Epoxidation of Enamines by Dimethyldioxirane: Formation of 1,4‐Dioxanes by Enamine Epoxide Dimerization

Adam, Waldemar; Peters, E.‐M.; Peters, Karl; Schnering, Hans Georg̀ von; Voerckel, V.

doi:10.1002/cber.19921250536

Cited by 25 publications

(6 citation statements)

References 19 publications

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“…This is consistent with the reactivity of enamines (e.g. NADH, MDHNA) towards dimethyldioxirane, an organic equivalent of hydrogen peroxide that can promote the production of highly reactive epoxides prone to solvolysis and alkylation 41 . Interestingly, epoxide hydrolases have been detected in the mitochondria of mammalian cells to prevent accumulation of these chemically reactive species that can potentially lead to alkylation by-products 42 .…”

Section: Discussionsupporting

confidence: 81%

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Solier

Müller

Cañeque

et al. 2022

Preprint

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Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral infections (SARS-CoV-2), improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

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Section: Discussionsupporting

confidence: 81%

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Solier

Müller

Cañeque

et al. 2022

Preprint

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“…This conformation relieves 1,3-diaxial interactions that exist between a pair of respective cyclohexane methylene groups in either flip form of the corresponding chair conformation of the 1,4-dioxane ring. Formally, dimers 18 are produced from the addition of the alkoxy group (or hydroxyl group if protonated) from each of two molecules of intermediate 21 to the iminium moiety of the other (Scheme ). , …”

Section: Resultsmentioning

confidence: 99%

Cyclic Seleninate Esters as Catalysts for the Oxidation of Sulfides to Sulfoxides, Epoxidation of Alkenes, and Conversion of Enamines to α-Hydroxyketones

et al. 2012

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Cyclic seleninate esters serve as catalysts for the rapid oxidation of sulfides to sulfoxides, alkenes to epoxides, and enamines to α-hydroxyketones. Optimal conditions were found that minimize the overoxidation of the product sulfoxides to sulfones and the hydrolysis of epoxides to diols. In some examples such as styrene derivatives, oxidative cleavage was observed instead of epoxidation. The enamine oxidations proceed via the initial formation of dimeric 2,5-diamino-1,4-dioxane species, which were hydrolyzed in situ to the final products. The structure of one such dimer was confirmed by X-ray crystallography.

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“…[6] Scheme 3. [10] To examine the potential involvement of a spiroepoxide V as an intermediate in the NHC-catalyzed benzoin condensation, we envisaged the generation of this species by epoxidation of the exocyclic double bond of enediamines VIII derived from N-heterocyclic carbenes (Scheme 3b). 572 asc.wiley-vch.de (DAC) have recently been described by Bielawski and co-workers (Scheme 4).…”

mentioning

confidence: 99%

On the Involvement of a Spiroepoxide Intermediate in N‐Heterocyclic Carbene (NHC)‐Catalyzed Benzoin Condensations – An Approach by Oxygenation of Deoxy‐Breslow Intermediates

Berkessel

Elfert

2014

Adv Synth Catal

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The involvement of a spiroepoxide, an isomer of the Breslow intermediate, in the catalytic cycle of the N-heterocyclic carbene (NHC)-catalyzed benzoin condensation was suggested by S. Gronert in 2007, based on calculations. To test this hypothesis, enediamines were generated in situ from (in part 13 C-labeled) N-heterocyclic carbenes, benzyl bromide and base, and subsequently treated with various single-oxygen atom oxidants. Clean oxidation occurred with a triazolylidene-derived enediamine and an N-sulfonyloxaziridine as oxidant, but NMR monitoring gave no hint to the accumulation of a spiroepoxide. Instead, oxidative cleavage of the enediamine to the free carbene and benzaldehyde was observed, with subsequent oxidation of the carbene to a urea. Presumably, electrophilic oxygenation of the enediamine occurs at the exocyclic methylene carbon atom and affords a zwitterion -identical to the primary carbene-aldehyde adduct of the benzoin cycle -which undergoes retro-cleavage to carbene and aldehyde. However, the occurrence of a spiroepoxide as transient intermediate of the oxidative C=C bond cleavage cannot rigorously be excluded.

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Epoxidation of Enamines by Dimethyldioxirane: Formation of 1,4‐Dioxanes by Enamine Epoxide Dimerization

Abstract: The 1,4-dioxanes 3a-f, which constitute dimers of the enamine epoxides 2a -f, were obtained in excellent yields as crystalline products during the oxygen transfer to the corresponding enamines by dimethyldioxirane (DMD) in acetone.

Cited by 25 publications

References 19 publications

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Cyclic Seleninate Esters as Catalysts for the Oxidation of Sulfides to Sulfoxides, Epoxidation of Alkenes, and Conversion of Enamines to α-Hydroxyketones

On the Involvement of a Spiroepoxide Intermediate in N‐Heterocyclic Carbene (NHC)‐Catalyzed Benzoin Condensations – An Approach by Oxygenation of Deoxy‐Breslow Intermediates

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