Chiral Sulfoxides Research Articles

N-Directed, Radical Relay Enantioconvergent Sulfinylation of Distal C(sp3)-H Bonds via Cobalt Catalysis.

Cobalt-catalyzed enantioconvergent cross-coupling of C(sp3)-H bonds with in situ-generated sulfenate anions is achieved to access chiral sulfoxides, which are found in the structures of many biologically active agents. The more challenging aliphatic C-H bonds as well as sterically hindered substrates containing tertiary C-H bonds could also be tolerated well. Mechanistic studies indicate that the transformation could undergo a CoIIS(O)R-mediated single-electron transfer with N-fluorocarboxamides, followed by a 1,5-hydrogen atom transfer and then a pivotal organocobalt(IV)-controlled enantioselective cross-coupling process. This novel asymmetric radical reaction for C-S bond construction could open a new door for the synthesis of sulfur-centered chiral compounds.

Visible-light-driven photobiocatalytic synthesis of chiral sulfoxides over immobilized chloroperoxidase on magnetic yolk–shell Fe3O4@Cu-H-TiO2 photocatalyst

Chloroperoxidase (CPO) is promising for the asymmetric synthesis of sulfoxides from sulfides, owing to its high enantioselectivity under mild reaction conditions. However, suffering from the stability and recyclability issue, the application of free CPO is heavily restricted in current stage. In this work, an integrated photobiocatalyst was designed and fabricated by immobilizing CPO on a magnetically recyclable photocatalyst, Fe3O4@Cu-H-TiO2, which can supply H2O2 for CPO in situ continuously and suppress the destruction of CPO caused by excess H2O2. The obtained CPO@Fe3O4@Cu-H-TiO2 can catalyze the synthesis of enantiopure (R)-sulfoxides from sulfides with high yield up to 88% and high ee value up to >99% over this TiO2-based photobiocatalyst. The enhanced performance of the integrated photobiocatalyst is attributed to the controllable supply of H2O2, the improved stability of immobilized CPO and the enhanced proximity effect between photo- and bio- catalytic modules.

Deracemization of Sulfoxides Combining Electrocatalysis and Biocatalysis

Comprehensive SummaryThe concurrent implementation of cascade reactions that combine biocatalysis and chemocatalysis is a challenging undertaking. Electrocatalysis provides versatile catalytic abilities and allows for mild reaction conditions, offering the potential for designing concurrent chemoenzymatic cascade reactions. The research on bioelectrocatalysis has primarily concentrated on utilizing electrocatalysis to achieve cofactor regeneration of enzymes. In contrast with previous reports, herein, we developed a deracemization strategy involving the concurrent combination of biocatalytic reduction and anodic oxidation in an undivided cell to achieve chiral sulfoxides, demonstrating the good compatibility. We anticipate this study will offer an alternative pathway for the design of the cascade reaction combined with electrocatalysis and biocatalysis.

Brønsted Acid Catalyzed Asymmetric Synthesis of Cyclopentenones with C4-Quaternary Centers Starting from Vinyl Sulfoxides and Allenyl Ketones or Allenoates.

Starting with chiral vinyl sulfoxides and allenyl ketones or allenoates, a triflic acid-catalyzed asymmetric [3,3]-sigmatropic rearrangement of sulfoniums is reported to have a direct access to highly functionalized C4-chiral cyclopentenones (19 examples, up to 85% yield and >95% enantiomeric excesses). In addition to the use of these chiral compounds as key building blocks in organic synthesis, the antiproliferative activities of sulfoxide substrates and the corresponding cyclopentenones were evaluated, and promising cytotoxicity against the HL-60 human tumor cell line was found.

Catalytic Enantioselective Sulfoxidation of Functionalized Thioethers Mediated by Aspartic Acid-Containing Peptides.

A peptide-catalyzed enantioselective oxidation of sulfides to yield pharmaceutically relevant chiral sulfoxides is reported. Experimental evidence suggesting that a hydrogen bond-donating moiety must be present in the substrate to achieve high levels of enantioinduction is supported by computational modeling of transition states. These models also indicate that dual points of contact between the peptidic catalyst and substrate are likely responsible for the formation of one desired sulfoxide in 94:6 er.

Rh-Catalyzed Asymmetric Hydrogenation of 2-Substituted 4H-(Thio)chromenes for Synthesis of Chiral (Thio)chromanes.

