Synthesis of ω-functionalized ketones from strained cyclic alcohols by ring-opening and cross-recombination between alkyl and N-oxyl radicals.

Radical ring-opening oxyimidation of cyclobutanols and cyclopropanols with the formation of ω-functionalized ketones was discovered. The oxidative C-O coupling proceeds via the interception of a primary alkyl radical generated from a cyclic alcohol with a reactive radical generated in situ, which is an electron-deficient N-oxyl radical. The developed conditions allow for the balanced generation rates of carbon- and N-oxyl radicals, which are necessary for their selective cross-recombination. Thus, typical competitive dimerization processes of carbon-centered radicals, their intermolecular cyclization, and N-oxyl radical self-decay are suppressed. The method is applicable to a wide range of cyclobutanols and results in oxyimidated ketones in yields of up to 82%.

C═N Bond Ozonolysis and ß-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 in situ 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. A major advantage of the approach is the ability to use different cycloalkanone semicarbazones, including those with large cycles and substituents in them. The possibility of carrying out ozonolysis in the presence of various alcohols makes it possible to obtain the corresponding esters of ω-substituted carboxylic acids.

Secosteroid diacylhydrazines as novel effective agents against hormone-dependent breast cancer cells.

This research aimed to develop novel selective secosteroids that are highly active against hormone-dependent breast cancer. A simple and convenient approach to N'-acylated 13,17-secoestra-1,3,5(10)-trien-17-oic acid hydrazides was disclosed and these novel types of secosteroids were screened for cytotoxicity against the hormone-dependent human breast cancer cell line MCF7. Most secosteroid N'-benzoyl hydrazides have demonstrated high cytotoxicity against MCF7 cells with IC50 values below 5 µM, which are superior to that of the reference drug cisplatin. Hit compounds 2c, 2e and 2i were characterized by high cytotoxicity (IC50 = 1.6-1.9 µM) and very good selectivity towards MCF7 breast cancer cells. The lead secosteroids 2c, 2e and 2i also exhibit antiestrogenic effects and alter the expression of cell cycle regulating proteins. The effect of selected compounds on PARP (poly(ADP-ribose) polymerase) and Bcl-2 (B-cell CLL/lymphoma 2) indicates their proapoptotic potential. The synthesized secosteroids may be considered as new promising anti-breast cancer agents targeting ERα and apoptosis pathways.

Electrochemical hydrocarboxylation of enol derivatives with CO2: access to ß-acetoxycarboxylic acids.

Electrochemical hydrocarboxylation of enol acetates with CO2 is developed. The disclosed process provides ß-acetoxycarboxylic acids in 25-66% yields, in contrast to the electrolysis of ketones, silyl enol ethers and vinyl tosylates with CO2, which leads mainly to alcohols.

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).

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.

Electrochemical Generation of Peroxy Radicals and Subsequent Peroxidation of 1,3-Dicarbonyls in an Undivided Cell.

The generation of peroxy radicals from hydroperoxides with subsequent selective peroxidation of 1,3-dicarbonyls in an undivided electrochemical cell under constant current conditions is reported. The method provides a variety of peroxy-containing barbituric acids and 4-hydroxy-2(5H)-furanones with yields of up to 74%. Only the combination of anodic and cathodic processes provides efficient peroxidation by generating a set of alkoxy and peroxy radicals. NaNO3 acts as both an electrolyte and a redox mediator of radical reactions.

C-O Coupling of Hydrazones with Diacetyliminoxyl Radical Leading to Azo Oxime Ethers-Novel Antifungal Agents.

Selective oxidative C-O coupling of hydrazones with diacetyliminoxyl is demonstrated, in which diacetyliminoxyl plays a dual role. It is an oxidant (hydrogen atom acceptor) and an O-partner for the oxidative coupling. The reaction is completed within 15-30 min at room temperature, is compatible with a broad scope of hydrazones, provides high yields in most cases, and requires no additives, which makes it robust and practical. The proposed reaction leads to the novel structural family of azo compounds, azo oxime ethers, which were discovered to be highly potent fungicides against a broad spectrum of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, Sclerotinia sclerotiorum).

Secosteroid thiosemicarbazides and secosteroid-1,2,4-triazoles as antiproliferative agents targeting breast cancer cells: Synthesis and biological evaluation.

