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Title: Development of New Multicomponent Processes based on Unexplored Chemistry of Isocyanides: Access to Heterocyclic Scaffolds and Applications
Author: Ghashghaei, Ouldouz
Director/Tutor: Lavilla Grífols, Rodolfo
Keywords: Química farmacèutica
Síntesi orgànica
Processos químics
Pharmaceutical chemistry
Organic synthesis
Chemical processes
Issue Date: 26-Sep-2017
Publisher: Universitat de Barcelona
Abstract: [eng] 1. It was observed that the interaction of imines and isocyanides in the presence of a Lewis acid can lead to a variety of scaffolds including α-aminoamides, α-aminoamidines, indoles and diiminoazetidines. The reaction conditions were optimized to yield the later as the main product. Screening the scope of amines, aldehydes and isocyanides led to a small library of azetidine adducts. Also, a few spiro-azetidine adducts were prepared using isatine ketimines. A unified mechanism was proposed to explain the structural diversity that the process offers. In case of the main azetidine adduct, the process goes through consecutive insertion of two isocyanides followed by a 4-exo-dig cyclization. The structural elucidation of the azetidine compounds confirms the unexpected syn nature of the formed imine bonds. 2. It was shown that N-insertion of isocyanides to N-substituted propargylamines in the presence of HCl yields 1,3,4,5-tetrasubstituted imidazoliums salts. As the propargylamines arise from A3 reactions, the scope of the process in terms of aldehydes, amines, alkynes, and isocyanides was studied. The described conditions do not apply for aliphatic amines as opposed to the Zhu reaction [1] who used a different activation method (dual metallic catalysis). However, mild reaction conditions allow the incorporation of tert-Bu isocyanide, avoiding undesired elimination, as in Zhu conditions. Furthermore, the A3 reaction was successfully combined with the new reaction to obtain the imidazolium salts in a one pot process. We also explored the properties of the MCR adducts: As a proof of concept, an adduct was used as an NHC ligand for to catalyze a standard Suzuki coupling. Interestingly, some of the obtained compounds displayed potent antiparasitic activity against Trypanosoma brucei and T. cruzi at nanomolar level. 3. A TMSCl- catalyzed Reissert type MCR was studied. The process features insertion of isocyanide to N-Si bond as the mechanistical key step. Computational and experimental methods were applied to study this novel interaction of isocyanides and N-Si bonds. The reaction yields aminoimidazolium salts from the incorporation of two isocyanide units into azines. The new activation mode offers significantly wider scope. Regioselective incorporation of two distinct isocyanides was successfully performed. Furthermore, some obtained adducts demonstrated potent antiparasitic properties against Trypanosoma Brucei and Cruzi. [1] S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2015, 54, 1293–1297. The paper of Zhu group was published when the project was in the course of manuscript writing. 4. The application of multiple Groebcke-Bienaymé-Blackburn reactions on di- and triaminoazines leads to the formation of a variety of new N-fused heterocyclic scaffolds (aminoimidazopyridines) with several diversity points. The selective reactivity mode of diaminopyrimidine provides controlled synthesis of non-symmetrical adducts. The scope of reaction was studied (analyzing the range of the aldehyde, isocyanide and aminoazine components) and post- modifications were applied to further diversify the rich structural outcome of the process. Adducts arising from melamine were structurally enlarged, exploiting cross-coupling reactions to achieve nanosized tripodal structures. The synthesized adducts displayed interesting pH and environment sensitive fluorescent properties. Interestingly, a novel borylated BODYPY-type adduct was successfully synthesized and used for staining lysosomes in mammal cells Moreover, some adducts demonstrated potent antiviral activity against Adenovirus. Furthermore, selected compounds they showed selective affinity to G-quadruplex DNA sequences, suggesting potential applications in medicinal and biological chemistry.
[spa] • La interacción de iminas e isocianuros en presencia de un ácido de Lewis puede conducir a una variedad de tipos estructurales incluyendo diiminoazetidinas. La selección del alcance de la reacción dio lugar a una pequeña biblioteca de aductos de azetidina. También, se prepararon unos pocos aductos de espiro-azetidina usando isatinas. Se propuso un mecanismo unificado para explicar la diversidad estructural que ofrece el proceso. • La inserción de isonitrilos en el enlace N-H de propargilaminas N-sustituidas en presencia de HCl proporcionó sales de imidazolio 1,3,4,5-tetrasustituidas. Como las propargilaminas proceden de reacciones de A3, se estudió el alcance del procedimiento en términos de aldehídos, aminas, alquinos e isocianuros. La reacción de A3 se combinó con la nueva reacción para obtener las sales de imidazolio en un proceso de una sola etapa. También se exploraron las propiedades de los aductos MCR: Como una prueba de concepto, un aducto se utilizó como un ligando NHC para catalizar un acoplamiento estándar de Suzuki. Algunos de los compuestos obtenidos mostraron una potente actividad antiparasitaria contra T. brucei y T. cruzi a nivel nanomolar. • Se estudió una MCR de tipo Reissert catalizada por TMSCl. El procedimiento presenta la inserción de isocianuro en enlace N-Si como paso clave. Se aplicaron métodos computacionales y experimentales para estudiar esta nueva interacción de isocianuros y enlaces N-Si. La reacción produce sales de aminoimidazolio a partir de la incorporación de dos isocianuros en azinas. El nuevo modo de activación ofrece un alcance mucho más amplio. Se realizó incorporación regioselectiva de dos isocianuros distintos. Algunos aductos demostraron potentes propiedades antiparasitarias contra Trypanosoma Brucei y Cruzi. • La aplicación de múltiples reacciones de GBB sobre poliaminoazinas dio lugar a la formación de nuevos tipos estructurales heterocíclicos N-fusionados con varios puntos de diversidad. El modo regioselectivo sobre diaminopirimidinas proporciona una síntesis controlada de aductos no simétricos. Se estudió el alcance de la reacción y se aplicaron modificaciones posteriores para diversificar aún más el resultado estructural del proceso. Los aductos de melamina se aumentaron de tamaño, explotando reacciones de acoplamiento cruzado para conseguir estructuras tridimensionales nanométricas. Los aductos sintetizados mostraron interesantes propiedades fluorescentes sensibles al pH y al medio ambiente. Se sintetizó un nuevo aducto de tipo BODYPY borilado y se usó para teñir lisosomas en células de mamífero. Además, algunos aductos demostraron una potente actividad antiviral contra Adenovirus humanos. Los compuestos seleccionados mostraron afinidad selectiva a las secuencias de ADN de G- quadruplex, lo que sugiere aplicaciones potenciales en química medicinal y biológica.
Appears in Collections:Tesis Doctorals - Departament - Farmacologia, Toxicologia i Química Terapèutica

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