Vers la synthèse totale de la (-)-norsuavéoline (synthèse d'oxindoles et dihydrophénanthridines par séquences réaction de Ugi / cyclisations intramoléculaires)

Le projet de thèse s'est articulé en plusieurs parties. Nous nous sommes dans un premier temps intéressés à la synthèse totale d'un alcaloïde, la (-)-norsuavéoline. Nous avons réussi, en quelques étapes, à préparer l'intermédiaire clé de la synthèse envisagée, à savoir un oxazole, à partir d'un acide aminé naturel, le (-)-tryptophane. Dans un deuxième temps nous avons développé des synthèses rapides d'hétérocycles facilement variables et très fonctionnalisés, via des séquences réaction de Ugi / cyclisation intramoléculaire (amidation intramoléculaire ou arylation directe). Nous avons pu mettre au point deux séquences complémentaires et chimiosélectives permettant d'obtenir, en deux étapes à partir de produits commerciaux ou facilement accessibles, des oxindoles ou des dihydrophénanthridines. Ces séquences sont d'une grande efficacité synthétique, elles sont convergentes et permettent une variation aisée des substituants en quatre points de la molécule. Enfin, nous avons mené une étude préliminaire pour aborder de manière originale la synthèse de la physostigmine, par une réaction radicalaire tandem cyclisation / piégeage du radical par un isonitrile / bêta-scission. Nous avons réalisé les premiers travaux, qui ont démontré la viabilité d'une telle approche.The project was divided in several parts. First we have focused on the total synthesis of an alcaloid, (-)-norsuaveoline. In a few steps, we have been able to synthesize one of the key-intermadiates of the synthesis, an oxazole prepared from natural (-)-tryptophane. In a second part we have developped rapid diversity-oriented access to highly-functionalized heterocycles, via Ugi reaction / intramolecular cyclizations (amidations or direct arylations) sequences. We have developped two complementary and chemoselective sequences for the synthesis of oxindoles and dihydrophenenthridines, from readily available reagents. These syntheses are of great synthetic efficiency, and enable easy 4-points variations on the molecule. In a last part, we have carried out preliminary studies to synthesize physostigmine with an original approach, based on tandem radicalar reaction: cyclization / trapping of the radical / beta-scission. The first results were promising and demonstrated that this reaction can afford the key-intermediate in the synthesis of physostigmine.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Rapid access to oxindoles by the combined use of an Ugi four-component reaction and a microwave-assisted intramolecular Buchwald-Hartwig amidation reaction

A two-step sequence involving an Ugi four-component reaction (Ugi-4CR) and a palladium-catalyzed intramol. amidation of aryl iodide has been developed for rapid access to functionalized oxindoles, e.g., I. Microwave heating was used to accelerate and to improve the efficiency of the intramol. Buchwald-Hartwig reaction. [on SciFinder (R)

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium-catalyzed intramolecular C-H functionalization

Background<p>Small polyfunctionalized heterocyclic compounds play important roles in the drug discovery process and in the isolation and structural identification of biological macromolecules. It is expected that ready access to diverse sets of heterocycles can not only help improving the known biological and pharmacokinetic properties of drugs, but also assist the discovery of molecules that exhibit biological effects beyond those associated with previously known macromolecules. By virtue of their inherent convergence, high productivity, their exploratory and complexity-generating power, multicomponent reactions (MCRs) are undoubtedly well suited for creating molecular diversity. The combination of MCRs with an efficient post-functionalization reaction has proven to be an efficient strategy to increase the skeleton diversity.</p><p>Results</p><p>The Ugi reaction of an o-iodobenzaldehyde (2), an aniline (3), an isocyanide (4), and a carboxylic acid (5) afforded α-acetamido-α-phenylacetamide (6) in good to excellent yields. The palladium-catalyzed intramolecular C-H functionalization of these adducts under ligandless conditions provided the functionalized dihydrophenanthridines (1).</p><p>Conclusion</p><p>Highly functionalized dihydrophenanthridines are synthesized in only two steps from readily accessible starting materials in good to excellent overall yields.</p