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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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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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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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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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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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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Synthesis of Sulfilimines via Multicomponent Reaction of Arynes, Sulfamides, and Thiosulfonates

Organic Letters, Год журнала: 2023, Номер 25(33), С. 6133 - 6138

Опубликована: Авг. 14, 2023

In this work, a facile and efficient method for the synthesis of sulfilimines through multicomponent reaction arynes, sulfamides, thiosulfonates was developed. A variety structurally diverse substrates functional groups were very compatible in reaction, giving corresponding good to high yields. This protocol could be conducted on gram scale, product easily converted sulfide sulfoximine. Mechanism studies revealed that sulfenamide generated situ is key intermediate reaction.

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 functionalized sulfilimines via iron-catalyzed sulfur alkylation of sulfenamides with diazo compounds

Green Chemistry, Год журнала: 2023, Номер 25(22), С. 9092 - 9096

Опубликована: Янв. 1, 2023

An efficient iron-catalyzed sulfur alkylation of sulfenamides with diazo compounds for the synthesis functionalized sulfilimines is developed under air conditions.

Язык: Английский

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Synthesis of N‐Acylsulfenamides from (Hetero)Aryl Iodides and Boronic Acids by One‐Pot Sulfur‐Arylation and Dealkylation

Angewandte Chemie International Edition, Год журнала: 2023, Номер 63(3)

Опубликована: Ноя. 28, 2023

Abstract A general one‐pot approach to diverse N ‐acylsulfenamides from a common S ‐phenethylsulfenamide starting material is reported. This was demonstrated by C−S bond formation utilizing commercially abundant (hetero)aryl iodides and boronic acids provide sulfilimine intermediates that undergo thermal elimination of styrene. In contrast, all prior approaches rely on thiol inputs introduce sulfenamide ‐substituents. broad scope reaction including for approved drugs drug precursors with dense display functionality. Several different types sulfur functionalization were performed derived complex precursor the blockbuster anticoagulant apixaban, highlighting utility this introduction high oxidation state groups in bioactive compounds. Mechanistic studies established key styrene step proceeds concerted does not require reagents or catalysts, therefore, should be applicable synthesis electrophiles conditions formation.

Язык: Английский

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