Electrochemical Synthesis of Spirolactones from α-Tetralone Derivatives with Methanol as a C1 Source.

Spirolactones are widely found in pharmaceuticals and bioactive natural products. However, efficient and environmentally friendly approaches to accessing spirolactones are still highly desirable. Herein, a novel electrochemical synthesis of spirolactones from α-tetralone derivatives with methanol as a C1 source is described. This electrochemical reaction exhibits a high efficiency and good functional group tolerance.

Asymmetric Sulfonylation from a Reaction of Cyclopropan-1-ol, Sulfur Dioxide, and 1-(Alkynyl)naphthalen-2-ol.

Asymmetric sulfonylation from a reaction of cyclopropan-1-ol, sulfur dioxide, and 1-(alkynyl)naphthalen-2-ol in the presence of a catalytic amount of organocatalyst at room temperature is developed. Axially chiral (S)-(E)-1-(1-(alkylsulfonyl)-2-arylvinyl)naphthalen-2-ols are generated in moderate to good yields with excellent enantioselectivity and regioselectivity under mild conditions. During this transformation, γ-keto sulfinate generated in situ from cyclopropan-1-ol and sulfur dioxide acts as the key intermediate.

A three-component reaction of cyclobutanone oxime esters, sulfur dioxide and N-alkyl-N-methacryloyl benzamides.

A three-component reaction of cyclobutanone oxime esters, DABCO·(SO2)2 and N-alkyl-N-methacryloyl benzamides is described. This reaction proceeds without the addition of any oxidant or transition metal, affording sulfonyl-containing isoquinoline-1,3-(2H,4H)-diones in moderate to good yields. Various functional groups are tolerated well in this transformation. Mechanistic studies suggest that a radical pathway is involved, including ß-scission, sulfur dioxide insertion, and intramolecular cyclization processes.

On the Dynamic Mechanism of Long-Flexible Fatty Acid Binding to Fatty Acid Binding Protein: Resolving the Long-Standing Debate.

Fatty acids (FAs) are one of the essential energy sources for physiological processes, and they play a vital role in regulating immune and inflammatory responses, promoting cell differentiation and apoptosis, and inhibiting tumor growth. These functions are carried out by FA binding proteins (FABPs) that recognize and transport FAs. Although the crystal structure of the FA-FABPs complex has long been characterized, the mechanism behind FA binding and dissociation from FABP remains unclear. This study employed conventional MD simulations and enhanced sampling technologies to investigate the atomic-scale complexes of heart fatty acid binding proteins and stearic acid (SA). The results revealed two primary pathways for the binding or dissociation of the flexible long-chain ligand, with the orientation of the SA carboxyl head during dissociation determining the chosen path. Conformational changes in the portal region of FABP during the ligand binding/unbinding were found to be trivial, and the overturn of the ″cap″ or the unfolding of the α2 helix was not required. This study resolves the long-standing debate on the binding mechanism of SA with the long-flexible tail to FABP, which significantly improves the understanding of the transport mechanism of FABPs and the development of related therapeutic agents.

Construction of ß-Amino Sulfones from Sodium Metabisulfite via a Radical 1,4-Amino Migration.

A three-component reaction of alkenyl-tethered oxime ethers, sodium metabisulfite, and aryldiazonium tetrafluoroborates under mild conditions is developed. This reaction proceeds at room temperature without any oxidants or additives, affording ß-amino sulfones with good functional group tolerance through aminosulfonylation of unactivated alkene. Mechanistic studies show that this transformation undergoes a radical process, including radical trapping with sulfur dioxide and radical 1,4-amino migration.

Alkoxysulfonyl radical species: acquisition and transformation towards sulfonate esters through electrochemistry.

Sulfonyl radical mediated processes have been considered as a powerful strategy for the construction of sulfonyl compounds. However, an efficient and high atom-economical radical approach to the synthesis of sulfonate esters is still rare, owing to the limited tactics to achieve alkoxysulfonyl radicals. Herein, an electrochemical anodic oxidation of inorganic sulfites with alcohols is developed to afford alkoxysulfonyl radical species, which are utilized in subsequent alkene difunctionalization to provide various sulfonate esters. This transformation features excellent chemoselectivity and broad functional group tolerance. This new discovery presents the potential prospect for the construction of sulfonate esters, and enriches the electrochemical reaction type.

Access to chiral ß-sulfonyl carbonyl compounds via photoinduced organocatalytic asymmetric radical sulfonylation with sulfur dioxide.

