Aromatic Ring Strain in Arylselenenyl Bromides: Role in Facile Synthesis of Selenenate Esters via Intramolecular Cyclization

The synthesis and reactivity of 2,6‐disubstituted arylselenium compounds derived from 2‐bromo‐5‐tert‐butylisophthalic acid ( 43 ) are described. The syntheses of bis(5‐tert‐butylisophthalic acid dimethyl ester)diselenide ( 46 ) and bis(5‐tert‐butylisophthalic acid diisopropyl ester)diselenide ( 47 ) have been achieved by the reaction of the corresponding ester precursors with disodium diselenide. Reduction of diselenide 46 with lithium aluminum hydride affords 2,2′‐bis(5‐tert‐butylbenzene‐1,3‐dimethanol)diselenide ( 53 ). Diselenides 46 and 47 exhibit intramolecular Se???O interaction. Compound 53 does not show any intramolecular Se???O interaction. The anomalous Se???O nonbonded coordination observed in the single‐crystal X‐ray structures of compounds 46 , 47 and 53 is compared and contrasted. The corresponding selenenyl bromides 54 and 55 , derived from the reaction of diselenides 46 and 47 with bromine, are quite stable in the solid state. However, they undergo hydrolysis and subsequent intramolecular cyclization upon heating or after having been kept in solution over a period of time to give the corresponding selenenate esters 56 and 57 . The X‐ray crystallographic study and density functional theory calculations on 54 at the B3LYP/6‐31G(d) level of theory indicate a significant distortion in planarity of the aromatic ring. Glutathione peroxidase‐like activities of diselenides 46 and 47 and their selenenate esters 56 and 57 have been studied both by thiophenol and bioassay methods. The very low glutathione peroxidase‐like activity of the diselenides ( 46 and 47 ) and their selenenate esters ( 56 and 57 ) in the thiophenol assay is attributed to the presence of the relatively strong Se???O intramolecular interaction in the selenenyl sulfide intermediates. The interaction retards the catalytic activity through both thiol exchange and an intramolecular cyclization reaction.     

Polycondensed heterocycles. I. Synthesis of 11-oxo-5H, 11H-pyrrolo[2,1-c][1,4]benzothiazepine,Derivative of a novel ring system

The synthesis of the title compound 4 by cyclization of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 9 , prepared by treating with ethyl chloroformate the 1-(2-mercaptobenzyl)pyrrole 7 previously obtained by debenzylation of 1-(2-benzylthiobenzyl)pyrrrole 6 , failed. On the other hand 4 was successfully synthesized by intramolecular cyclization of 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 15 by DMAP -catalyzed DCC method. The pyrrole 6 and 1-(2-benzylthiobenzyl)pyrrole-2-carboxaldehyde 11 were useful as starting materials to obtain 1-(2-benzylthiobenzyl)pyrrole-2-carbonitrile 13 , which was hydrolyzed to corresponding amide 16 . Debenzylation of 16 afforded 1-(2-mercaptobenzyl)pyrrole-2-carboxyamide 17 , whose hydrolysis led to required acid 15 .     

Simple and catalyst-free method for the synthesis of diaryl selenides by reactions of arylselenols and arenediazonium salts

We describe here a simple and catalyst-free method to synthesize diaryl selenides by reaction of arenediazonium tetrafluoroborate salts with arylselenols, generated in situ by using diaryl diselenides and hypophosphorous acid (H₃PO₂), using THF as solvent. This is a direct nucleophilic aromatic substitution (SNAr) reaction performed with diaryl diselenides and arenediazonium salts bearing electron-withdrawing and electron-donating groups affording the corresponding diaryl selenides in moderated to good yields.     

Glutathione peroxidase-like antioxidant activity of diaryl diselenides: a mechanistic study.

