An electrochemical access to 2-amino-2,3-dihydro-1,4-benzodioxanes derived from hydroxytyrosol.

The anodic oxidation of a natural antioxidative catechol, hydroxytyrosol, was developed in an acetonitrile/dimethylsulfoxide (or acetonitrile/water) solvent mixture to produce in a stable way the resulting non-activated -quinone and generate structural analogues. 2-Amino-2,3-dihydro-1,4-benzodioxane derivatives were obtained as two regioisomers in good to high overall yields (65-90%) and 1 : 3 ratios, through an inverse electron demand Diels-Alder (IEDDA) reaction between the electrogenerated -quinone and tertiary enamines. The insertion of an electron withdrawing (or electron donating) group on the catechol modified their relative proportions, so that the reaction became regiospecific.

Aerobic catalytic systems inspired by copper amine oxidases: recent developments and synthetic applications.

Recent efforts to design synthetic quinone-based catalysts for the efficient aerobic oxidation of amines to imines have been inspired by copper amine oxidases (CuAOs), a family of metalloenzymes which selectively converts primary amines into aldehydes, using molecular oxygen through the cooperation of a quinone-based cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ) and a copper ion. Two distinct classes of bioinspired quinone-based catalytic systems have been developed. The first class consists of catalytic systems, which mimic the activity of CuAOs by exhibiting exquisite selectivity for primary amines.

A Bioinspired Organocatalytic Cascade for the Selective Oxidation of Amines under Air.

A bioinspired organocatalytic cascade reaction for the selective aerobic oxidative cross-coupling of primary amines to imines is described. This approach takes advantages of commercially available pyrogallol monomeric precursor to deliver low loadings of natural purpurogallin in situ, under air. This is further engaged in a catalytic process with the amine substrate affording, under single turnover, the active biomimetic quinonoid organocatalyst and the homocoupled imine intermediate, which is then converted into cross-coupled imine after dynamic transimination.

A bioinspired catalytic aerobic oxidative C-H functionalization of primary aliphatic amines: synthesis of 1,2-disubstituted benzimidazoles.

Aerobic oxidative CH functionalization of primary aliphatic amines has been accomplished with a biomimetic cooperative catalytic system to furnish 1,2-disubstituted benzimidazoles that play an important role as drug discovery targets. This one-pot atom-economical multistep process, which proceeds under mild conditions, with ambient air and equimolar amounts of each coupling partner, constitutes a convenient environmentally friendly strategy to functionalize non-activated aliphatic amines that remain challenging substrates for non-enzymatic catalytic aerobic systems.

Regiospecific synthesis of neuroprotective 1,4-benzoxazine derivatives through a tandem oxidation-Diels-Alder reaction.

The tandem oxidation-inverse electron demand Diels-Alder reaction of o-aminophenol derivatives and enamines has been accomplished at room temperature using a stoichiometric amount of manganese dioxide as the oxidant to furnish highly substituted 1,4-benzoxazine cycloadducts with complete regiochemical control. Because of its efficiency in introducing diverse elements in both cycloaddition partners, this one-pot process should allow the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives. In this respect, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3n was found to be a potent neuroprotective agent in an animal model of excitotoxic lesions in newborn mice.

A metalloenzyme-like catalytic system for the chemoselective oxidative cross-coupling of primary amines to imines under ambient conditions.

The direct oxidative cross-coupling of primary amines is a challenging transformation as homocoupling is usually preferred. We report herein the chemoselective preparation of cross-coupled imines through the synergistic combination of low loadings of Cu(II) metal-catalyst and o-iminoquinone organocatalyst under ambient conditions. This homogeneous cooperative catalytic system has been inspired by the reaction of copper amine oxidases, a family of metalloenzymes with quinone organic cofactors that mediate the selective oxidation of primary amines to aldehydes.

A convenient biomimetic synthesis of optically active putative neurotoxic metabolites of MDMA ("ecstasy") from R-(-)- and S-(+)-N-methyl-α-methyldopamine precursors.

