Sulfilimines from a Medicinal Chemist’s Perspective: Physicochemical and in Vitro Parameters Relevant for Drug Discovery

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

While sulfoximines are nowadays a well established functional group for medicinal chemistry, the properties of sulfilimines significantly less studied, and no sulfilimine has progressed to clinic date. In this account, physicochemical in vitro reported compared those other more traditional groups. Furthermore, impact on real drug scaffolds is studied two series sulfilimine-containing analogs imatinib hNE inhibitors. We show that can be chemically configurationally stable under physiologically relevant conditions they basic highly polar thus often beneficial solubility metabolic stability, although at cost reduced permeability. conclude S-cyclopropyl,S-(hetero)aryl S,S-di(hetero)aryl so far neglected but potentially valuable S(IV) based pharmacophores deserve considered as part chemistry toolbox.

Язык: Английский

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Dual Copper/Photoredox Catalysis for Radical-Mediated Arylation and Alkylation of Sulfenamides

ACS Catalysis, Год журнала: 2025, Номер unknown, С. 4007 - 4016

Опубликована: Фев. 20, 2025

Язык: Английский

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Nitrene-mediated glycosylation with thioglycoside donors under metal catalysis

Science Advances, Год журнала: 2025, Номер 11(8)

Опубликована: Фев. 21, 2025

Glycosylation chemistry plays a pivotal role in glycoscience. Recent substantial developments have poised the field to address emerging challenges related sustainability, cost efficiency, and robust applicability complex substrate settings. The transition from stoichiometric activation metal-catalyzed methods promises enhanced chemoselectivity greater precision controlling glycosidic bond breakage formation, key overcoming existing obstacles. Here, we report nitrene-mediated glycosylation strategy using regular aryl sulfide glycosyl donors easily accessible 3-methyl dioxazolone as an activator under catalysis of iron or ruthenium. iron-catalyzed system demonstrates exceptional catalytic reactivity, requiring little 0.1 mole % catalyst at room temperature, works well for peptide substrates. ruthenium-catalyzed can accommodate acid-sensitive functional groups challenging low-reactivity acceptors. Mechanistic investigations unveiled unusual multistep pathways involving sulfur imidation via nitrene transfer sulfur-to-oxygen rearrangement N-acyl sulfilimines donors.

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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Decarboxylative Radical Sulfilimination via Photoredox, Copper, and Brønsted Base Catalysis

Angewandte Chemie International Edition, Год журнала: 2023, Номер 63(6)

Опубликована: Дек. 21, 2023

Sulfilimines, the aza-variants of sulfoxides, are key structural motifs in natural products, pharmaceuticals, and agrochemicals; sulfilimine synthesis is therefore important organic chemistry. However, methods for radical sulfilimination remain elusive, as a result, diversity currently available sulfilimines limited. Herein, we report first protocol decarboxylative reactions between sulfenamides N-hydroxyphthalimide esters primary, secondary, tertiary alkyl carboxylic acids, which were achieved via combination photoredox, copper, Brønsted base catalysis. This novel provided wide variety sulfilimines, addition to serving an efficient route S-alkyl/S-aryl homocysteine S-(4-methylphenyl) sulfoximine. Moreover, it could be used late-stage introduction group into structurally complex molecules, thereby avoiding need preserve labile organosulfur moieties through multistep synthetic sequences. A mechanism involving photocatalytic substrate transformation copper-mediated C(sp

Язык: Английский

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Selective S-Arylation of Sulfenamides with Arynes: Access to Sulfilimines

Organic Letters, Год журнала: 2023, Номер 25(39), С. 7192 - 7197

Опубликована: Сен. 21, 2023

Sulfilimines, the aza analogues of sulfoxides, are increasing interest in medicinal and agrochemical research programs. However, development efficient routes for their synthesis has remained relatively unexplored. In this study, we report a transition metal-free, selective S-arylation reaction between sulfenamides arynes, enabling facile preparation structurally diverse sulfilimines under mild redox-neutral conditions good yields. The application value our method was further demonstrated by scale-up synthesis, downstream derivatization, robustness screen.

Язык: Английский

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Enantioselective Synthesis of Sulfinamidines via Asymmetric Nitrogen Transfer from N−H Oxaziridines to Sulfenamides

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(35)

Опубликована: Май 15, 2024

Sulfinamidines are promising aza-S

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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Synthesis of chiral sulfilimines by organocatalytic enantioselective sulfur alkylation of sulfenamides

Science Advances, Год журнала: 2024, Номер 10(37)

Опубликована: Сен. 13, 2024

Sulfilimines are versatile synthetic intermediates and important moieties in bioactive molecules. However, their applications drug discovery underexplored, efficient asymmetric methods highly desirable. Here, we report a transition metal–free pentanidium-catalyzed sulfur alkylation of sulfenamides with exclusive chemoselectivity over nitrogen high enantioselectivity. The reaction conditions were mild, wide range enantioenriched aryl alkyl sulfilimines obtained. utility practicability this robust protocol further demonstrated through gram-scale reactions late-stage functionalization drugs.

Язык: Английский

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The Catalytic Synthesis of Aza-Sulfur Functional Groups

Synthesis, Год журнала: 2024, Номер unknown

Опубликована: Сен. 26, 2024

Abstract Sulfur-containing compounds are found in myriad applications. Sulfones and sulfonamides the most common functional groups used medicinal agrochemical endeavours. Isosteres of these groups, for example, sulfoximines sulfonimidamides, emerging functionalities, they increasingly relevant patent literature. However, general, associated synthetic routes still have limitations, including use harsh reaction conditions highly reactive reagents. A variety catalytic reactions that employ a diverse range substrate classes been developed to address issues. This short review highlights recent syntheses aza-sulfur compounds, which we hope will open new directions discovery chemistry. 1 Introduction 2 Reactions N-Sulfinylamines 3 with Sulfenamides 4 Sulfinates 5 Sulfinamides 6 Other Aza-Sulfur Compounds 7 Conclusion

Язык: Английский

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