The synthesis, structure, and thiol peroxidase-like antioxidant activities of several diaryl diselenides having intramolecularly coordinating amino groups are described. The diselenides derived from enantiomerically pure R-(+)- and S-(-)-N,N-dimethyl(1-ferrocenylethyl)amine show excellent peroxidase activity. To investigate the mechanistic role of various organoselenium intermediates, a detailed in situ characterization of the intermediates has been carried out by (77)Se NMR spectroscopy. While most of the diselenides exert their peroxidase activity via selenol, selenenic acid, and selenenyl sulfide intermediates, the differences in the relative activities of the diselenides are due to the varying degree of intramolecular Se.N interaction. The diselenides having strong Se.N interactions are found to be inactive due to the ability of their selenenyl sulfide derivatives to enhance the reverse GPx cycle (RSeSR + H(2)O(2) = RSeOH). In these cases, the nucleophilic attack of thiol takes place preferentially at selenium rather than sulfur and this reduces the formation of selenol by terminating the forward reaction. On the other hand, the diselenides having weak Se.N interactions are found to be more active due to the fast reaction of the selenenyl sulfide derivatives with thiol to produce diphenyl disulfide and the expected selenol (RSeSR + PhSH = PhSSPh + RSeH). The unsubstituted diaryl diselenides are found to be less active due to the slow reactions of these diselenides with thiol and hydrogen peroxide and also due to the instability of the intermediates. The catalytic cycles of 18 and 19 strongly resemble the mechanism by which the natural enzyme, glutathione peroxidase, catalyzes the reduction of hydroperoxides.     

Synthesis and antioxidant activity of peptide-based ebselen analogues

A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.     

Efficient Synthesis of Conformationally Restricted Apoptosis Inhibitors Bearing a Triazole Moiety

Apoptosis is a biological process relevant to different human diseases that is regulated through protein–protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis/trans conformers of an exocyclic tertiary amide bond in slow exchange has been characterized. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3‐triazole moiety, in which different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogues have been carried out through an Ugi multicomponent reaction followed by an intramolecular cyclization. The unexpected formation of a β‐lactam scaffold prompted us to study the course of the intramolecular cyclization of the Ugi adducts. In order to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated.     

The use of aminoiminomethanesulfinic acid (thiourea dioxide) under phase transfer conditions for generating organochalcogenate anions. Synthesis of sulfides,selenides and tellurides

A procedure is described which allows for the in situ synthesis of arylalkyl, diaryl and dialkylchalcogenides under phase transfer conditions starting from the corresponding diorganodichalcognides. The dichalcogenides are reduced by aminoiminomethanesulfinic acid (thiourea dioxide) in alkaline medium and catalyzed by a quaternary ammonium salt. The reduction proceeds easily for diaryl disulfides and diaryl diselenides at a sodium hydroxide concentration of 13%; diaryl ditellurides require a 50% sodium hydroxide solution to give the aryl tellurolate anion. The dialkyl diselenides and dialkyl ditellurides are more difficult to reduce. The intermediate arylthiolates and arylselenolates are quenched by alkyl and activated aryl halides to give the corresponding sulfides and selenides in high yield (77–97%). The aryltellurolates react with alkyl halides giving the aryl alkyl tellurides in 81–96% yield. The procedure could not be successfully used for the synthesis of dialkylselenides and dialkyl tellurides; low yields and mixture of products were formed.     

Damage of aromatic amino acids by the atmospheric free radical oxidant NO3˙ in the presence of NO2˙, N2O4, O3 and O2

Analysis of the products formed in the reaction of NO(3)˙ with the N- and C-protected aromatic amino acids 1-5, which was performed under conditions that simulate exposure of biosurfaces to environmental pollutants, revealed insight how this important atmospheric free-radical oxidant can cause irreversible damage. In general, NO(3)˙ induced electron transfer at the aromatic ring is the exclusive initial pathway in a multi-step sequence, which ultimately leads to nitroaromatic compounds. In the reaction of NO(3)˙ with tryptophan 5 tricyclic products 12 and 13 are formed through an intramolecular, oxidative cyclization involving the amide moiety. In addition to this, strong indication for formation of N-nitrosamides was obtained, which likely result from reaction with N(2)O(4) through an independent non-radical pathway.     

Synthesis and biological evaluation of leucine enkephalin turn mimetics

A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1-4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a beta-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to micro- and delta-opioid receptors in rat brain membranes. With the exception of the beta-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the micro- and delta-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1-4) beta-turn.     

Aspects of organochalcogen (S, Se, Te) compounds stabilized by intramolecular coordination

The application of intramolecular coordination in the isolation of novel diaryl diselenides and their derivatives, monomeric chalcogenolato complexes of group 12 metals, glutathione peroxidase mimics, hybrid bi-, tri- and multidentate ligands and selenium-containing azamacrocycles is described.     

