Proline and pyrrolidine derivatives: new drug cadidates for hepatitis C treatment

The more advantageous hepatitis C virus (HCV) inhibitors (most of them incorporating polysubstituted prolines or pyrrolidines) are detailed in this paper. The improvement of current treatments by combination of antiviral drugs is the driving force of this race to reduce the fast proliferation of this virus. The enhancement of efficiency in short periods of treatment is crucial in the economical point of view and for the hope of all infected people. New protease or polymerase inhibitors have been recently developed in order to substitute the traditional highly toxic PEG-interferon α-2b/ribavirin tandem. The contribution of our group in this field concerns the elaboration of the first and second generation GSK polymerase inhibitors through enantioselective processes based on silver(I)- and gold(I)-catalyzed 1,3-dipolar cycloadditions of azomethine ylides.

Multicomponent synthesis of unnatural pyrrolizidines using 1,3-dipolar cycloaddition of proline esters

The synthesis of unnatural pyrrolizidines has been studied using a multicomponent-domino process involving proline or 4-hydroxyproline esters, an aldehyde and a dipolarophile. The formation of the iminium salt promotes the 1,3-dipolar cycloaddition affording highly substituted pyrrolizidines under mild conditions and high regio- and diastereoselectivities.

Remote Substituent Effects on the Stereoselectivity and Organocatalytic Activity of Densely Substituted Unnatural Proline Esters in Aldol Reactions

The organocatalytic activities of highly substituted proline esters obtained through asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters have been analyzed by 19F NMR and through kinetic isotope effects. Kinetic rate constants have been determined for unnatural proline esters incorporating different substituents. It has been found that exo-L and endo-L unnatural proline methyl esters yield opposite enantiomers in aldol reactions between cyclic ketones and aromatic aldehydes. The combined results reported in this study show subtle and remote effects that determine the organocatalytic behavior of these synthetic but readily available amino acid derivatives. These data can be used as design criteria for the development of new pyrrolidine-based organocatalysts.

Enantioselective 1,3-dipolar cycloadditions of azlactones and electrophilic alkenes catalyzed by dimeric BinapAuTFA complexes

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as Δ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH3CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group.

Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes

Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.

Synthetic scope and DFT analysis of the chiral binap-gold (I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(Sa)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

Solvent-Free Enantioselective Organocatalyzed Aldol Reactions

The use of proline as catalyst for the aldol process has given a boost to the development of organocatalysis as a research area. Since then, a plethora of organocatalysts of diverse structures have been developed for this and other organic transformations under different reaction conditions. The use of an organic molecule as catalyst to promote a reaction meets several principles of Green Chemistry. The implementation of solvent-free methodologies to carry out the aldol reaction was soon envisaged. These solvent-free processes can be performed using conventional magnetic stirring or applying ball milling techniques and are even compatible with the use of supported organocatalysts as promoters, which allows the recovery and reuse of the organocatalysts. In addition, other advantages such as the reduction of the required amount of nucleophile and the acceleration of the reaction are accomplished by using solvent-free conditions leading to a “greener” and more sustainable process.

Silver-catalysed multicomponent 1,3-dipolar cycloaddition of 2-oxoaldehydes-derived azomethine ylides

The silver-catalysed multicomponent reaction between ethyl glyoxylate, 2,2-dimethoxyacetaldehyde, or phenylglyoxal as aldehyde components with a α-amino ester hydrochloride and a dipolarophile in the presence of triethylamine is described. This domino process takes place at room temperature by in situ liberation of the α-amino ester followed by the formation of the imino ester, which is the precursor of a metalloazomethine ylide. The cycloaddition of this species and the corresponding dipolarophile affords polysubstituted proline derivatives. Ethyl glyoxylate reacts with glycinate, alaninate, phenylalaninate and phenylglycinate at room temperature in the presence of representative dipolarophiles affording endo-2,5-cis-cycloadducts in good yields and high diastereoselection. In addition, 2,2-dimethoxyacetaldehyde is evaluated with the same amino esters and dipolarophiles, under the same mild conditions, generating the corresponding endo-2,5-cis-cycloadducts with higher diastereoselections than the obtained in the same reactions using ethyl glyoxylate. In the case of phenylglyoxal the corresponding 5-benzoyl-endo-2,5-cis cycloadducts are obtained in short reaction times and similar diasteroselection.

