Chiral Sulfoximines Research Articles

Photoinduced Asymmetric Alkene Aminohetarylation with Chiral Sulfoximine Reagents.

Given the pivotal role of β-(het)arylethylamine moiety in bioactive molecules, the direct amino(het)arylation of alkenes occupies a privileged position in the construction of (het)arylethylamine derivatives. Herein we devise chiral sulfoximines as novel bifunctional reagents which exhibit remarkable efficiency in the challenging asymmetric alkene aminohetarylation reaction, particularly in terms of reactivity and stereo-control. The chiral reagents can be conveniently accessed in gram scale, and efficiently generate N-centered radicals under mild photochemical conditions. The transformation proceeds through enantioselective 1,4-hetaryl migration, ensuring precise chirality transfer from sulfur- to carbon-centers, rendering wide applicability to both aromatic and aliphatic alkenes. Furthermore, the method is straightforward to operate and does not require transition metals or photosensitizers, making it an attractive and practical option.

Photoinduced Asymmetric Alkene Aminohetarylation with Chiral Sulfoximine Reagents

AbstractGiven the pivotal role of β‐(het)arylethylamine moiety in bioactive molecules, the direct amino(het)arylation of alkenes occupies a privileged position in the construction of (het)arylethylamine derivatives. Herein we devise chiral sulfoximines as novel bifunctional reagents which exhibit remarkable efficiency in the challenging asymmetric alkene aminohetarylation reaction, particularly in terms of reactivity and stereo‐control. The chiral reagents can be conveniently accessed in gram scale, and efficiently generate N‐centered radicals under mild photochemical conditions. The transformation proceeds through enantioselective 1,4‐hetaryl migration, ensuring precise chirality transfer from sulfur‐ to carbon‐centers, rendering wide applicability to both aromatic and aliphatic alkenes. Furthermore, the method is straightforward to operate and does not require transition metals or photosensitizers, making it an attractive and practical option.

Chiral Sulfoximine Mediated Cobalt-Catalyzed Atropselective C-H Annulation of Ynamides.

An achiral Cp*Co(III)-catalyzed enantioselective C-H activation/annulation of chiral sulfoximine-enabled thioamides with ynamides is presented herein. This method successfully synthesizes axially chiral five-membered 2-amidoindenones with good enantiocontrol. Interestingly, the annulation with chiral oxazolidone-containing ynamides could provide a separable mixture of diastereomers (up to ~10 : 1 dr). Moreover, enantiopure sulfoximines could be recovered with ~99 % purity, making this method practical. DFT studies show valuable insight into the mechanism and origin of asymmetric induction.

Chiral Brønsted Acid-Catalyzed Kinetic Resolution of Sulfoximines for the Synthesis of Benzothiadiazine-1-Oxides.

Benzothiadiazine-1-oxide scaffolds with S-stereogenic centers are prevalent in bioactive and pharmaceutical molecules. Reported works mainly focused on the metal-catalyzed asymmetric C-H amination/cyclization reaction for the synthesis of benzothiadiazine-1-oxides. Here, we reported a chiral phosphoric acid-catalyzed kinetic resolution of sulfoximines, providing chiral benzothiadiazine-1-oxides and recovered chiral sulfoximines with moderate to good enantioselectivities (s factors up to 36.6).

Probing Chiral Sulfoximine Auxiliaries in Ru(II)-Catalyzed One-Pot Asymmetric C-H Hydroarylation and Annulations with Alkynes.

Developed herein is a chiral sulfoximine-enabled Ru(II)-catalyzed asymmetric C-H activation/functionalization involving intramolecular hydroarylation and functionalization/annulation of alkynes. This process constructs dihydrobenzofuran- or indoline-fused isoquinolinones having a tertiary or quaternary stereocenter with good yields and enantioselectivities (up to 97:3 enantiomeric ratio). The chiral sulfoxide precursor used in synthesizing the enantiopure sulfoximines is spontaneously eliminated during the reaction. It can be recovered without losing enantiopurity (∼99% enantiomeric excess) and reused.

Practical Asymmetric Synthesis of Sulfoximines and Sulfimides from Sulfinamides

AbstractChiral sulfoximines and sulfimides are an interesting class of compounds in various areas. However, methodologies for preparing these chiral sulfur compounds in a stereoselective manner have been underdeveloped. Herein, we briefly summarize our recent studies on asymmetric synthesis of sulfoximines and sulfimides from readily available enantioenriched sulfinamides. In these studies, optically pure sulfoximines and sulfimides having various carbon substituents on their sulfur atom could be obtained.1 Introduction2 Asymmetric Synthesis of Chiral Sulfoximines3 Asymmetric Synthesis of Chiral Sulfimides4 Conclusion

Chromatographic Enantioseparation of Chiral Sulfoximines on Polysaccharide-Based Chiral Stationary Phases.

