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).

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 ß,δ'-triketones with hydrazides and H2O2 to the direction where both nucleophiles and all three electrophilic carbons are involved in the formation of a tricyclic sp3-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: SnCl4-Catalyzed Synthesis and an In Vitro Study against S. mansoni.

A synthesis of bridged 1,2,4-trioxolanes (bridged ozonides) from 1,5-diketones and hydrogen peroxide catalyzed by SnCl4 was developed. It was shown that the ratio of target ozonides can be affected by the application of SnCl4 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%. The ozonide cycle was moderately resistant to the reduction of the ester group near the peroxide cycle to alcohol with LiAlH4. The bridged ozonides were evaluated for their antischistosomal activity. These ozonides exhibited a very high activity against newly transformed schistosomula and adult Schistosoma mansoni.

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 ß,δ'-triketones, H2O2, 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 H2O2 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. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone.

Although carbon is the central element of organic chemistry, oxygen is the central element of stereoelectronic control in organic chemistry. Generally, a molecule with a C-O bond has both a strong donor (a lone pair) and a strong acceptor (e.g., a σ*C-O orbital), a combination that provides opportunities to influence chemical transformations at both ends of the electron demand spectrum. Oxygen is a stereoelectronic chameleon that adapts to the varying situations in radical, cationic, anionic, and metal-mediated transformations. Arguably, the most historically important stereoelectronic effect is the anomeric effect (AE), i.e., the axial preference of acceptor groups at the anomeric position of sugars. Although AE is generally attributed to hyperconjugative interactions of σ-acceptors with a lone pair at oxygen (negative hyperconjugation), recent literature reports suggested alternative explanations. In this context, it is timely to evaluate the fundamental connections between the AE and a broad variety of O-functional groups. Such connections illustrate the general role of hyperconjugation with oxygen lone pairs in reactivity. Lessons from the AE can be used as the conceptual framework for organizing disjointed observations into a logical body of knowledge. In contrast, neglect of hyperconjugation can be deeply misleading as it removes the stereoelectronic cornerstone on which, as we show in this review, the chemistry of organic oxygen functionalities is largely based. As negative hyperconjugation releases the "underutilized" stereoelectronic power of unshared electrons (the lone pairs) for the stabilization of a developing positive charge, the role of orbital interactions increases when the electronic demand is high and molecules distort from their equilibrium geometries. From this perspective, hyperconjugative anomeric interactions play a unique role in guiding reaction design. In this manuscript, we discuss the reactivity of organic O-functionalities, outline variations in the possible hyperconjugative patterns, and showcase the vast implications of AE for the structure and reactivity. On our journey through a variety of O-containing organic functional groups, from textbook to exotic, we will illustrate how this knowledge can predict chemical reactivity and unlock new useful synthetic transformations.

Correction: Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone.

Correction for 'Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone' by Igor V. Alabugin et al., Chem. Soc. Rev., 2021, DOI: 10.1039/d1cs00386k.

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. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pKa units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C-O interaction with the two antiperiplanar C-O bonds. Due to the weakness of the complementary nO→σ*C-N donation from the peroxide oxygens (a consequence of "inverse α-effect"), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

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, ß,γ'-triketones are converted into three-dimensional polycyclic peroxides in the presence of H2O2 under acid catalysis. These transformations are fueled by stereoelectronic frustration of H2O2, the parent peroxide, where the lone pairs of oxygen are not involved in strongly stabilizing orbital interactions. Computational analysis reveals how this frustration is relieved in the tricyclic peroxide products, where strongly stabilizing anomeric nO→σC-O* interactions are activated. The calculated potential energy surfaces for these transformations combine labile, dynamically formed cationic species with deeply stabilized intermediate structures that correspond to the introduction of one, two, or three peroxide moieties. Paradoxically, as the thermodynamic stability of the peroxide products increases along this reaction cascade, the kinetic barriers for their formation increase as well. This feature of the reaction potential energy surface, which allows separation of mono- and bis-peroxide tricyclic products, also explains why formation of the most stable tris-peroxide is the least kinetically viable and is not observed experimentally. Such unique behavior can be explained through the "inverse α-effect", a new stereoelectronic phenomenon with many conceptual implications for the development of organic functional group chemistry.

