. Ce procédé a été exploité par la suite pour concevoir et synthétiser les analogues glycosidiques du résvératrol. Enfin, nous avons mis au point une méthode efficace et peu couteuse d’azidation de sucres protégés.Chronic myeloid leukemia (CML) is a malignant hematological disorder characterized by the formation, in the blood and bone marrow, of an excessive number of white blood cells, some of which are immature. Currently, the main treatment of CML is based on tyrosine-kinase inhibitors, such as Imatinib, the first approved drug of this class of compounds and marketed as Gleevec ®. However, this treatment results, in some patients, to the emergence of resistance, which complicates the treatment and requires a wide range of active molecules to circumvent resistance mechanisms. Therefore, the search for new bioactive molecules featuring new mode of action still remains a challenging.In this thesis project, we were interested in the design and discovery of new bioactive molecules in nucleoside series to circumvent resistance mechanisms in CML models, as well as in the development of new synthetic methods for the preparation of these targeted molecules. We first developed a clean and efficient procedure for the synthesis of new C- nucleoside analogues using iron catalysis. Then, several post-synthetic modifications were carried out, starting from halogenated nucleoside derivatives, to access highly functionalized C- nucleosides, as new analogues of thiophenefurin . We also developed a new procedure for the synthesis of O-glycosides using a cooperative effect of iron catalysis and ultrasound activation. This method has been applied for the synthesis of resveratrol O-glycosides. Finally, we developed an effecient and inexpensive method for anomeric sugar azidation. This method was applied for the synthesis of 1,2,3-triazolyl glycosides using a one-pot azidation-click procedure

N,S—Heterocyclic derived from L-methionine : synthesis of endocyclic sulfilimines and sulfoximines

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Synthesis of Heterospirocycles through Gold‐(I) Catalysis, Useful Building Blocks for Medicinal Chemistry

International audienceGold-(I) catalysis was used for the intramolecular cyclization of tertiary alcohols with terminal alkynes to form diverse aza-spirocycles. The reaction was carried out with low catalyst loading under microwave irradiation to give both sulfonylated and acylated spirocyclic nitrogen derivatives. Gram scale spirocyclization was carried out and demonstrates the robustness of the reaction. An intramolecular Mizoroki-Heck reaction was performed to give several tetracyclic spirocycles. Double bond reduction and selective protecting group manipulation gave spiropiperazine and spiromorpholine derivatives. These compounds were incorporated into biologically relevant scaffolds to give the first selective spirocyclic inhibitors of LIMK

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

International audienceThis review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. Green syntheses and solvent-free procedures have been introduced whenever possible. The syntheses discussed herein have been selected to illustrate the huge potential of microwave in the synthesis of highly functionalized molecules with potential therapeutic applications, in high yields, enhanced reaction rates and increased chemoselectivity, compared to conventional methods. More than 100 references from the recent literature are listed in this review

Mechanistic investigation of the NH-sulfoximination of sulfide. Evidence for λ 6 -sulfanenitrile intermediates

International audienceWe report a new procedure for the preparation of NH-sulfoximines from sulfides using PIDA as an oxidant and ammonium carbamate as the ammonia source. Excellent yields were obtained with a wide range of sulfides. The formation of acetoxy- and methoxy-λ6-sulfanenitrile as intermediates was proposed, both of which were converted to the NH-sulfoximine by the action of the solvent. The structure of these intermediates was confirmed by 1H, 13C and 15N NMR and HRMS analysis

Microwave-assisted synthesis of bioactive six-membered heterocycles and their fused analogues

International audienceThis review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, starting with heterocyclic systems containing one, two and three heteroatoms and their fused analogues. Recent microwave applications are reviewed, with special focus on the chemistry of bioactive compounds. Selected examples from the 2006 to 2015 literature are discussed