Chiral sulfoximines have significant roles in pharmaceutical industry and agricultural chemicals. Furthermore, chiral structurally related sulfoximines are used for their wide potential applications in some uncharted territory. However, chromatographic study on these compounds has not been systematically performed. Herein, this paper describes the enantioseparation of 12 chiral sulfoximines on polysaccharide-based chiral stationary phases (CSPs). Separation factors of chiral column, high-performance liquid chromatography parameters such as mobile phase composition and column temperature were carefully investigated. Chiralcel OJ-H column can resolve all of the 12 compounds, while Chiralpak AD-H column and Chiralpak AS-H column can separate eight and nine molecules, respectively. The sulfoximines are effectively resolved with Chiralcel OJ-H column with a mixture of n-hexane/2-propanol (80:20) as the mobile phase.

Synthesis of Chiral Sulfoximines via Iridium‐Catalyzed Regio‐ and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand

AbstractTransition metal‐catalyzed enantioselective C−H activation of prochiral sulfoximines for non‐annulated products remains a formidable challenge. We herein report iridium‐catalyzed enantioselective C−H borylation ofN‐silyl diaryl sulfoximines using a well‐designed chiral bidentate boryl ligand with a bulky side arm. This method is capable of accommodating a broad range of substrates under mild reaction conditions, affording a vast array of chiral sulfoximines with high enantioselectivities. We also demonstrated the synthetic utility on a preparative‐scale C−H borylation for diverse downstream transformations, including the synthesis of chiral version of bioactive molecules. Computational studies showed that the bulky side arm of the ligand confers high regio‐ and enantioselectivity through steric effect.

Synthesis of Chiral Sulfoximines via Iridium-Catalyzed Regio-and Enantioselective C-H Borylation: A Remarkable Sidearm Effect of Ligand.

Transition metal-catalyzed non-annulation enantioselective C-H activation of prochiral sulfoximines remains a formidable challenge. We herein report iridium-catalyzed enantioselective C-H borylation of N-silyl protected diaryl sulfoximines using a well-designed chiral bidentate boryl ligand with a bulky side arm. A broad spectrum of functional groups could be well-tolerated, affording a vast array of chiral sulfoximines with high enantioselectivities. We also demonstrated the synthetic utility on a preparative-scale C-H borylation for diverse downstream transformations, including chiral version of bioactive molecules. Computational studies showed the bulky side arm of the ligand confers high regio- and enantioselectivity through steric effect.

Catalytic Enantioselective Sulfur Alkylation of Sulfenamides for the Asymmetric Synthesis of Sulfoximines.

Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first S-alkylation of sulfenamides, which are readily accessible sulfur compounds with one carbon and one nitrogen substituent, represents the key step. A broad scope for S-alkylation was achieved by rhodium-catalyzed coupling with diazo compounds under mild conditions. When a chiral rhodium catalyst was utilized with loadings as low as 0.1 mol %, the S-alkylation products were obtained in high yields and with enantiomeric ratios up to 98:2 at the newly generated chiral sulfur center. The S-alkylation products were efficiently converted to a variety of sulfoximines with complete retention of stereochemistry. The utility of this approach was further demonstrated by the asymmetric synthesis of a complex sulfoximine agrochemical.

Practical Asymmetric Synthesis of Chiral Sulfoximines via Sulfur-Selective Alkylation.

Chiral sulfoximines have recently been considered as promising bioisosteres in medicinal chemistry. However, methods for preparing chiral sulfoximines in a stereoselective manner are underdeveloped. Herein, we demonstrate an asymmetric synthesis of chiral sulfoximines through a stereospecific S-alkylation of readily accessible chiral sulfinamides under practical conditions. A key to establishing the practical conditions was the identification of the intermediate structure in our previously reported S-alkylation by X-ray crystallographic analysis.

Catalytic Enantioselective Synthesis of Pyridyl Sulfoximines.

