Formal [3+2] Cycloaddition Reactions of Electron-Rich Aryl Epoxides with Alkenes under Lewis Acid Catalysis Affording Tetrasubstituted Tetrahydrofurans

We report on the regio- and stereoselective synthesis of tetrahydrofurans by reaction between epoxides and alkenes in the presence of a Lewis acid. This is an unprecedented formal [3+2] cycloaddition reaction between an epoxide and an alkene. The chemical reaction represents a very concise synthesis of tetrahydrofurans from accessible starting compounds

Elucidating the Dual Mode of Action of Dipeptidyl Enoates in the Inhibition of Rhodesain Cysteine Proteases

A computational study of the two possible inhibition mechanisms of rhodesain cysteine protease by the dipeptidyl enoate Cbz-Phe-Leu-CH=CH−CO2C2H5 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The low free energy barriers confirm that the Cys25 residue can attack both Cβ and C1 atoms of the inhibitor, confirming a dual mode of action in the inhibition of the rhodesain by enoates. According to the results, the inhibition process through the Cys25 attack on the Cβ atom of the inhibitor is an exergonic and irreversible process, while the inhibition process when Cys25 attacks on the C1 atom of the inhibitor is and exergonic but reversible process. The interactions between the inhibitor and rhodesain suggest that P2 is the most important fragment to consider in the design of new efficient inhibitors of rhodesain. These results may be useful for the design of new inhibitors of rhodesain and other related cysteine proteases based on dipeptidyl enoates scaffolds.Funding for open access charge: CRUE-Universitat Jaume

Stereoisomerization of α-hydroxy-β-sulfenyl-α,β-dimethyl naphthoquinones controlled by nonbonded sulfur–oxygen interactions

The anti α-hydroxy-β-sulfenyl-α,β-dimethyl naphthoquinones isomerize in basic media into syn/anti mixtures of isomers, giving the syn isomer as the major product. Conversely, anti α-hydroxy-β-alkoxy-α,β-dimethyl naphthoquinones isomerize to furnish the anti isomer as the major product. The crystal structure of syn α-hydroxy-β-phenylsulfenyl-α,β-dimethyl naphthoquinone has been determined. The X-ray and experimental work demonstrated that an attractive 1,4 intramolecular interaction of divalent sulfur with hydroxyl oxygen is the driving force for the aforementioned stereochemical preference

Dramatic effect of the gas atmosphere on the deprotection of (Z)-γ -hydroxy- α , β-unsaturated esters

The deprotection of O-protected (Z)-α-methyl-γ-hydroxy-α,β-unsaturated ester 1 furnishes dimer 2 when the reaction is performed under a nitrogen atmosphere, while compound 3 forms when the reaction is performed under an oxygen atmospher

Fast methodology for the reliable determination of nonylphenol in water samples by minimal labeling isotope dilution mass spectrometry

In this work we have developed and validated an accurate and fast methodology for the determination of 4-nonylphenol (technical mixture) in complex matrix water samples by UHPLC–ESI-MS/MS. The procedure is based on isotope dilution mass spectrometry (IDMS) in combination with isotope pattern deconvolution (IPD), which provides the concentration of the analyte directly from the spiked sample without requiring any methodological calibration graph. To avoid any possible isotopic effect during the analytical procedure the in-house synthesized 13C1-4-(3,6-dimethyl-3-heptyl)phenol was used as labeled compound. This proposed surrogate was able to compensate the matrix effect even from wastewater samples. A SPE pre-concentration step together with exhaustive efforts to avoid contamination were included to reach the signal-to-noise ratio necessary to detect the endogenous concentrations present in environmental samples. Calculations were performed acquiring only three transitions, achieving limits of detection lower than 100 ng/g for all water matrix assayed. Recoveries within 83–108% and coefficients of variation ranging from 1.5% to 9% were obtained. On the contrary a considerable overestimation was obtained with the most usual classical calibration procedure using 4-n-nonylphenol as internal standard, demonstrating the suitability of the minimal labeling approach

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-7

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs

La eritrulosa como quirón de partida para la síntesis de productos naturales. Estudio de la reactividad del grupo carbonilo.

Se ha llevado a cabo un estudio sistemático de la estereoselectividad en las reacciones de adición de compuestos organometálicos a derivados de eritrulosa que poseían los grupos hidroxilo protegidos con grupos favorecedores de la quelación y grupos no-favorecedores en las diferentes posiciones, observándose una elevada selectividad cuando el hidroxilo de la posición alfa al carbonilo está protegido como bencil éter y el nucleófilo es un Grignard, este resultado se puede explicar mediante el modelo de quelación de Cram

Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes

In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz‐Phe‐Ala‐CH=CH‐NO2 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free‐energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β‐carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data. The origin of these differences may lie in the different stabilizing electrostatic interactions established between the inhibitor and the residues of the active site and S2 pocket of these enzymes. These results may be useful for the rational design of new dipeptidyl nitroalkenes with higher and more selective inhibitory activity against cysteine proteases

Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines

Nitroepoxides are easily transformed into benzodiazepines, tetrahydrobenzodiazepines, imidazopyridines, and N-alkyl tetrahydroquinoxalines by treatment with 2-aminobenzylamines, 2-aminopyridines, and N-alkyl 1,2-diaminobenzenes, respectively. Regioselectivity is controlled through attack of the most nucleophilic nitrogen of the unsymmetrical diamine to the β position of the epoxide. These reactions represent an efficient way to prepare privileged bioactive structures

Amidation through carbamates

N-Alkyl carbamates of primary amines are easily converted into amides under treatment with Grignard reagents. Consequently, primary amines can be converted into amides in a one-pot reaction through carbamate protection and Grignard addition. © 2009 Elsevier Ltd. All rights reserved