Les réactions multicomposant à base d'isonitrile (I-MCR) combinées à des transformations de post-condensation constituent des outils de synthèse extrêmement puissants pour la préparation de structures moléculaires complexes et diverses avec de nouvelles propriétés pharmacologiques.Dans un premier temps, nous nous sommes intéressés à l'extension du couplage de Ugi-Smiles aux dérivés de purines, en utilisant la 6-mercaptopurine comme partenaire de couplage. Cette méthodologie permet un accès direct et rapide aux dérivés d'adénine avec des rendements modérés à bons à partir de précurseurs simples et facilement accessibles.Par la suite, nous avons démontré que les produits d'addition Ugi dérivés d'aldéhydes aromatiques peuvent être convertis en 2-pyrrolines par addition d'accepteurs de Michael, sous irradiation par micro-ondes. La réaction peut se dérouler via la formation inhabituelle d’ylures azométhines suivie d'une cycloaddition [3 + 2] avec des accepteurs de Michael.Enfin, nous avons montré que les adduits Passerini issus de cinnamaldéhyde peuvent être efficacement convertis en α-cétoamides lorsqu'ils sont traités en milieu basique et dans des conditions de chauffage sous irradiations micro-ondes. / The isocyanide based multicomponent reactions (I-MCRs) with subsequent post-condensation transformations constitute extremely powerful synthetic tools for the preparation of structurally diverse complex molecules with novel properties.In this context, we first investigated the extension of Ugi-Smiles coupling to purines, by using 6-mercaptopurine as coupling partner. This methodology allows direct access to adenine derivatives in moderate to good yields starting from readily available precursors.Then, we demonstrated that Ugi adducts derived from aromatic aldehydes may be converted to pyrrolines via addition of Michael acceptors under microwave irradiation. The reaction may proceed via unusual formation of azomethine ylides followed by a [3+2] cycloaddition using Michael acceptors.Finally, we described that the Passerini adducts of cinnamaldehyde and analogues may be efficiently converted into α-ketoamides when heated with a base under microwave conditions.

Les réactions de type Ugi sont connues depuis une cinquantaine d’années. Ces réactions multicomposants mettent en jeu un aldéhyde, une amine, un isonitrile ainsi qu’un dérivé acide (acide carboxylique ou phénol activé). Dans ces travaux, la structure électronique des isonitriles, composé au coeur de ces réactions a été étudiée. La forme carbénique RN=C s’est révélée majoritaire contrairement à toute attente. La linéarité de la molécule a pu être interprétée grâce aux contributions des formes minoritaires. La seconde partie s’est focalisée sur l’étude théorique et expérimentale des couplages de type Ugi. Contrairement à la réaction de Ugi-Smiles, le réarrangement final de la réaction de Ugi, un réarrangement de Mumm, s’est révélé non cinétiquement déterminant. L’importance du rôle de l’environnement a été étudiée par le biais d’une microsolvatation. La compréhension accrue de la réaction de Ugi-Smiles a fait émerger deux nouveaux partenaires acides : les trichlorophenols et les nitrosophenols. Les premiers ont permis d’isoler pour la première fois desaryl-imidates de phénol. Les seconds ont été utilisés pour développer une nouvelle voie de synthèse debenzimidazoles à partir des adduits de Ugi-Smiles correspondants. Enfin, les adduits de type Ugi ont été mis à profit pour développer une nouvelle réaction palladocatalysée d’ouverture d’aminocyclopropanes. Cette ouverture conduit à l’accès rapide de produits hétérocycliques dont des tétracycles complexes suite à une réaction tandem impliquant un couplagede Heck. / Ugi type reactions are well known for decades. These multicomponent reactions involve an aldehyde,an amine, an isocyanide and an acid compound (carboxylic acid or activated phenol). Herein, electronicstructure of isocyanides, as key compounds of these reactions, was studied. Surprisingly, thecarbenic form RN=C was found to be the major one. Contribution of minor mesomeric structureexplains the linearity of the molecule. Then, Ugi and Ugi-Smiles couplings were studied theoreticallyand experimentally. Contrary to the Ugi-Smiles reaction, the final rearrangement of the Ugi coupling,a Mumm one, was not found to be a rate determining step. Importance of microsolvation was investigated.The comprehension of the mechanism of Ugi-Smiles reaction prompted us to investigatetheoretically new acidic partners. Trichlorophenols permitted to isolate the aryl-imidate for the firsttime with a phenol. Nitrosophenols were also considered. Confirmed experimentally, these new adductswere used to propose a new synthesis of benzimidazole. Finally, Ugi type adducts have been used todevelop a new palladium-catalyzed ring-opening of aminocyclopropanes. Rapid access to heterocycliccompounds, such as complex tetracycle with a tandem Heck coupling, can be obtained by this strategy.

<p> </p> <p>Infectious diseases caused by bacteria, fungi, and plasmodium parasites are a huge global health problem which ultimately leads to millions of deaths annually. The emergence of strains that exhibit resistance to nearly every class of antimicrobial agents, and the inability to keep up with these resistance trends has brought to the fore the need for new therapeutic agents (antibacterial, antifungal, and antimalarial) with novel scaffolds and functionalities capable of targeting microbial resistance. A novel class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically relevant strains of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Synthesis, structure-activity relationship (SAR) studies, and biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory activity as low as 1 – 2 µM. The most potent compounds have also been shown to have low toxicity against mammalian cells and exhibit <i>in vivo</i> efficacy in MRSA skin and thigh infection mouse models.</p> <p>The novel aryl isonitriles have also been evaluated for antifungal activity. This study examines the SAR of aryl isonitrile compounds and showed the isonitriles as compounds that exhibit broad spectrum antifungal activity against species of <i>Candida</i> and <i>Cryptococcus</i>. The most potent derivatives are capable of inhibiting growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit excellent safety profile and are non-toxic to mammalian cells up to 256 µM.</p> <p>Beyond the antibacterial and antifungal activities, structure-antimalarial relationship analysis of over 40 novel aryl isonitrile compounds has established the importance of the isonitrile functionality as an important moiety for antimalarial activity. Of the many isonitrile compounds exhibiting potent antimalarial activity, two have emerged as leads with activity comparable to that of Artemisinin. The SAR details presented in this study will prove essential for the development new aryl isonitrile analogues to advance them to the next step in the antimalarial drug discovery process.</p> <p>17-nor-Excelsinidine, a zwitterion monoterpene indole alkaloid isolated from <i>Alstonia scholaris</i> is a subject of synthetic scrutiny. This is primarily due to its intriguing chemical structure which includes a bridged bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein we describe a six-step total synthesis of (±)-17-nor-Excelsinidine from tryptamine. Key to the success of this synthesis is the use of palladium-catalyzed carbonylative heck lactamization methodology which built the 6, 7-membered ring lactam in one step. The resulting pentacyclic product, beyond facilitating the easy access to (±)-17-nor-Excelsinidine, could also serve as a precursor to other related indole alkaloids.</p> <br> <p> </p> <p></p>