Rh-catalyzed asymmetric hydrogenation of 2-substituted 4H-thiochromenes and 4H-chromenes was successfully developed. This method provided highly efficient access to a series of chiral 2-substituted thiochromanes and chromanes in high yields with excellent enantioselectivities (up to 99% yield, 86-99% ee). The obtained chiral 2-substituted thiochromane products were also successfully transformed to corresponding chiral α-substituted sulfoxides and sulfones with excellent enantioselectivities. Furthermore, this highly enantioselective hydrogenation process could be successfully applied to the concise and practical synthesis of the chiral pharmaceutical BW683C.

Bifunctional Squaramide-Catalyzed Oxidative Kinetic Resolution: Simultaneous Access to Axially Chiral Thioether and Sulfoxide.

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo- and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene-based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.

Chiral Thianthrenes.

The absolute configuration and stability of two thianthrene chiral sulfoxides has been determined by means of X-ray single-crystal structure determinations. The analyses and configurations allow verification that the diastereomeric sulfoxides are stable in solution and are not interconverting, which has been suggested in some studies of sulfoxides. The two thianthrene sulfoxides have slightly different Rf values, which allowed their separation using flash chromatography on silica. The spots run back-to-back, which posed a challenge for their separation. The pure, separated compounds in solution remain as separate, single spots on a Thin Layer Chromatography (TLC) plate.

Synthesis of Chiral Sulfoxides by A Cyclic Oxidation-Reduction Multi-Enzymatic Cascade Biocatalysis.

Optically pure sulfoxides are valuable organosulfur compounds extensively employed in medicinal and organic synthesis. In this study, we present a biocatalytic oxidation-reduction cascade system designed for the preparation of enantiopure sulfoxides. The system involves the cooperation of a low-enantioselective chimeric oxidase SMO (styrene monooxygenase) with a high-enantioselective reductase MsrA (methionine sulfoxide reductase A), facilitating "non-selective oxidation and selective reduction" cycles for prochiral sulfide oxidation. The regeneration of requisite cofactors for MsrA and SMO was achieved via a cascade catalysis process involving three auxiliary enzymes, sustained by cost-effective D-glucose. Under the optimal reaction conditions, a series of heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were synthesized through this "one-pot, one step" cascade reaction. The obtained compounds exhibited high yields of >90 % and demonstrated enantiomeric excess (ee) values exceeding 90 %. This study represents an unconventional and efficient biocatalytic way in utilizing the low-enantioselective oxidase for the synthesis of enantiopure sulfoxides.

Engineering of methionine sulfoxide reductase A with simultaneously improved stability and activity for kinetic resolution of chiral sulfoxides

Methionine sulfoxide reductase A (MsrA) has emerged as promising biocatalysts in the enantioselective kinetic resolution of racemic (rac) sulfoxides. In this study, we engineered robust MsrA variants through directed evolution, demonstrating substantial improvements of thermostability. Mechanism analysis reveals that the enhanced thermostability results from the strengthening of intracellular interactions and increase in molecular compactness. Moreover, these variants demonstrated concurrent improvements in catalytic activities, and notably, these enhancements in stability and activity collectively contributed to a significant improvement in enzyme substrate tolerance. We achieved kinetic resolution on a series of rac-sulfoxides with high enantioselectivity under initial substrate concentrations reaching up to 93.0 g/L, representing a great improvement in the aspect of the substrate concentration for biocatalytic preparation of chiral sulfoxide. Hence, the simultaneously improved thermostability, activity and substrate tolerance of MsrA represent an excellent biocatalyst for the green synthesis of optically pure sulfoxides.

Metallo‐Supramolecular Helical Fibres from Chiral Phenylacetylene Monomers: Cation Induced Self‐Assembly

AbstractChiral metallo‐supramolecular fibres can be easily obtained by mixing a chloroform solution of a phenylacetylene monomer (PA) that bears a chiral sulfoxide group as pendant, with different equivalents of a methanolic solution of AgClO4. Thus, while the PA is found molecularly dissolved in chloroform, the addition of Ag+ ions induce its aggregation through the formation of an axially chiral metallo‐supramolecular aggregate with high thermal stable properties. In this case, the ability of the metal ion to coordinate the PA triple bond, combined with the argentophilicity of the metal ion and the planarity of the phenylacetylene drives to the formation of a helical coordination polymer, whose P or M axial chirality is determined by the chirality of the sulfoxide used as substituent of the PA. Depending on the PA/Ag+ (mol/mol) ratio, it is possible to tune the morphology of the metallo‐supramolecular aggregate from chiral fibers to chiral gel.