Novel 1,3,4-thiadiazole conjugates derived from protocatechuic acid: Synthesis,antioxidant activity,and computational and electrochemical studies

A series of 15 novel 1,3,4-thiadiazole amide derivatives containing a protocatechuic acid moiety were synthesized and structurally characterized. In addition, the corresponding imino (4) and amino (5) analogues of a phenyl-substituted 1,3,4-thiadiazole amide derivative 3a were prepared to compare the effects of the structural changes on the radical-scavenging activity. The obtained compounds were examined for their antioxidative potential by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. In addition, selected compounds were studied by density functional theory (DFT) and cyclic voltammetry experiments. The tested compounds showed high potential to scavenging DPPH radical and ABTS radical cation compared with the referent antioxidants ascorbic acid and nordihydroguaiaretic acid (NDGA). On the basis of the calculated thermodynamic parameters, it can be concluded that the sequential proton loss electron transfer (SPLET) mechanism represents the most probable reaction path in a polar solvent for DPPH radical–scavenging activity. On the other hand, the single electron transfer followed by proton transfer (SET-PT) can be a likely mechanistic pathway in the case of an ABTS radical cation.     

Reaction of anthranilic acid amides with cyclic anhydrides

Anthranilic acid amide reacts with cyclic anhydrides to give the corresponding N-acyl derivatives at the amino group, while analogous reactions of o-aminobenzohydroxamic acid lead lead to formation of 3-hydroxy-quinazolin-4-ones under mild conditions. N-Acyl derivatives of anthranilic acid amide undergo intramolecular cyclization to imides on microwave irradiation or on melting, and their treatment with acetic anhydride in the presence of sodium acetate on heating yields quinazolin-4-ones.     

A short route to enantiomerically pure benzophenanthridinone skeleton: synthesis of lactone analogues of narciclasine and lycoricidine

Condensation of functionalized o-toluamide anions on a carbohydrate-derived lactone, followed by intramolecular aldol cyclization, provides enantiomerically pure 2-arylcyclohexenones. Different approaches for the stereoselective transformation of the carbonyl group of these key intermediates into an amino group were unsuccessful. However 1,4-addition of thiolate and concomitant ring closure to isocoumarine provided a useful method for the transformation of the tertiary amide function. Opening of the isocoumarin with ammonia provided the corresponding amide and recovery of the enone system. Subsequent reductive amination of this cyclohexenone was found to depend on the nature of the protecting groups and led to the protected form of 4-epi- and -iso-narciclasine. Oxo analogues of narciclasine and epi-narciclasine and lycoricidine were also obtained after reduction of the enone and subsequent lactonization. They showed no biological activity as antitumor agents.     

Stereochemical diversity in asymmetric cyclization via memory of chirality

An enantiodivergent asymmetric cyclization of N-Boc-N-omega-bromoalkyl-alpha-amino acid derivatives has been developed. With potassium amide bases in DMF, cyclization proceeds with retention of configuration, while inversion of configuration was observed with lithium amide bases in THF. Chirality of the parent amino acids was preserved during enolate formation and cyclization to give aza-cyclic amino acids in up to 98% ee with retention of configuration or inversion of configuration, depending on the reaction conditions. Thus, both enantiomers of cyclic amino acids with a tetrasubstituted stereocenter were prepared in high enantiomeric purity from readily available l-alpha-amino acids. This protocol is also applicable to a spirocyclization and an intramolecular conjugate addition of alpha-amino acid derivatives, giving either of the enantiomers of a diazaspiro compound and a tetrahydroisoquinoline derivative, respectively, in up to 99% ee.     

Photochemical intramolecular cyclization of o-alkynylaryl isocyanides with organic dichalcogenides leading to 2,4-bischalcogenated quinolines

When a mixture of o-alkynylaryl isocyanides and organic dichalcogenides such as diselenides or ditellurides was irradiated with light of wavelength over 300 or 400 nm, the intramolecular cyclization of the isocyanides took place to afford the corresponding 2,4-bischalcogenated quinolines selectively. The photochemical cyclization of 2-(phenylethynyl)phenyl isocyanide could also proceed in the presence of hydrogen transfer reagents such as tris(trimethylsilyl)silane, tributylgermyl hydride, alkanethiols, and benzeneselenol, providing the corresponding 3-phenylquinoline as the result of 2,4-dihydrogenation.     

Synthesis of Cyclopentapeptides with Three to Five Aib Units

Four new Aib‐containing cyclopentapeptides have been synthesized by cyclization of the corresponding linear pentapeptides using the diethyl phosphorocyanidate (DEPC)/EtN(ⁱPr)₂ method. The linear precursors were prepared via the ‘azirine/oxazolone method’, i.e., the Aib units were introduced by the reaction of amino acids or peptide acids with a 2,2‐dimethyl‐2H‐azirin‐3‐amine, followed by selective hydrolysis of the terminal amide function. Most remarkably, cyclo[(Aib)₅] exists in CDCl₃ solution in a symmetrical conformation, i.e., no intramolecular H‐bonds are detectable.     

