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 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 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.

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.

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.

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.