An organocatalytic enantioselective radical reaction of potassium alkyltrifluoroborates, DABCO·(SO2)2 and α,ß-unsaturated carbonyl compounds under photoinduced conditions is developed, which provides an efficient pathway for the synthesis of chiral ß-sulfonyl carbonyl compounds in good yields with excellent enantioselectivity (up to 96% ee). Aside from α,ß-unsaturated carbonyl compounds with auxiliary groups, common chalcone substrates are also well compatible with this organocatalytic system. This method proceeds through an organocatalytic enantioselective radical sulfonylation under photoinduced conditions, and represents a rare example of asymmetric transformation involving sulfur dioxide insertion.

Access to Sulfoxides under NHC/Photocatalysis via a Radical Pathway.

A photocatalyzed transformation from sulfinic acids to sulfoxides under visible-light irradiation in the presence of N-heterocyclic carbene is established. Various alkyl groups from four-substituted Hantzsch esters or Meyer nitriles are smoothly converted to the corresponding sulfoxides through a radical coupling pathway in the presence of 1,1-carbonyldiimidazole. This method allows sulfoxide synthesis to refrain from relying on the oxidation of sulfides and provides an alternative route for the preparation of sulfoxides.

Generation of Heteroaryl-Substituted Sulfonyl Compounds from Sulfur Dioxide via Remote Heteroaryl ipso-Migration.

The generation of heteroaryl-substituted sulfonyl compounds via a catalyst-, base-, and additive-free three-component reaction of heteroaryl-substituted tertiary alcohols, aryldiazonium tetrafluoroborates, and DABCO·(SO2)2 under mild conditions is developed. Various functional groups are tolerated well in this transformation, and a broad substrate scope is demonstrated. A preliminary mechanistic investigation shows that this reaction undergoes a radical process, including the insertion of sulfur dioxide, sulfonyl radical addition to unactivated alkene, and remote heteroaryl ipso-migration.

S(vi) in three-component sulfonamide synthesis: use of sulfuric chloride as a linchpin in palladium-catalyzed Suzuki-Miyaura coupling.

Sulfuric chloride is used as the source of the -SO2- group in a palladium-catalyzed three-component synthesis of sulfonamides. Suzuki-Miyaura coupling between the in situ generated sulfamoyl chlorides and boronic acids gives rise to diverse sulfonamides in moderate to high yields with excellent reaction selectivity. Although this transformation is not workable for primary amines or anilines, the results show high functional group tolerance. With the solving of the desulfonylation problem and utilization of cheap and easily accessible sulfuric chloride as the source of sulfur dioxide, redox-neutral three-component synthesis of sulfonamides is first achieved.

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species.

Liver S9 (LS9) is a nearly complete collection of all hepatic drug-metabolizing enzymes. It is a low-cost model for predicting drug metabolic activity. This study aimed to identify the suitability of using LS9 of different animal sources in drug metabolism profiling with respect to the possible translation of the in vitro outcomes to clinical studies. The in vitro hepatic metabolism of curcumin diethyl disuccinate (CDD) in LS9 of rats, dogs, monkeys, and humans was evaluated. The identity of CDD metabolites and the metabolism kinetic parameters, including degradation rate constant, in vitro/in vivo intrinsic clearance, and half-life, were determined. CDD was rapidly metabolized into monoethylsuccinyl curcumin and curcumin in LS9 of all tested species mainly by carboxylesterases (CESs), including CES1 and CES2, and butyrylcholinesterase. The in vitro intrinsic clearance of CDD was in the order of human > dog > monkey > rat, whereas that of monoethylsuccinyl curcumin in the order of dog > monkey > human > rat; this parameter was not correlated with their respective in vivo clearance, which followed the order of dog > monkey > rat > human. Therefore, in vitro drug metabolism data inferred from LS9 of nonhuman origin, especially from monkeys and dogs, cannot be used as preclinical data for human trials, as humans have a smaller liver-to-body weight ratio than monkeys, dogs, and rats. The in vivo drug metabolism is dictated by the anatomical factors of the test subject.

A metal-free reaction of sulfur dioxide, cyclopropanols and electron-deficient olefins.

The importance of γ-keto sulfones in medicinal chemistry and organic synthesis is known. An efficient route to γ-keto sulfones via a metal-free reaction of cyclopropanols, sulfur dioxide and electron-deficient olefins is achieved. This reaction proceeds smoothly under mild conditions without the need of catalyst, oxidant or additive. A plausible mechanism is proposed, which occurs through a γ-keto sulfinate intermediate generated in situ from the reaction of cyclopropanol with sulfur dioxide. The γ-keto sulfinate intermediate would be trapped by the electron-deficient olefin, resulting in the formation of γ-keto sulfones. Various functional groups in the cyclopropanols and electron-deficient olefins are compatible in this transformation.

Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696.

LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial production had to be developed for sacubitril. The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art technologies allowed to efficiently build up the structure of sacubitril and achieve the defined performance targets.