Synthesis and Structure–Activity Correlation Studies of Secondary‐ and Tertiary‐Amine‐Based Glutathione Peroxidase Mimics

In this study, a series of secondary‐ and tertiary‐amino‐substituted diaryl diselenides were synthesized and studied for their glutathione peroxidase (GPx) like antioxidant activities with H₂O₂, cumene hydroperoxide, or tBuOOH as substrates and with PhSH or glutathione (GSH) as thiol cosubstrates. This study reveals that replacement of the tert‐amino groups in benzylamine‐based diselenides by sec‐amino moieties drastically enhances the catalytic activities in both the aromatic thiol (PhSH) and GSH assay systems. Particularly, the N‐propyl‐ and N‐isopropylamino‐substituted diselenides are 8–18 times more active than the corresponding N,N‐dipropyl‐ and N,N‐diisopropylamine‐based compounds in all three peroxide systems when GSH is used as the thiol cosubstrate. Although the catalytic mechanism of sec‐amino‐substituted diselenides is similar to that of the tert‐amine‐based compounds, differences in the stability and reactivity of some of the key intermediates account for the differences in the GPx‐like activities. It is observed that the sec‐amino groups are better than the tert‐amino moieties for generating the catalytically active selenols. This is due to the absence of any significant thiol‐exchange reactions in the selenenyl sulfides derived from sec‐amine‐based diselenides. Furthermore, the seleninic acids (RSeO₂H) derived from the sec‐amine‐based compounds are more stable toward further reactions with peroxides than their tert‐amine‐based analogues.     

Copper catalyzed/mediated synthetic methodology for ebselen and related isoselenazolones

Scope of the copper catalyzed/mediated selenium-nitrogen coupling reaction has been studied for the synthesis of isoselenazolones. It is noticed that the 2-chloro, 2-bromo-, and 2-iodo-aryl amides substrates can be exploited in the selenium-nitrogen coupling reaction by employing 25-100 mol % of CuI/1,10-phenanthroline (L) and potassium carbonate as a base in DMF. Furthermore, electron rich 2-chloro-arylamides also underwent selenium-nitrogen coupling reaction to give biologically important selenium-nitrogen heterocycles. Also, copper-catalyzed selenium-nitrogen coupling reaction has been meticulously applied for the synthesis of diaryl diselenides having methoxy, amine, and amide functionality from respective aryl iodides in the presence of stoichiometric amount of succinimide as an external Se-N coupling partner.     

Tuning the activity of glutathione peroxidase mimics through intramolecular Se···N,O interactions: a DFT study incorporating solvent-assisted proton exchange (SAPE)

Diaryl diselenide mimics of the antioxidant selenoprotein glutathione peroxidase (GPx) often incorporate intramolecular Se···N,O interactions to enhance their GPx-like activity. Although the strength of the interaction is defined by the Lewis basicity of the donating group and the strength of the Se-X bond, there is not a clear relationship between the interaction and the GPx-like activity. Density-functional theory and natural bond orbital (NBO) calculations are used to show the range of Se···N,O interactions for various functional groups. The strongest interactions are found for groups which stabilize the donor-acceptor interaction through aromatic stabilization. The activation barriers for the GPx-like mechanism of activity of several substituted areneselenols are calculated using DFT and solvent-assisted proton exchange (SAPE), a technique that incorporates networks of solvent molecules into the theoretical model to facilitate proton transfer between sites in the reactant and product. DFT-SAPE models show that, in addition to decreasing the barrier to oxidation of the selenol, Se···N,O interactions generally increase the barriers for selenenic acid reduction and selenol regeneration because the Se···N,O interaction must be broken for the reaction to proceed. Calculated activation barriers for the rate-determining step are consistent with the relative experimental GPx-like activities of a series of diaryl diselenides.     

Palladium-Catalyzed Carbonylative Lactonization of Propargyl Alcohols with Organic Dichalcogenides and Carbon Monoxide

The reaction of propargylic alcohols with diaryl disulfides and carbon monoxide in the presence of tetrakis(triphenylphosphine)palladium leads to a novel thiolative lactonization to afford beta-(arylthio)-alpha,beta-unsaturated lactones in moderate to good yields. Similar conditions can be employed with homopropargylic alcohols, giving the corresponding delta-lactones with a beta-arylthio group successfully. The reaction using diaryl diselenides in lieu of diaryl disulfides also attains a similar one-pot thiolation/lactonization sequence to provide the corresponding beta-selenobutenolides (7).