Search Results (9)

Selenoxide syn elimination is a widely used method for the synthesis of alkenes because it proceeds under exceptionally mild conditions, typically with excellent regio- and stereoselectivity. Surprisingly, hetero-selenoxide eliminations, where one or both olefinic carbon atoms are replaced with heteroatoms, have been little investigated, and their selenonyl counterparts even less so. A variety of such reactions, where the heteroatoms included combinations of O, N and S, as well as C, were investigated computationally. Selenoxides typically have lower activation energies and are slightly endothermic, while the corresponding selenones display higher activation energies and are exothermic in the gas state. The results are consistent with concerted, five-centre processes, leading to the formation of dioxygen, aldehydes, diazenes and imines from seleninyl or selenonyl peroxides, esters, hydrazines and amines, respectively. The more acidic selenenyl hydrodisulfide analogue undergoes proton transfer to the basic selenoxide oxygen atom instead of concerted elimination, resulting in the formation of a zwitterion. However, the formation of the corresponding selenonyl zwitterion is disfavoured compared to concerted syn elimination. The effects of solvents were also computed along with changes in enthalpy, entropy and free energy. Solvent effects were variable, while free energy calculations indicated overall ΔG values ranging between 3.60 and −32.12 kcal mol⁻¹ for the syn eliminations of methyl methanethioseleninate and methaneperoxyselenonic acid, respectively. These computations suggest that the olefin-forming selenoxide syn elimination may be more general than currently understood and that replacement of the two carbon atoms with heteroatoms can lead to viable processes. Full article

Selenocysteine selenenic acids (Sec–SeOHs) and selenocysteine selenenyl iodides (Sec–SeIs) have long been recognized as crucial intermediates in the catalytic cycle of glutathione peroxidase (GPx) and iodothyronine deiodinase (Dio), respectively. However, the observation of these reactive species remained elusive until our recent study, where we successfully stabilized Sec–SeOHs and Sec–SeIs using a protective molecular cradle. Here, we report the first demonstration of the chemical transformation from a Sec–SeI to a Sec–SeOH through alkaline hydrolysis. A stable Sec–SeI derived from a selenocysteine methyl ester was synthesized using the protective cradle, and its structure was determined by crystallographic analysis. The alkaline hydrolysis of the Sec–SeI at −50 °C yielded the corresponding Sec–SeOH in an 89% NMR yield, the formation of which was further confirmed by its reaction with dimedone. The facile and nearly quantitative conversion of the Sec–SeI to the Sec–SeOH not only validates the potential involvement of this process in the catalytic mechanism of Dio, but also highlights its utility as a method for producing a Sec–SeOH. Full article

The antioxidant drug ebselen has been widely studied in both laboratories and in clinical trials. The catalytic mechanism by which it destroys hydrogen peroxide via reduction with glutathione or other thiols is complex and has been the subject of considerable debate. During reinvestigations of several key steps, we found that the seleninamide that comprises the first oxidation product of ebselen underwent facile reversible methanolysis to an unstable seleninate ester and two dimeric products. In its reaction with benzyl alcohol, the seleninamide produced a benzyl ester that reacted readily by selenoxide elimination, with formation of benzaldehyde. Oxidation of ebselen seleninic acid did not afford a selenonium seleninate salt as previously observed with benzene seleninic acid, but instead generated a mixture of the seleninic and selenonic acids. Thiolysis of ebselen with benzyl thiol was faster than oxidation by ca. an order of magnitude and produced a stable selenenyl sulfide. When glutathione was employed, the product rapidly disproportionated to glutathione disulfide and ebselen diselenide. Oxidation of the S-benzyl selenenyl sulfide, or thiolysis of the seleninamide with benzyl thiol, afforded a transient thiolseleninate that also readily underwent selenoxide elimination. The S-benzyl derivative disproportionated readily when catalyzed by the simultaneous presence of both the thiol and triethylamine. The phenylthio analogue disproportionated when exposed to ambient or UV (360 nm) light by a proposed radical mechanism. These observations provide additional insight into several reactions and intermediates related to ebselen. Full article