Recent advances in sulfonylation reactions using potassium/sodium metabisulfite.

Recently, sulfonylation reactions using potassium/sodium metabisulfite as the sulfur dioxide surrogate have been developed rapidly. In most cases, the transformations go through radical processes with the insertion of sulfur dioxide under mild conditions. Additionally, transition metal catalysis is applied in the reactions for the synthesis of sulfonyl-containing compounds. Among the approaches, photoinduced conversions under visible light or ultraviolet irradiation are also involved. In this updated report, the insertion of sulfur dioxide from potassium metabisulfite or sodium metabisulfite is summarized.

Photoinduced synthesis of 2-sulfonylacetonitriles with the insertion of sulfur dioxide under ultraviolet irradiation.

Metal-free insertion of sulfur dioxide with aryl iodides and 3-azido-2-methylbut-3-en-2-ol under ultraviolet irradiation at room temperature is achieved, giving rise to 2-(arylsulfonyl)acetonitriles in moderate to good yields. Alkyl iodide is also workable under these conditions. This transformation proceeds smoothly under mild conditions with a broad substrate scope. Various functional groups are compatible including amino, ester, halo, and trifluoromethyl groups. No metal catalyst or additive is needed during the reaction process. Mechanistic studies show that under ultraviolet irradiation, an aryl radical is generated in situ from aryl iodide, which undergoes subsequent sulfonylation via the insertion of sulfur dioxide leading to arylsulfonyl radical intermediates. Then the arylsulfonyl radical reacts with 3-azido-2-methylbut-3-en-2-ol giving rise to the corresponding 2-(arylsulfonyl)acetonitrile.

Photoredox-catalyzed synthesis of sulfones through deaminative insertion of sulfur dioxide.

Katritzky salts are used as the alkyl radical precursors with the insertion of sulfur dioxide under photoredox catalysis. This transformation first enables direct generation of various alkylsulfonyl radicals by photoinduced single electron reduction, leading to diverse dialkyl sulfones in good to excellent yields. A radical pathway is proposed under visible-light induced conditions with the insertion of sulfur dioxide.

Photoredox-Catalyzed Sulfonylation of O-Acyl Oximes via Iminyl Radicals with the Insertion of Sulfur Dioxide.

A multicomponent sulfonylation of O-acyl oximes via iminyl radicals with the insertion of sulfur dioxide under photoredox catalysis is achieved. This multicomponent reaction of O-acyl oximes, potassium metabisulfite, alkenes, and nucleophiles under visible-light irradiation is efficient, giving rise to a range of sulfones in moderate to good yields. A broad reaction scope is presented with good functional group compatibility.

Thiourea dioxide as a source of sulfonyl groups: photoredox generation of sulfones and sulfonamides from heteroaryl/aryl halides.

Thiourea dioxide as the source of sulfonyl groups for the efficient synthesis of heteroaryl sulfones and sulfonamides from heteroaryl halides under visible light irradiation is reported. This transformation proceeds smoothly via heteroaryl sulfinate intermediates, which can be trapped in situ by various electrophiles. A broad reaction scope is demonstrated, especially for the electron-deficient heteroaryl halides. Mechanistic studies show that the radical coupling of the heteroaryl radical and sulfur dioxide radical anion may be the key step during the reaction process, as supported by EPR spectroscopy and DFT calculations.

Photoredox-catalyzed sulfonylation of alkyl iodides, sulfur dioxide, and electron-deficient alkenes.

A photoredox-catalyzed sulfonylation of alkyl iodides, sulfur dioxide, and electron-deficient alkenes under mild conditions is achieved. This reaction proceeds through alkyl radicals formed in situ from alkyl iodides under visible light irradiation in the presence of a photoredox catalyst. The alkyl radical intermediates would react with sulfur dioxide leading to alkylsulfonyl radicals, which would be trapped by electron-deficient alkenes giving rise to alkyl sulfones. Various functional groups including nitro, halo, acetyl, sufonyl, and pyridinyl are all tolerated under the photoredox conditions.

Synthesis of 3-(Methylsulfonyl)benzo[ b]thiophenes from Methyl(2-alkynylphenyl)sulfanes and Sodium Metabisulfite via a Radical Relay Strategy.

A radical relay strategy for the generation of 3-(methylsulfonyl)benzo[ b]thiophenes through a reaction of methyl(2-alkynylphenyl)sulfanes with sodium metabisulfite in the presence of a photocatalyst under visible light irradiation is developed. This photoinduced sulfonylation proceeds efficiently under mild conditions by using a catalytic amount of sodium methylsulfinate as an initiator. During the reaction process, the methyl radical generated in situ is the key intermediate, which undergoes a radical relay with the combination of sulfur dioxide to afford methylsulfonyl-containing compounds.