Danielle L. J. Pinheiro

Chemoselective Reduction of Azlactones Using Schwartz’s Reagent

Highly chemoselective addition of Schwartzs reagent to widely available azlactones is described. This method allows the preparation of challenged functionalized α-amino aldehydes, in good to high isolated yields at room temperature, after only 2 min reaction. The presence of sensitive functionalities or electronic factors does not compromise the potential of the method. The use of an excess of the reducing reagent gave a very functionalized allylic alcohol derivative in 86% yield.

Biological activity of the azlactone derivative EPA-35 against Trypanosoma cruzi

Abstract Chagas disease, caused by Trypanosoma cruzi, affects six to seven million people worldwide. Treatment is based on benznidazole, producing several side effects and debatable efficacy, highlighting the need for new alternative drugs. We investigated the activity of four C‐4 functionalized azlactone derivatives (EPA‐27, EPA‐35, EPA‐63 and EPA‐91) as potential T. cruzi inhibitors. Screening with epimastigotes indicated EPA‐35 as the best compound (IC50/24 h: 33 &mgr;M). This compound was 14.1 times more potent against intracellular amastigotes (IC50/24 h: 2.34 &mgr;M). Treatment of infected Vero cells for 72 h (up to 30 &mgr;M EPA‐35) resulted in a dose‐dependent decrease in number of trypomastigotes and amastigotes released in the supernatant, but the amastigote/trypomastigote ratio remained constant, indicating that amastigote growth was disturbed, but cell differentiation was unaffected. Analysis of treated epimastigotes by flow cytometry indicated that the plasma membrane remained intact, but there was a significant decrease in mitochondrial membrane potential. The pattern of cell distribution in the cell cycle stages (G1, G2, M) was unaltered in treated epimastigotes, indicating a trypanocidal rather than a trypanostatic activity. Scanning electron microscopy and flow cytometry showed epimastigotes with a round shape and decrease in cell size. Taken together, our data indicate that the EPA‐35 is effective against T. cruzi. Synthetic transformation of EPA‐35 into other derivatives may provide promising compounds for further evaluation against this parasite.

Old Drawback on Azlactone Formation Revealed by a Combination of Theoretical and Experimental Studies

New insights into the formation of azlactone heterocycles bearing different substituents are hereby presented. The sum of both kinetic and thermodynamic factors contributes for the formation of 2-alkyl or 2-aryl substituted azlactones, while the cyclization of 2-alcoxy azlactones is less favored. These results are in perfect accordance with experimental observations obtained by infrared (IR) and electrospray ionization mass spectrometry (ESI(+)-MS) of the crude reaction mixture.

Combined Role of the Asymmetric Counteranion-Directed Catalysis (ACDC) and Ionic Liquid Effect for the Enantioselective Biginelli Multicomponent Reaction

This work describes new chiral task-specific ionic liquids bearing chiral anions as the catalysts for the enantioselective multicomponent Biginelli reaction. For the first time, the combined role of asymmetric counteranion-directed catalysis (ACDC) and ionic liquid effect (ILE) for the chiral induction in the Biginelli multicomponent reaction is demonstrated. The chiral induction arises from a supramolecular aggregate where the anion and the cation of the catalyst are alongside with a key cationic intermediate of the reaction. Each component of the new catalyst had a vital role for the chiral induction success. The mechanism of an asymmetric version of this multicomponent reaction is in addition demonstrated for the first time using electrospray (tandem) mass spectrometry, ESI-MS(/MS). The analyses indicated the reaction takes place preferentially and exclusively through the iminium mechanism. Unprecedented supramolecular aggregates were detected by ESI-MS and characterized by ESI-MS/MS. No intermediate of the other two possible reactions pathways could be detected. Theoretical calculations shed light on the transition state of the transformation during the key step of the chiral induction and helped to elucidate the roles of the chiral anion (ACDC contribution) and of the imidazolium-containing nonchiral cation derivative (ILE contribution) in the molecular reaction process.

A Brønsted base-promoted diastereoselective dimerization of azlactones

A novel Brønsted base system for the diastereoselective dimerization of azlactones using trichloroacetate salts and acetonitrile has been developed. Desired products were obtained in good yields (60–93%) and with up to >19:1 dr after one hour of reaction. Additionally, the relative stereochemistry of the major dimer was assigned as being trans, by X-ray crystallographic analysis. The kinetic reaction profile was determined by using 1H NMR reaction monitoring and revealed a second order overall kinetic profile. Furthermore, by employing this methodology, a diastereoselective total synthesis of a functionalized analogue of streptopyrrolidine was accomplished in 65% overall yield.