Metallo-Supramolecular Helical Fibres from Chiral Phenylacetylene Monomers: Cation Induced Self-Assembly.

Chiral metallo-supramolecular fibres can be easily obtained by mixing a chloroform solution of a phenylacetylene monomer (PA) that bears a chiral sulfoxide group as pendant, with different equivalents of a methanolic solution of AgClO4 . Thus, while the PA is found molecularly dissolved in chloroform, the addition of Ag+ ions induce its aggregation through the formation of an axially chiral metallo-supramolecular aggregate with high thermal stable properties. In this case, the ability of the metal ion to coordinate the PA triple bond, combined with the argentophilicity of the metal ion and the planarity of the phenylacetylene drives to the formation of a helical coordination polymer, whose P or M axial chirality is determined by the chirality of the sulfoxide used as substituent of the PA. Depending on the PA/Ag+ (mol/mol) ratio, it is possible to tune the morphology of the metallo-supramolecular aggregate from chiral fibers to chiral gel.

Advancements in Asymmetric Synthesis of Esomeprazole and Chiral Sulfoxide Drugs: A Comprehensive Review and Future Perspectives

Chiral sulfoxides are widely present in biologically active molecules and pharmaceuticals, and their efficient and green synthesis has been a hot research topic. This article reviews three main methods employed in the industrial-scale synthesis of esomeprazole: transition metal catalysis, bio-enzyme catalysis, and oxaziridine oxidation. The advantages, disadvantages, and innovative progress of each method are discussed, and the challenges faced in large-scale production are analyzed. Solutions such as catalyst design, reaction process optimization, and continuous flow processes are proposed, pointing out directions for achieving efficient and green manufacturing of chiral sulfoxides drugs, which is of great significance for promoting the sustainable development of related industries.

Directed evolution of Baeyer-Villiger monooxygenase for highly secretory expressed in Pichia pastoris and efficient preparation of chiral pyrazole sulfoxide.

The methylotrophic yeast Pichia pastoris (Komagataella phaffii) is a highly distinguished expression platform for the excellent synthesis of various heterologous proteins in recent years. With the advantages of high-density fermentation, P. pastoris can produce gram amounts of recombinant proteins. While not every protein of interest can be expressed to such high titers, such as Baeyer-Villiger monooxygenase (BVMO) (AcPSMO) which is responsible for pyrazole sulfide asymmetric oxidation. In this work, an excellent yeast expression system was established to facilitate efficient AcPSMO expression, which exhibited 9.5-fold enhanced secretion. Subsequently, an ultrahigh throughput screening method based on fluorescence-activated cell sorting by fusing super folder green fluorescent protein (sfGFP) in the C-terminal of AcPSMO was developed, and directed evolution was performed. The protein expression level of the superior mutant AcPSMOP1 (S58T/T252P/E336N/H456D) reached 84.6 mg/L at 100 mL shaking flask, which was 4.7 times higher than the levels obtained with the wild-type. Finally, the optimized chassis cells were used for high-density fermentation on a 5-L scale, and AcPSMOP1 protein yield of 3.4 g/L was achieved, representing approximately 85% of the total protein secreted. By directly employing the pH-adjusted supernatant as a biocatalyst, 20 g/L pyrmetazole sulfide was completely transformed into the corresponding (S)-sulfoxide, with a 78.8% isolated yield. This work confers dramatic benefits for efficient secretion of other BVMOs in P. pastoris.

Peroxygenase-Catalysed Sulfoxidations in Non-Aqueous Media.

Chiral sulfoxides are valuable building blocks in asymmetric synthesis. However, the biocatalytic synthesis of chiral sulfoxides is still challenged by low product titres. Herein, we report the use of peroxygenase as a catalyst for asymmetric sulfoxidation under non-aqueous conditions. Upon covalent immobilisation, the peroxygenase showed stability and activity under neat reaction conditions. A large variety of sulfides was converted into chiral sulfoxides in very high product concentration with moderate to satisfactory optical purity (e. g. 626 mM of (R)-methyl phenyl sulfoxide in approx. 89 % ee in 48 h). Further polishing of the ee value via cascading methionine reductase A (MsrA) gave>99 % ee of the sulfoxide. The robustness of the enzymes and high product titer is superior to the state-of-the-art methodologies. Gram-scale synthesis has been demonstrated. Overall, we demonstrated a practical and facile catalytic method to synthesize chiral sulfoxides.

