Unlocking Chiral Sulfinimidoyl Electrophiles: Asymmetric Synthesis of Sulfinamides Catalyzed by Anionic Stereogenic-at-Cobalt(III) Complexes

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Asymmetric catalysis involving a sulfoxide electrophile intermediate presents an efficient methodology for accessing stereogenic-at-sulfur compounds, such as sulfinate esters, sulfinamides, etc., which have garnered increasing attention in modern pharmaceutical sciences. However, the aza-analog of electrophiles, asymmetric issues about electrophilic sulfinimidoyl species remain largely unexplored and represent significant challenge sulfur stereochemistry. Herein, we exhibit anionic stereogenic-at-cobalt(III) complex-catalyzed synthesis chiral sulfinamides via iodide intermediates. Mechanistic investigations reveal that catalytic cycle is initiated by oxidative iodination, generating iodides. These active intermediates subsequently undergo enantiospecific nucleophilic substitution with water, affording diverse array enantioenriched sulfinamides. Notably, these promising antifungal activities against Sclerotinia sclerotiorum serve ideal platform molecules facilitating stereospecific transformation into various stereogenic aza-sulfur compounds.

Язык: Английский

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Assembly of (hetero)aryl sulfilimines via copper-catalyzed enantioselective S-arylation of sulfenamides with (hetero)aryl Iodides

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 8, 2025

The (hetero)aryl sulfoximines are important structures for developing bioactive molecules, whose synthesis relies on oxidation of sulfilimines. However, asymmetric approaches assembling sulfilimines still rare. Here we show that combination CuI and NOBIN-derived amide ligands offers an effective catalytic system enantioselective coupling iodides with sulfenamides. A large number functional groups heterocycles tolerated under the conditions, providing a powerful approach diverse enantioenriched efficiency reaction is highly dependent electronic nature Both (hetero)aryl- some bulky alkyl-substituted sulfenamides give excellent enantioselectivities, while smaller alkyl substituents lead to formation moderate enantioselectivities. Density theory (DFT) calculations reveal proper steric repulsions in transition states intramolecular SNAr crucial achieving desirable enantioselectivity. (Hetero)aryl useful bioisosteres sulfones medicinal chemistry as they have improved aqueous solubility metabolic stability. Here, authors report via copper-catalysed

Язык: Английский

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Ligand-Enabled Copper-Catalyzed Ullmann-Type S–C Bond Formation to Access Sulfilimines

Organic Letters, Год журнала: 2024, Номер unknown

Опубликована: Сен. 12, 2024

A copper-catalyzed Ullmann-type cross-coupling reaction of sulfenamides with aryl iodides is developed. The key to success the use a 2-methylnaphthalen-1-amine-derived amide ligand, which enables formation an S-C bond access functionalized sulfilimines in good excellent yields at room temperature. This method has advantages mild conditions, broad substrate scope, functional group compatibility, and high chemoselectivity. utility this protocol highlighted through late-stage modification drug-relevant molecules sulfilimine product derivatization.

Язык: Английский

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Intermolecular amination of Ethyl Benzo ylacetate via photocatalytic nitrene transfer reactions

Organic Chemistry Frontiers, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This study reports a photocatalytic nitrene transfer reaction of 1,3-dicarbonyl. A broad range substrates and iodinanes are shown, enabling direct C–H functionalization without the need for pre-formed nucleophilic enolate equivalents.

Язык: Английский

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Iron-catalysed stereoselective NH transfer enables dynamic kinetic resolution of sulfoxides

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 8, 2025

Transition metal-catalysed asymmetric nitrene transfer provides a powerful means to access various bioactive N-containing compounds as single enantiomers. However, enantioselective NH that allows concise assembly of unprotected enantioenriched amines remains an enduring challenge. We report here iron-catalysed stereoselective imidation sulfoxide, which is integrated with photocatalytic racemisation enabling dynamic kinetic resolution (DKR) strategy for direct and synthesis NH-sulfoximines. This approach distinct from the existing methods by avoiding protecting group manipulations and/or use chiral substrates. Computational studies on reaction suggest involvement iron-aminyl radical intermediate, its sulfoxide proceeds through synchronous nucleophilic addition nitrogen center ligand-to-metal electron process form N–S bond. In addition, stereoselectivity primarily dictated difference in dispersion interactions transition states. Enantioselective Here, authors