A convenient and selective approach to 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-arylcarbothioamido]hydrazides and hybrid molecules containing secosteroid and 1,2,4-triazole fragments was disclosed and these novel types of secosteroids were screened for cytotoxicity against hormone-dependent human breast cancer cell line MCF-7. Most of secosteroid-1,2,4-triazole hybrids showed significant cytotoxic effect comparable or superior to that of the reference drug cisplatin. Hit secosteroid-1,2,4-triazole hybrids 4b and 4h were characterized by high cytotoxicity and good selectivity towards MCF-7 breast cancer cells. PARP cleavage (marker of apoptosis) and ERα and cyclin D1 downregulation were discovered in MCF-7 cells treated with lead secosteroid-1,2,4-triazole hybrid 4b. The synthesized secosteroids may be considered as new promising anticancer agents.

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.

The diacetyliminoxyl radical in oxidative functionalization of alkenes.

The intermolecular oxime radical addition to CC bonds was observed and studied for the first time. The diacetyliminoxyl radical was proposed as a model radical reagent for the study of oxime radical reactivity towards unsaturated substrates, which is important in the light of the active development of synthetic applications of oxime radicals. In the present work it was found that the diacetyliminoxyl radical reacts with vinylarenes and conjugated dienes to give radical addition products, whereas unconjugated alkenes can undergo radical addition or allylic hydrogen substitution by diacetyliminoxyl depending on the substrate structure. Remarkably, substituted alkenes give high yields of C-O coupling products despite the significant steric hindrance, whereas unsubstituted alkenes give lower yields of the C-O coupling products. The observed atypical C-O coupling yield dependence on the alkene structure was explained by the discovered ability of the diacetyliminoxyl radical to attack alkenes with the formation of a C-N bond instead of a C-O bond giving side products. This side process is not expected for sterically hindered alkenes due to lower steric availability of the N-atom in diacetyliminoxyl than that of the O-atom.

Free Radicals in the Queue: Selective Successive Addition of Azide and N-Oxyl Radicals to Alkenes.

The selective successive addition of azide (•N3) and N-oxyl radicals to alkenes is demonstrated, despite each of the two radicals being known to attack C═C bonds and the mixture of radical adducts possibly being expected. The proposed radical mechanism was supported by density functional theory calculations, electron paramagnetic resonance, and radical trapping experiments. The reaction proceeds at room temperature with the available reagents: NaN3, N-hydroxy compounds, and PhI(OAc)2 as the oxidant. The method can be applied for N-hydroxyimides, N-hydroxyamides, N-hydroxybenzotriazole, and oximes as N-oxyl radical precursors. Vinylarenes, aliphatic alkenes, and even electron-deficient methyl methacrylate were successfully functionalized.

Multicomponent Assembly of Bicyclic Aza-peroxides Catalyzed by Samarium Complexes and Their Cytotoxic Activity.

An original strategy toward bridged tetraoxazaspirobicycloalkanes was developed. The synthesis is based on a three-component condensation-cyclization reaction of primary arylamines with 1,1'-peroxybis (1-hydroperoxycycloalkanes) and pentane-1,5-dial catalyzed by Sm(NO3)3·6H2O. The structures and conformations of the products were determined by X-ray diffraction analysis and 1H and 13C NMR spectroscopy. High cytotoxic activity and biological potential toward ferroptosis induction were found for the synthesized bicyclic aza-peroxides.

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.

Two Discoveries in One Crystal: σ-Type Oxime Radical as an Unforeseen Building Block in Molecular Magnetics and Its Spatial Structure.

In the present work, the study of the unusual interaction between copper hexafluoroacetylacetonate and the diacetyliminoxyl radical resulted in two discoveries from different fields: the determination of the oxime radical spatial structure and the introduction of an oxime radical into the field of molecular magnetic material design. Oxime radicals are key plausible intermediates in the processes of oxidative CH-functionalization and in the synthesis of functionalized isoxazolines from oximes. Due to the lack of X-ray diffraction data for oxime radicals, the knowledge about their structure is based mainly on indirect approaches, spectroscopic methods (electron paramagnetic resonance and IR), and quantum chemical calculations. The structure of the oxime radical was determined for the first time by stabilizing the diacetyliminoxyl radical in the form of its complex with copper (II) hexafluoroacetylacetonate (Cu(hfac)2), followed by single-crystal X-ray diffraction analysis. Although oxime radicals are known to undergo oxidative coupling with acetylacetonate ligands in transition-metal complexes, a complex is formed with intact hfac ligands. X-ray diffraction studies have shown that the oxime radical is coordinated with copper ions through the oxygen atoms of the carbonyl groups without the direct involvement of the C═N-O• radical moiety. The structure of the coordinated diacetyliminoxyl is in good agreement with the density functional theory (DFT) prediction for free diacetyliminoxyl due to the very weak interaction of the radical molecule with copper ions. Remarkably, both weak ferromagnetic and antiferromagnetic interactions between Cu (II) and oxime radicals have been revealed by modeling the temperature dependence of magnetic susceptibility and confirmed by DFT calculations, rendering diacetyliminoxyl a promising building block for the design of molecular magnets.

