FeCl-Mediated Rearrangement of Aminoperoxides into Functionalized Tetrahydrofurans: Dynamic Non-innocence of O-Ligands at an Fe Center Coordinates a Radical Cascade.

The selective reaction of cyclic aminoperoxides with FeCl proceeds through a sequence of O-O and C-C bond cleavages, followed by intramolecular cyclization, yielding functionalized tetrahydrofurans in 44-82% yields. Replacing the peroxyacetal group in the peroxide structure with a peroxyaminal fragment fundamentally alters the reaction pathway. Instead of producing linear functionalized ketones, this modification leads to the formation of hard-to-access substituted tetrahydrofurans.

C═N Bond Ozonolysis and β-Scission: A Breakthrough Approach to the Synthesis of ω-Functionalized Compounds from Carbonyl Derivatives.

This work discloses a two-step, one-pot approach to ω-functionalized esters via cleavage of the alicyclic fragment of cycloalkanone semicarbazones. This approach is based on a combination of the synthesis of various alkoxyhydroperoxides via cycloalkanone semicarbazone ozonolysis and interaction of these peroxides with transition metal salts, leading to cleavage of the aliphatic cycle and subsequent ω-functionalized ester formation. A broad series of ω-halogen or pseudohalogen esters have been successfully synthesized in yields ranging from 23 to 73% per starting semicarbazone.

Interrupted Dance of Five Heteroatoms: Reinventing Ozonolysis to Make Geminal Alkoxyhydroperoxides from C═N Bonds.

Four heteroatoms dance in the cascade of four pericyclic reactions initiated by ozonolysis of C═N bonds. Switching from imines to semicarbazones introduces the fifth heteroatom that slows this dance, delays reaching the thermodynamically favorable escape path, and allows efficient interception of carbonyl oxides (Criegee intermediates, CIs) by an external nucleophile. The new three-component reaction of alcohols, ozone, and oximes/semicarbazones greatly facilitates synthetic access to monoperoxyacetals (alkoxyhydroperoxides).

Peroxide derivatives as SARS-CoV-2 entry inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Host cell invasion is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, bio-layer interferometry (BLI) was used to screen a series of fifty-two peroxides, including aminoperoxides and bridged 1,2,4 - trioxolanes (ozonides), with the aim of identifying small molecules that interfere with the RBD-ACE2 interaction.

Two-Component versus Three-Component Condensations in the Race between Hydrazide, Triketone, and Hydrogen Peroxide-How do All Six Reactive Centers Cooperate to Incorporate the Most Diverse Set of Heteroatomic Bridges in a Tricyclic Frame?

Relief of stereoelectronic frustration drives the acid-catalyzed three-component condensation of β,δ'-triketones with hydrazides and HO to the direction where both nucleophiles and all three electrophilic carbons are involved in the formation of a tricyclic sp-rich ring system that includes four heteroatoms. The otherwise inaccessible tricyclic N-substituted aminoperoxides are prepared rapidly and selectively from relatively simple substrates in good to high yields.

Bridged 1,2,4-Trioxolanes: SnCl-Catalyzed Synthesis and an In Vitro Study against .

A synthesis of bridged 1,2,4-trioxolanes (bridged ozonides) from 1,5-diketones and hydrogen peroxide catalyzed by SnCl was developed. It was shown that the ratio of target ozonides can be affected by the application of SnCl as a catalyst and varying the solvent. A wide range of bridged 1,2,4-trioxolanes (ozonides) was obtained in yields from 50 to 84%.

Cascade Assembly of Bridged N-Substituted Azaozonides: The Counterintuitive Role of Nitrogen Source Nucleophilicity.

Counterintuitively, the low basicity of the NH group in hydrazides makes them preferred nucleophiles for the synthesis of the N-substituted azaozonides in acid-catalyzed three-component condensation with 1,5-diketones and HO. In the case of more basic N sources, e.g.

Antimalarial and Anticancer Activity Evaluation of Bridged Ozonides, Aminoperoxides, and Tetraoxanes.

Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P.

Lewis Acids and Heteropoly Acids in the Synthesis of Organic Peroxides.