Язык: Английский

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Asymmetric Catalytic (3 + 2) Cyclization and Sequential Reaction to Construct Dihydrofuran- and Azepine-Based Spirooxindoles

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 22, 2025

The enantioselective formal (3 + 2) cyclization and sequential reaction of 2-malononitrile-substituted oxindoles with benzaldehydes ortho-aminobenzaldehydes were achieved by chiral N,N′-dioxide/metal complex Lewis acid catalysts. This protocol supplies facile efficient access to highly functionalized dihydrofuran- azepine-based spirooxindoles. Based on the control experiments deuterium labeling studies, interconversion diastereomeric intermediates under conditions reversible 1,5-H transfer step disclosed.

Язык: Английский

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Anionic Stereogenic-at-Cobalt(III) Complex-Enabled Asymmetric Oxidation of N,N-Dialkyl Sulfenamides

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

An asymmetric oxidation of N,N-dialkyl sulfenamides is exhibited by using anionic stereogenic-at-cobalt(III) complexes as catalysts. This protocol provides an alternative approach to access a diverse set chiral tertiary sulfinamides with high enantioselectivities (24 examples, up 94:6 e.r.). Additionally, control experiments suggest that this could be accomplished through cationic S(IV) intermediate.

Язык: Английский

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Cu-Catalyzed Enantioselective S-Arylation of Sulfenamides Enabled by Confined Ligands

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

Chiral sulfilimines, aza analogues of sulfoxides, are essential in natural products and pharmaceuticals, highlighting the importance their synthesis asymmetric catalysis. However, efficient approaches for synthesizing chiral diaryl sulfilimines still rare challenging, particularly those with two sterically similar aryl groups. Herein, we present a mild protocol generating diverse enantioenriched alkyl via copper-catalyzed enantioselective S-arylation N-acyl sulfenamides diaryliodonium salts. A bulky PyBox ligand is crucial stereocontrol, delivering various up to 95% ee (51 examples).

Язык: Английский

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Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant S-Methyl and S-Cyclopropyl Sulfoximines

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Апрель 28, 2025

Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S-methyl or S-cyclopropyl substituent. Here, we report on a general efficient sequence for the asymmetric synthesis of both these substitution patterns. The sulfilimine intermediates by first Ru-catalyzed enantioselective alkylation sulfenamides enables examples S-alkylation monosubstituted diazo compounds. reaction proceeds at ≤1 mol % Ru-catalyst loading, tert-butyl diazoacetate, high yields ≥98:2 er achieved exceedingly broad range sulfenamides, including S-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, -tert-butyl substituents sterically electronically diverse N-acyl groups. Sulfenamides derived from densely functionalized advanced drug also alkylated 99:1 er. After oxidation N-pivaloyl S-tert-butyl acetate substituted to corresponding sulfoximine, treatment trifluoracetic acid aprotic solvent resulted decarboxylation while aqueous HCl cleavage group give NH sulfoximine. Alternatively, dibromoethane followed acid-mediated provided preclinical candidate LTGO-33 formal phase II ART0380 demonstrate utility disclosed approach.

Язык: Английский

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Visible-Light-Mediated Copper-Catalyzed S-Arylation of Sulfenamides with Aryl Thianthrenium Salts

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Май 2, 2025

The site-selective incorporation of sulfilimine functionalities into aromatic compounds provides a vital strategy for drug discovery in medicinal chemistry. However, green and sustainable methods realizing the goal are still limited. Here, we report copper-catalyzed S-arylation sulfenamides with aryl thianthrenium salts irradiated by visible light without photocatalyst, which exhibited fine functional-group compatibility gave desired products high yields. Mechanistic investigations revealed that key to achieving these results is generation an electron donor-acceptor (EDA) complex between under basic conditions.

Язык: Английский

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