The Ozone and Hydroperoxide Teamwork: Synthesis of Unsymmetrical Geminal Bisperoxides from Alkenes.

Alkene ozonolysis is mostly known as a textbook reaction, resulting in carbonyl compounds. The combination of ozone and hydroperoxide was found to lead to the construction of more oxygen-rich compounds, unsymmetrical geminal bisperoxides, avoiding as well further oxidation with ozone, hydroperoxide, and oxygen as peroxide rearrangements. The discovered three-component synthesis provided alkylperoxy hydroperoxides in 41-63% yield from alkenes.

An environmentally benign way to synthesize 2-thiocyano-1,3-dicarbonyl compounds with high antifungal activity: a key role of solvent.

The introduction of thiocyano groups into organic molecules is important for the preparation of many active ingredients and synthetic intermediates. A commonly used and attractive strategy is the nucleophilic substitution of halogens with the SCN anion or oxidative thiocyanation using an excess amount of external oxidants. A sustainable alternative to stoichiometric reagents is electrochemistry based on anodic oxidation of the SCN anion and other intermediates. Electrochemical thiocyanation of various organic compounds, carried out in the usual non-acidic organic solvents, is well known. Here, we present an electrochemical thiocyanation of 1,3-dicarbonyl compounds in which high efficiency was only achieved using AcOH as the solvent. Electrolysis proceeds in an undivided cell under constant current conditions without any additional halogen-containing electrolytes. Ammonium thiocyanate was used as the source of the SCN group and the electrolyte. Electrochemical thiocyanation of 1,3-dicarbonyl compounds begins with the generation of (SCN)2 from the thiocyanate anion, followed by the addition of thiocyanogen to the double bond of the enol tautomer of 1,3-dicarbonyl compounds, which finally gives the products. A variety of thiocyanated 1,3-dicarbonyl compounds bearing different functional groups were obtained in 37-82% yields and were shown to exhibit high antifungal activity.

Heterogeneous Photocatalysis as a Potent Tool for Organic Synthesis: Cross-Dehydrogenative C-C Coupling of N-Heterocycles with Ethers Employing TiO2/N-Hydroxyphthalimide System under Visible Light.

Despite the obvious advantages of heterogeneous photocatalysts (availability, stability, recyclability, the ease of separation from products and safety) their application in organic synthesis faces serious challenges: generally low efficiency and selectivity compared to homogeneous photocatalytic systems. The development of strategies for improving the catalytic properties of semiconductor materials is the key to their introduction into organic synthesis. In the present work, a hybrid photocatalytic system involving both heterogeneous catalyst (TiO2) and homogeneous organocatalyst (N-hydroxyphthalimide, NHPI) was proposed for the cross-dehydrogenative C-C coupling of electron-deficient N-heterocycles with ethers employing t-BuOOH as the terminal oxidant. It should be noted that each of the catalysts is completely ineffective when used separately under visible light in this transformation. The occurrence of visible light absorption upon the interaction of NHPI with the TiO2 surface and the generation of reactive phthalimide-N-oxyl (PINO) radicals upon irradiation with visible light are considered to be the main factors determining the high catalytic efficiency. The proposed method is suitable for the coupling of π-deficient pyridine, quinoline, pyrazine, and quinoxaline heteroarenes with various non-activated ethers.

Secosteroid-quinoline hybrids as new anticancer agents.

An elegant approach to unknown secosteroid-quinoline hybrids is disclosed. A series of 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-(iso)quinolylmethylene]hydrazides was prepared and these novel type of secosteroids was screened for antiproliferative activity against estrogen-responsive human breast cancer cell line MCF-7. Most of the synthesized compounds showed a cytotoxic effect superior to that of reference drug cisplatin; the lead compound exhibits the highest activity with the IC50 value of about 0.8 µM and is 7 times more active than cisplatin. A high selectivity index was observed for the hit 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-quinolylmethylene]hydrazides 2a and 2c. Compounds 2a and 2c evaluated in luciferase reporter assays exhibited high antiestrogenic potency which was superior to that of tamoxifen. These hit compounds were characterized by high activity against MCF-7 cells that retained towards multidrug-resistant NCI/ADR-RES cells.