Organic peroxides are an important class of compounds for organic synthesis, pharmacological chemistry, materials science, and the polymer industry. Here, for the first time, we summarize the main achievements in the synthesis of organic peroxides by the action of Lewis acids and heteropoly acids. This review consists of three parts: (1) metal-based Lewis acids in the synthesis of organic peroxides; (2) the synthesis of organic peroxides promoted by non-metal-based Lewis acids; and (3) the application of heteropoly acids in the synthesis of organic peroxides.

Inverse α-Effect as the Ariadne's Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities.

Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of β,δ'-triketones, HO, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the "stereoelectronic frustration" of HO and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states.

Synthesis and in vitro Study of Artemisinin/Synthetic Peroxide-Based Hybrid Compounds against SARS-CoV-2 and Cancer.

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e.

Synthesis of cyclic aza-peroxides (microreview).

A summary of approaches developed for the synthesis of stable cyclic aza-peroxides is presented.

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides.

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at -10 °C.

Application of BF·EtO in the synthesis of cyclic organic peroxides (microreview).

A summary of recent applications of Lewis acid BF·EtO as a catalyst in the synthesis of cyclic organic peroxides is presented.

How to Build Rigid Oxygen-Rich Tricyclic Heterocycles from Triketones and Hydrogen Peroxide: Control of Dynamic Covalent Chemistry with Inverse α-Effect.

We describe an efficient one-pot procedure that "folds" acyclic triketones into structurally complex, pharmaceutically relevant tricyclic systems that combine high oxygen content with unusual stability. In particular, β,γ'-triketones are converted into three-dimensional polycyclic peroxides in the presence of HO under acid catalysis. These transformations are fueled by stereoelectronic frustration of HO, the parent peroxide, where the lone pairs of oxygen are not involved in strongly stabilizing orbital interactions.

Cyclic Synthetic Peroxides Inhibit Growth of Entomopathogenic Fungus without Toxic Effect on Bumblebees.

In recent years, the number of pollinators in the world has significantly decreased. A possible reason for this is the toxic effects of agrochemicals reducing the immunity of insects that leads to their increased susceptibility to pathogens. is a dangerous entomopathogenic fungus, afflicting both honeybees and bumblebees.

Synthetic Peroxides Promote Apoptosis of Cancer Cells by Inhibiting P-Glycoprotein ABCB5.

This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells; in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5-tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds 11 b and 12 a are 8 and 5, respectively).

Catalyst Development for the Synthesis of Ozonides and Tetraoxanes Under Heterogeneous Conditions: Disclosure of an Unprecedented Class of Fungicides for Agricultural Application.

The catalyst H PMo Mo O supported on SiO was developed for peroxidation of 1,3- and 1,5-diketones with hydrogen peroxide with the formation of bridged 1,2,4,5-tetraoxanes and bridged 1,2,4-trioxolanes (ozonides) with high yield based on isolated products (up to 86 and 90 %, respectively) under heterogeneous conditions. Synthesis of peroxides under heterogeneous conditions is a rare process and represents a challenge for this field of chemistry, because peroxides tend to decompose on the surface of a catalyst . A new class of antifungal agents for crop protection, that is, cyclic peroxides: bridged 1,2,4,5-tetraoxanes and bridged ozonides, was discovered.

Ozone-Free Synthesis of Ozonides: Assembling Bicyclic Structures from 1,5-Diketones and Hydrogen Peroxide.

Reactions of 1,5-diketones with HO open an ozone-free approach to ozonides. Bridged ozonides are formed readily at room temperature in the presence of strong Brønsted or Lewis acids such as HSO, p-TsOH, HBF, or BF·EtO. The expected bridged tetraoxanes, the products of double HO addition, were not detected.

Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity.

Twenty six peroxides belonging to bridged 1,2,4,5-tetraoxanes, bridged 1,2,4-trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for their in vitro antimalarial activity against Plasmodium falciparum (3D7) and for their cytotoxic activities against immortalized human normal fibroblast (CCD19Lu), liver (LO ), and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer-cell lines. Synthetic ozonides were shown to have the highest cytotoxicity on HepG2 (IC =0.19-0.

Stereoelectronic Control in the Ozone-Free Synthesis of Ozonides.

The value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H O . The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H O were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.