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.

Precise regulation of the substrate selectivity of Baeyer-Villiger monooxygenase to minimize overoxidation of prazole sulfoxides

Baeyer-Villiger monooxygenases (BVMOs) can catalyze the asymmetric oxidation of sulfides to valuable chiral sulfoxides, but the overoxidation of sulfoxides to undesired sulfones limits the synthetic application of BVMOs. This overoxidation is caused by insufficient substrate selectivity of BVMOs, where the desired product sulfoxide can be further oxidized. In this study, a mathematical model was constructed to quantitatively define the substrate selectivity based on the ratio of the specificity constant (kcat/Km) between sulfide and sulfoxide. The substrate selectivity of a pyrmetazole monooxygenase (AcPSMO) was precisely regulated using a structure-guided substrate tunnel engineering approach, which successfully minimized sulfoxide overoxidation. The sulfone content of variant F277L was less than 1% (mol/mol), compared with 65% for the wild-type, in the pyrmetazole oxidation reaction after 24 h. Molecular dynamics simulations and quantum mechanics/molecular mechanics studies showed that the altered H-bonding networks surrounding the flavin hydroperoxide (FADH-OOH) can modulate the mechanism and activity for sulfoxide oxidation. Furthermore, the redesigned mutants of AcPSMO were successfully applied for the controllable synthesis of other chiral prazole sulfoxides.

Enantio-resolution of some chiral sulfoxide drugs on amylose and cellulose-based stationary phases: Elution order, absolute configuration and chiral mechanism determination

The enantio-separation of three chiral sulfoxide drugs (omeprazole, pantoprazole, and lansoprazole) was achieved on Chiralpak® AS-3R column with acetonitrile‐water (65:35) at 0.5 mL/min flow and 280 nm detection within 7 min. Chiralseparation was validated properly with 9.70–14.16 and 29.39–42.91 µg.mL−1 as LOD and LOQ. The thermodynamics parameters were in the range of (-0.51 to −1,288) kJmol−1K−1(ΔG). These values confirmed chiral separation as spontaneous and thermodynamically stable. Enantiomer elution order determined on Chiralpak® IA with ethanol-hexane (95:5)at 1.0 mL/min flow at 221, 254, 270, 280,301, and 330 nm wavelengths confirmed first elution od S-enantiomer followed by R-enantiomer. This observation was also confirmed by theoretical simulations of electronic circular dichroism (ECD) calculation. The docking study was used to explain the chiral resolution of the reported drugs. As a result, a simple, fast, reliable and spontaneous and thermodynamically stable HPLC method was developed for the separation and determination of enantiomer elution order of the reported chiral sulfoxide drugs.

Methionine Sulfoxide Reductase as an Efficient Catalyst for Kinetic Resolution of the Chiral Sulfoxides

Key words chiral sulfoxides - kinetic resolution - reductases - rational mutagenesis

Conversion of Racemic Alkyl Aryl Sulfoxides into Pure Enantiomers Using a Recycle Photoreactor: Tandem Use of Chromatography on Chiral Support and Photoracemization on Solid Support

Chiral sulfoxides are valuable in the fields of medicinal chemistry and organic synthesis. A recycle photoreactor utilizing the concept of deracemization, where a racemate is converted into a pure enantiomer, is developed and successfully applied in the syntheses of chiral alkyl aryl sulfoxides. The recycling system consists of rapid photoracemization using an immobilized photosensitizer and separation of the enantiomers via chiral high-performance liquid chromatography, and the desired pure chiral sulfoxides are obtained after 4-6 cycles. The key to the success of the system is the photoreactor site, wherein the photosensitizer 2,4,6-triphenylpyrylium is immobilized on the resin and irradiated (405 nm) to enable the rapid photoracemizations of the sulfoxides. As the green recycle photoreactor requires no chiral components, it should be a useful alternative system for application in producing chiral compounds.