A number of highly efficient methods for the preparation of novel derivatives of 9-selenabicyclo[3.3.1]nonane in high yields based on selenium dibromide and cis,cis-1,5-cyclooctadiene are reported. The one-pot syntheses of 2,6-diorganyloxy-9-selenabicyclo[3.3.1]nonanes using various O-nucleophiles including alkanols, phenols, benzyl, allyl, and propargyl alcohols were developed. New 2,6-bis(1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonanes were obtained by the copper-catalyzed 1,3-dipolar cycloaddition of 2,6-diazido-9-selenabicyclo[3.3.1]nonane with unsubstituted gaseous acetylene and propargyl alcohol. The synthesis of 2,6-bis(vinylsulfanyl)-9-selenabicyclo[3.3.1]nonane, based on the generation of corresponding dithiolate anion from bis[amino(iminio)methylsulfanyl]-9-selenabicyclo[3.3.1]nonane dibromide, followed by the nucleophilic addition of the dithiolate anion to unsubstituted acetylene, was developed. The glutathione peroxidase-like activity of the obtained water-soluble products was estimated and compounds with high activity were found. Overall, 2,6-Diazido-9-selenabicyclo[3.3.1]nonane exhibits the highest activity among the obtained compounds. Full article

Among the different green oxidative protocols, I₂-catalyzed/DMSO systems have recently received considerable attention due to being greener, efficient, atom-economical, low-cost, and offering the possibility to perform reactions under safe and mild conditions. Of particular interest is their application in the chalcogen–chalcogen bond activation that allows for the in situ formation of electrophilic species, promoting the formation of a number of Se-C bonds. Iodine acts as a catalytic oxidant in these reactions and is continuously regenerated by the DMSO, which can be used in stoichiometric amounts under solvent-free conditions. Methoxyselenylation reactions can be performed at room temperature; however, the reaction takes over 24 h to reach appreciable conversion yields. In this paper, activation by the use of a SynLED Parallel Photoreactor^® is investigated as an alternative energy source, and the results are critically compared with those previously reported in literature. Full article

The three isoenzymes of iodothyronine deiodinases (DIO1-3) are membrane-anchored homo-dimeric selenoproteins which share the thioredoxin-fold structure. Several questions regarding their catalytic mechanisms still remain open. Here, we addressed the roles of several cysteines which are conserved among deiodinase isoenzymes and asked whether they may contribute to dimerization and reduction of the oxidized enzyme with physiological reductants. We also asked whether amino acids previously identified in DIO3 play the same role in DIO1. Human DIO1 and 2 were recombinantly expressed in insect cells with selenocysteine replaced with cysteine (DIO1^U126C) or in COS7 cells as selenoprotein. Enzyme activities were studied by radioactive deiodination assays with physiological reducing agents and recombinant proteins were characterized by mass spectrometry. Mutation of Cys124 in DIO1 prevented reduction by glutathione, while 20 mM dithiothreitol still regenerated the enzyme. Protein thiol reductants, thioredoxin and glutaredoxin, did not reduce DIO1^U126C. Mass spectrometry demonstrated the formation of an intracellular disulfide between the side-chains of Cys124 and Cys(Sec)126. We conclude that the proximal Cys124 forms a selenenyl-sulfide with the catalytic Sec126 during catalysis, which is the substrate of the physiological reductant glutathione. Mutagenesis studies support the idea of a proton-relay pathway from solvent to substrate that is shared between DIO1 and DIO3. Full article

A primary-alkyl-substituted selenenyl iodide was successfully synthesized through oxidative iodination of a selenol with N-iodosuccinimide by taking advantage of a cavity-shaped steric protection group. The selenenyl iodide exhibited high thermal stability and remained unchanged upon heating at 100 °C for 3 h in [D₈]toluene. The selenenyl iodide was reduced to the corresponding selenol by treatment with dithiothreitol. Hydrolysis of the selenenyl iodide under alkaline conditions afforded the corresponding selenenic acid almost quantitatively, corroborating the chemical validity of the recent proposal that hydrolysis of a selenenyl iodide to a selenenic acid is potentially involved in the catalytic mechanism of an iodothyronine deiodinase. Full article

Density functional theory (DFT) models including explicit water molecules have been used to model the redox scavenging mechanism of aromatic cyclic seleninates. Experimental studies have shown that methoxy substitutions affect the rate of scavenging of reactive oxygen species differently depending upon the position. Activities are enhanced in the para position, unaffected in the meta, and decreased in the ortho. DFT calculations show that the activation barrier for the oxidation of the selenenyl sulfide, a proposed key intermediate, is higher for the ortho methoxy derivative than for other positions, consistent with the low experimental conversion rate. Full article

A method to synthesize 2-phenylselenenyl-1,3-anti-diols and 2-phenyl- selenenyl-1,3-anti-azidoalcohols via hydroxy- or azido-selenenylation of trans-allylic alcohols is reported. Moreover, the first example of hydroxyl-selenenylation of an allylic azide is presented. Yields ranging from moderate to good and diastereomeric ratios up to 95:5 are achieved. Full article