(±)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates.

Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate.

The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined.

A small molecule that mimics the metabolic activity of copper-containing amine oxidases (CuAOs) toward physiological mono- and polyamines.

Primary aliphatic biogenic amines have been successfully oxidized using a quinonoid species that mimics the metabolic activity of copper-containing amine oxidase (CuAO) enzymes. Especially, high catalytic performances were observed with aminoacetone, a threonine catabolite, and methylamine, a metabolite of adrenaline, and with the primary amino groups of putrescine and spermidine which are both decarboxylation products of ornithine and S-adenosyl-methionine. Furthermore, contrary to flavine adenine dinucleotide (FAD)-dependent amine oxidase enzymes, no activity was found toward secondary and tertiary amines.

Synthesis and in vitro cytotoxicity profile of the R-enantiomer of 3,4-dihydroxymethamphetamine (R-(-)-HHMA): comparison with related catecholamines.

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a chiral drug that is essentially metabolized in humans through O-demethylenation into 3,4-dihydroxymethamphetamine (HHMA). There has recently been a resurgence of interest in the possibility that MDMA metabolites, especially 5-(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (designated as 5-NAC-HHMA), might play a role in MDMA neurotoxicity. However, the chirality of MDMA was not considered in previously reported in vivo studies because HHMA, the precursor of the 5-NAC-HHMA metabolite, was used as the racemate.

Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity.

The mechanism by which the recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals.

A biomimetic electrocatalytic system for the atom-economical chemoselective synthesis of secondary amines.

A facile one-pot oxidation-imine formation-reduction route to secondary amines can be achieved electrolytically from primary amines. This atom-economical 1(ox)-mediated sequence, leaving ammonia as the sole byproduct, allows the rapid chemoselective synthesis of secondary amines, at both ambient temperature and pressure.

Environmentally friendly chemoselective oxidation of primary aliphatic amines by using a biomimetic electrocatalytic system.

Environmentally friendly oxidation of primary aliphatic amines to imines has been successfully achieved, under metal-free conditions, by the use of diverse electrogenerated o-azaquinone mediators. High catalytic performance, together with high chemoselectivity, were observed with electron-poor o-azaquinone catalysts generated from 2-aminoresorcinol derivatives. Similar to copper amine oxidase enzymes, these mediators exhibited lower reactivity toward alpha-branched primary amines and no reactivity toward secondary amines.

Bacterial plate assays and electrochemical methods: an efficient tandem for evaluating the ability of catechol-thioether metabolites of MDMA ("ecstasy") to induce toxic effects through redox-cycling.

Several catechol-thioether metabolites of MDMA (ecstasy), three monoadducts, 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine (1), 5-(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (2), and 5-(cystein-S-yl)-N-methyl-alpha-methyldopamine (3), and two bi-adducts, 2,5-bis(glutathion-S-yl)-N-methyl-alpha-methyldopamine (4) and 2,5-bis(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (5), have been synthesized through an environmentally friendly one-pot electrochemical procedure. Their cytotoxicity profiles were further characterized using simple Escherichia coli plate assays and compared with those of N-methyl-alpha-methyldopamine (HHMA), dopamine (DA), and its corresponding catechol-thioether conjugates (monoadducts 6-8 and bi-adducts 9 and 10). Toxicity mediated by reactive oxygen species (ROS-TOX) was detected in the OxyR- assay, using cells sensitive to oxidative stress due to a deficiency in the OxyR protein.

Electrochemically induced cascade reaction for the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives.

The scope and mechanism of an electrochemically induced cascade reaction, which leads to highly substituted 1,4-benzoxazine derivatives, have been explored through the variation of the structure of the o-azaquinone mediator. This reaction sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, allows the regiospecific inverse-electron-demand Diels-Alder (IEDDA) reaction of an o-azaquinone heterodiene and a secondary alkylenamine dienophile, two chemically nonaccessible unstable entities. The cascade reaction was found to be general with electron-poor o-azaquinone entities generated from substituted 2-aminoresorcinol substrates.