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

The catalyst H3+x PMo12-x +6 Mox +5 O40 supported on SiO2 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. Some ozonides and tetraoxanes exhibit a very high antifungal activity and are superior to commercial fungicides, such as Triadimefon and Kresoxim-methyl. It is important to note that none of the fungicides used in agricultural chemistry contains a peroxide fragment.

Cyclic Synthetic Peroxides Inhibit Growth of Entomopathogenic Fungus Ascosphaera apis 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. Ascosphaera apis is a dangerous entomopathogenic fungus, afflicting both honeybees and bumblebees. We investigated fungicide activity of cyclic synthetic peroxides against A. apis isolated from Bombus terrestris L. The peroxides exhibited high mycelium growth inhibition of A. apis up to 94-100% at concentration 30 mg/L. EC50 values were determined for the most active peroxides. Two peroxides showed higher antifungal activity against A. apis than the commercial fungicide Triadimefon. The studied peroxides did not reduce the ability of bumblebees to fly and did not lead to the death of bumblebees. A new field of application for peroxides was disclosed.

Chemiluminescence in the reaction of 1,2,4,5-tetraoxanes with ferrous ions in the presence of xanthene dyes: fundamentals and perspectives of analytical applications.

The reaction of biologically active bridged 1,2,4,5-tetraoxanes and diperoxide of trifluoroacetone with ferrous ions in the presence of xanthenes, methylene blue and methylene green is accompanied by bright chemiluminescence (CL) caused by the emission from electronically-excited dyes. The promising perspectives for the employment of the CL method for the analytical detection of tetraoxanes were demonstrated. The most convenient CL system was found to be their reaction with ferrous gluconate in the presence of rhodamine 3B, which allowed the detection of up to 10-9 M of diperoxides. The discovered CL-probe is selective towards tetraoxanes over reactive oxygen species such as singlet oxygen, hydroxyl radicals, hydrogen peroxide, hypochlorite and superoxide ions. It is suggested that electronically-excited states may be involved in biological activities of cyclic organic peroxides.

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

Reactions of 1,5-diketones with H2O2 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 H2SO4, p-TsOH, HBF4, or BF3·Et2O. The expected bridged tetraoxanes, the products of double H2O2 addition, were not detected. This procedure is readily scalable to produce gram quantities of the ozonides. Bridged ozonides are stable and can be useful as building blocks for bioconjugation and further synthetic transformations. Although less stabilized by anomeric interactions than bis-peroxides, ozonides have an intrinsic advantage of having only one weak O-O bond. The role of the synergetic framework of anomeric effects in bis-peroxides is to overcome this intrinsic disadvantage. As the computational data have shown, this is only possible when all anomeric effects in bis-peroxides are activated to their fullest degree. Consequently, the cyclization selectivity is determined by the length of the bridge between the two carbonyl groups of the diketone. The generally large thermodynamic preference for the formation of cyclic bis-peroxides disappears when 1,5-diketones are used as the bis-cyclization precursors. Stereoelectronic analysis suggests that the reason for the bis-peroxide absence is the selective deactivation of anomeric effects in a [3.2.2]tetraoxanonane skeleton by a structural distortion imposed on the tetraoxacyclohexane subunit by the three-carbon bridge.

Synthetic Strategies for Peroxide Ring Construction in Artemisinin.

The present review summarizes publications on the artemisinin peroxide fragment synthesis from 1983 to 2016. The data are classified according to the structures of a precursor used in the key peroxidation step of artemisinin peroxide cycle synthesis. The first part of the review comprises the construction of artemisinin peroxide fragment in total syntheses, in which peroxide artemisinin ring resulted from reactions of unsaturated keto derivatives with singlet oxygen or ozone. In the second part, the methods of artemisinin synthesis based on transformations of dihydroartemisinic acid are highlighted.

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions.

The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards.

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 H2 O2 . The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H2 O2 were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.2]tetraoxanonanes by the three-carbon bridge leads to the partial deactivation of anomeric effects. The new procedure is readily scalable to produce gram quantities of the ozonides. This reaction enables the selective preparation of ozonides without the use of ozone.

Rearrangements of organic peroxides and related processes.