Regio and diastereoselective multicomponent 1,3-dipolar cycloadditions between prolinate hydrochlorides, aldehydes and dipolarophiles for the direct synthesis of pyrrolizidines

A general synthesis of highly substituted pyrrolizidines can be performed by a multicomponent 1,3-dipolar cycloaddition using proline ester hydrochlorides, aldehydes and dipolarophiles, at room temperature without catalysts or in the presence of AgOAc (5 mol %). In the case of (2S,4R)-4-hydroxyproline derivatives it is possible to obtain enantioenriched pyrrolizidines with high control of the regio- and diastereoselectivity affording the adducts 2,4-trans-2,5-trans according to an endo-approach and a S-dipole geometry of the in situ generated azomethine ylide. For proline esters a similar regioselectivity and endo-diastereoselectivity are observed when the dipole promotes an α-attack. However, when ethyl glyoxylate is used as aldehyde component the γ-attack of the S-ylide takes place preferentially giving rise the opposite regioselectivity for acrylic dipolarophiles, being crucial the role of silver acetate. In this case, the exo-adducts with a 2,3-cis-2,5-trans relative configuration are diastereoselectively obtained. In addition, computational studies have also been carried out to shed light on the origins of the diastereo- and regioselectivity observed for the described 1,3-dipolar cycloadditions.

Bio-renewable enantioselective aldol reaction in natural deep eutectic solvents

Among the deep eutectic solvents (DES), natural deep eutectic solvents (NADES) formed by D-glucose and racemic malic acid are suitable media to perform the enantioselective L-proline catalyzed intermolecular aldol reaction, creating simultaneously and selectively a C–C bond and a new stereocenter. The scope of the reaction was found to be broad, with products being obtained with good levels of diastereo- and enantioselectivities. Furthermore, when the reaction was performed at a large scale, the catalyst together with the reaction media can be recovered by simple water extraction and reused at least three times affording similar results. Therefore, the use of NADES as reaction media to carry out a VOC-free selective process has been demonstrated for the first time. The process is clean, cheap, simple and scalable and meets most of the criteria to be considered as a sustainable and bio-renewable process, with the reaction media and catalyst arising directly from Nature.

New insights into plant salt acclimation: the roles of vesicle trafficking and reactive oxygen species signalling in mitochondria and the endomembrane system

In this study, we investigated the cellular and molecular mechanisms that regulate salt acclimation. The main objective was to obtain new insights into the molecular mechanisms that control salt acclimation. Therefore, we carried out a multidisciplinary study using proteomic, transcriptomic, subcellular and physiological techniques. We obtained a Nicotiana tabacum BY-2 cell line acclimated to be grown at 258 mM NaCl as a model for this study. The proteomic and transcriptomic data indicate that the molecular response to stress (chaperones, defence proteins, etc.) is highly induced in these salt-acclimated cells. The subcellular results show that salt induces sodium compartmentalization in the cell vacuoles and seems to be mediated by vesicle trafficking in tobacco salt-acclimated cells. Our results demonstrate that abscisic acid (ABA) and proline metabolism are crucial in the cellular signalling of salt acclimation, probably regulating reactive oxygen species (ROS) production in the mitochondria. ROS may act as a retrograde signal, regulating the cell response. The network of endoplasmic reticulum and Golgi apparatus is highly altered in salt-acclimated cells. The molecular and subcellular analysis suggests that the unfolded protein response is induced in salt-acclimated cells. Finally, we propose that this mechanism may mediate cell death in salt-acclimated cells.