A convenient approach for evaluating the toxicity profiles of in vitro neuroprotective alkylaminophenol derivatives.

The cytotoxicity profiles of a series of quinol-type derivatives were examined through simple Escherichia coli plate assays discriminating the two main cytotoxicity mechanisms associated with polyphenol oxidation to quinone. Toxicity mediated by reactive oxygen species (ROS-TOX) was detected in the OxyR(-) assay using cells sensitive to oxidative stress due to a deficiency in the OxyR function. Toxicity arising from the high susceptibility of quinone toward endogenous nucleophiles (Q-TOX) was detected using OxyR(+) cells, in the presence of a nitric oxide donor to promote the quinol oxidation to the corresponding quinone.

Protective effects of 4-hydroxycinnamic ethyl ester derivatives and related dehydrodimers against oxidation of LDL: radical scavengers or metal chelators?

4-Hydroxycinnamate derivatives are known to be potent protectors against oxidation of low-density lipoproteins (LDL), via a combination of free radical scavenging and transition metal chelation. Through a series of 4-hydroxycinnamic ethyl ester derivatives and related 8-8 dehydrodimers, we have tried to bring out the structural requirements for radical scavenging and cupric ion chelation. We found that the monomeric compounds, except for highly lipophilic tert-butyl derivative 3, exhibited rather low radical scavenging properties.

A one-pot regiospecific synthesis of highly functionalized 1,4-benzodioxin derivatives from an electrochemically induced Diels-Alder reaction.

[reaction: see text] The anodic oxidation of pyrogallol derivatives produces chemically unstable o-quinone heterodienes, which are trapped in situ by enamine dienophiles through regiospecific inverse-electron-demand Diels-Alder reactions. The possibility of introducing variations in both cycloaddition partners gives rise to highly substituted 1,4-benzodioxin cycloadducts with up to five elements of diversity. The reactions proceed under mild conditions with a good efficiency.

Novel 2-alkylamino-1,4-benzoxazine derivatives as potent neuroprotective agents: structure-activity relationship studies.

2-Alkylamino-substituted-1,4-benzoxazine derivatives, a new class of potential neuroprotective agents, were synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in vitro. Through structure-activity relationship studies, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3l was identified as the optimal candidate, owing to its potent neuroprotective activity, without the manifestation of intrinsic cytotoxicity. Accordingly, 3l proved to be effective in an animal model of excitotoxic lesions in newborn mice.

4-hydroxycinnamic ethyl ester derivatives and related dehydrodimers: Relationship between oxidation potential and protective effects against oxidation of low-density lipoproteins.

The electrochemical oxidation potential of a series of monomeric and dimeric 4-hydroxycinnamic ethyl ester derivatives has been compared with their antioxidant activity toward copper-catalyzed human low-density lipoproteins (LDL) oxidation. Within the series of monomeric hydroxycinnamate derivatives, both oxidation potential and IC50 values decreased in the following order: sinapate > ferulate > p-coumarate. Among the 4-hydroxycinnamate dehydrodimer derivatives, noncyclized 8-8 diphenol dehydrodimers followed the same aforementioned sequence order and were found to be better antioxidants than their monomer counterparts.

Simultaneously electrogenerated cycloaddition partners for regiospecific inverse-electron-demand Diels-Alder reactions: a route for polyfunctionalized 1,4-benzoxazine derivatives.

A multistep one-pot electrochemical synthesis of a variety of complex 2-alkylamino-1,4-benzoxazine derivatives is described. The reactions are regiospecific and diastereospecific in the case of heterocyclic annulation. This cascade sequence, wherein both cycloaddition partners are generated in situ, at room temperature, under metal-free conditions, allows the inverse-electron-demand Diels-Alder reaction of an o-iminoquinone diene and a secondary alkylenamine dienophile, two chemically nonaccessible unstable entities.