With unique chemical and biological activity, sulfoximines have attracted enormous attention in the past decades, whereas limited reports exist for their synthesis via asymmetric catalysis. We report the synthesis of chiral sulfoximines through the desymmetrizing N-oxidation of pyridyl sulfoximines using an aspartic acid-containing peptide catalyst. Various mono- and bis-pyridyl sulfoximine oxides are obtained with up to 99:1 er. The directing group introduced on the substrate highly enhances the enantioinduction and could be easily removed to give the free N-H sulfoximines. Additionally, peptides with methyl ester and the methyl amide C-terminal protecting group give the opposite enantiomers of the product. A binding model is proposed to explain this phenomenon.

Sulfur-Based Chiral Iodoarenes: An Underexplored Class of Chiral Hypervalent Iodine Reagents

AbstractChiral hypervalent iodine reagents are active players in modern stereoselective organic synthesis. Structurally diverse chiral hypervalent iodine reagents have been synthesised and extensively studied, but hypervalent iodine reagents containing chiral sulfur stereogenic centre are scarce and their synthesis is challenging. A small library of iodoarenes containing chiral sulfinamide and chiral sulfoximine moieties has been synthesised using commercially available reagents. The oxidation of the chiral iodoarene precursors to iodine(III) reagents was cumbersome due to facile overoxidation of the sulfoxide moiety and hence loss of chirality under various oxidation conditions. Oxidation of chiral sulfonimidoyl derivatives to the corresponding hypervalent iodine reagents was successful and led to novel sulfur-based chiral iodine(III) reagents.

Asymmetric Synthesis of Chiral Sulfoximines via the S-Arylation of Sulfinamides.

Optically active sulfoximines are a promising substance in medicinal chemistry. However, a methodology for preparing chiral sulfoximines in a stereoselective manner has been underdeveloped. Here, we report an asymmetric synthesis of chiral sulfoximines having an aryl group by the newly developed sulfur-selective arylation of easily accessible chiral sulfinamides. The utility of the present method is demonstrated by the asymmetric synthesis of a key intermediate of a COX-2 inhibitor.

Asymmetric Synthesis of Chiral Sulfoximines through the S-Alkylation of Sulfinamides.

Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult-to-access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur-selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S-alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.

Asymmetric Synthesis of Chiral Sulfoximines through the S‐Alkylation of Sulfinamides

AbstractInnovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult‐to‐access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur‐selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S‐alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.

Rhodium-Catalyzed Synthesis of Chiral Sulfoximines and 1,2-Benzothiazines

Key words sulfoximines - benzothiazines - rhodium catalysis - kinetic resolution - asymmetric catalysis

Efficient Kinetic Resolution of Sulfur-Stereogenic Sulfoximines by Exploiting CpX RhIII -Catalyzed C-H Functionalization.

Chiral sulfoximines with stereogenic sulfur atoms are promising motifs in drug discovery. We report an efficient method to access chiral sulfoximines through a C-H functionalization based kinetic resolution. A rhodium(III) complex equipped with a chiral Cpx ligand selectively participates in conjunction with phthaloyl phenylalanine in the C-H activation of just one of the two sulfoximine enantiomers. The intermediate reacts with various diazo compounds, providing access to chiral 1,2-benzothiazines with synthetically valuable substitution patterns. Both sulfoximines and 1,2-benzothiazines were obtained in high yields and excellent enantioselectivity, with s-values of up to 200. The utility of the method is illustrated by the synthesis of the key intermediates of two pharmacologically relevant kinase inhibitors.

Efficient Kinetic Resolution of Sulfur‐Stereogenic Sulfoximines by Exploiting CpXRhIII‐Catalyzed C−H Functionalization

AbstractChiral sulfoximines with stereogenic sulfur atoms are promising motifs in drug discovery. We report an efficient method to access chiral sulfoximines through a C−H functionalization based kinetic resolution. A rhodium(III) complex equipped with a chiral Cpx ligand selectively participates in conjunction with phthaloyl phenylalanine in the C−H activation of just one of the two sulfoximine enantiomers. The intermediate reacts with various diazo compounds, providing access to chiral 1,2‐benzothiazines with synthetically valuable substitution patterns. Both sulfoximines and 1,2‐benzothiazines were obtained in high yields and excellent enantioselectivity, with s‐values of up to 200. The utility of the method is illustrated by the synthesis of the key intermediates of two pharmacologically relevant kinase inhibitors.

Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines

AbstractA novel rearrangement of 2‐vinyl aziridine 2‐carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, and tolerates a wide substrate scope. A one‐pot process starting directly from sulfinimines provides access to complex chiral sulfoximines in only two steps from commercially available aldehydes. A mechanistic hypothesis and synthetic application in the formal synthesis of trachelanthamidine, by transformation of a cyclic sulfoximine into a pyrroline, is also disclosed.