This review is the first to collate and summarize main data on named and unnamed rearrangement reactions of peroxides. It should be noted, that in the chemistry of peroxides two types of processes are considered under the term rearrangements. These are conventional rearrangements occurring with the retention of the molecular weight and transformations of one of the peroxide moieties after O-O-bond cleavage. Detailed information about the Baeyer-Villiger, Criegee, Hock, Kornblum-DeLaMare, Dakin, Elbs, Schenck, Smith, Wieland, and Story reactions is given. Unnamed rearrangements of organic peroxides and related processes are also analyzed. The rearrangements and related processes of important natural and synthetic peroxides are discussed separately.

Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni.

Praziquantel is currently the only drug available to treat schistosomiasis. Since drug resistance would be a major barrier for the increasing global attempts to eliminate schistosomiasis as a public health problem, efforts should go hand in hand with the discovery of novel treatment options. Synthetic peroxides might offer a good direction since their antischistosomal activity has been demonstrated in the laboratory. We studied 19 bridged 1,2,4,5-tetraoxanes, 2 tricyclic monoperoxides, 11 bridged 1,2,4-trioxolanes, 12 silyl peroxides, and 4 hydroxylamine derivatives against newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Schistosomicidal compounds were tested for cytotoxicity followed by in vivo studies of the most promising compounds. Tricyclic monoperoxides, trioxolanes, and tetraoxanes revealed the highest in vitro activity against NTS (IC50s 0.4-20.2 µM) and adult schistosomes (IC50s 1.8-22.8 µM). Tetraoxanes showed higher cytotoxicity than antischistosomal activity. Selected trioxolane and tricyclic monoperoxides were tested in mice harboring an adult S. mansoni infection. The highest activity was observed for two trioxolanes, which showed moderate worm burden reductions (WBR) of 44.3% and 42.9% (p>0.05). Complexation of the compounds with ß-cyclodextrin with the aim to improve solubility and gastrointestinal absorption did not increase in vivo antischistosomal efficacy. The high in vitro antischistosomal activity of trioxolanes and tricyclic monoperoxides is a promising basis for future investigations, with the focus on improving in vivo efficacy.

Approach for the preparation of various classes of peroxides based on the reaction of triketones with H2O2: first examples of ozonide rearrangements.

The reaction of ß,δ-triketones with an ethereal solution of H2O2 catalyzed by heteropoly acids in the presence of a polar aprotic co-solvent proceeds via three pathways to form three classes of peroxides: tricyclic monoperoxides, bridged tetraoxanes, and a pair of stereoisomeric ozonides. The reaction is unusual in that produces bridged tetraoxanes and ozonides with one of the three carbonyl groups remaining intact. In the synthesis of bridged tetraoxanes, the peroxide ring is formed by the reaction of hydrogen peroxide with two carbonyl groups at the ß positions. The synthesis of ozonides from ketones and hydrogen peroxide is a unique process in which the ozonide ring is formed with the participation of two carbonyl groups at the δ positions. Rearrangements of ozonides were found for the first time after more than one century of their active investigation. Ozonides are interconverted with each other and rearranged into tricyclic monoperoxides, whereas ozonides and tricyclic monoperoxides are transformed into bridged tetraoxanes. The individual reaction products were isolated by column chromatography and characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. One representative of each class of peroxides was characterized by X-ray diffraction.

Photocatalytic Sulfonyl Peroxidation of Alkenes via Deamination of N-Sulfonyl Ketimines.

A photocatalytic three-component sulfonyl peroxidation of alkenes with N-sulfonyl ketimines and tert-butyl hydroperoxide is reported. The reaction takes place via the photoinduced EnT process, which allows the efficient synthesis of a variety of ß-peroxyl sulfones under mild reaction conditions in the absence of a transition metal catalyst. The downstream derivatizations of the peroxides were also performed. Furthermore, the utility of this protocol was manifested by the synthesis of 11ß-HSD1 inhibitor and the antiprostate cancer drug bicalutamide.

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. We found that two compounds, compound 21 and 29, exhibit the activity to inhibit RBD-ACE2. They are further demonstrated to inhibit SARS-CoV-2 cell entry, as shown in pseudovirus assay and experiment with authentic SARS-CoV-2. A comprehensive in silico analysis was carried out to study the physicochemical and pharmacokinetic properties, revealing that both compounds have good physicochemical properties as well as good bioavailability. Our results highlight the potential of small molecules targeting RBD inhibitors as potential therapeutic drugs for COVID-19.