Chiral Sulfoxides Research Articles

Synthesis of Enantioenriched Sulfoxides by an Oxidation-Reduction Enzymatic Cascade.

Chiral sulfoxides are versatile synthons and have gained a particular interest in asymmetric synthesis of active pharmaceutical and agrochemical ingredients. Herein, a linear oxidation-reduction bienzymatic cascade to synthesize chiral sulfoxides is reported. The extraordinarily stable and active vanadium-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) was used to oxidize sulfides into racemic sulfoxides, which were then converted to chiral sulfoxides by highly enantioselective methionine sulfoxide reductase A (MsrA) and B (MsrB) by kinetic resolution, respectively. The combinatorial cascade gave a broad range of structurally diverse sulfoxides with excellent optical purity (>99 % ee) with complementary chirality. The enzymatic cascade requires no NAD(P)H recycling, representing a facile method for chiral sulfoxide synthesis. Particularly, the envisioned enzymatic cascade not only allows CiVCPO to gain relevance in chiral sulfoxide synthesis, but also provides a powerful approach for (S)-sulfoxide synthesis; the latter case is significantly unexplored for heme-dependent peroxidases and peroxygenases.

Chalcogen bond-guided conformational isomerization enables catalytic dynamic kinetic resolution of sulfoxides

Conformational isomerization can be guided by weak interactions such as chalcogen bonding (ChB) interactions. Here we report a catalytic strategy for asymmetric access to chiral sulfoxides by employing conformational isomerization and chalcogen bonding interactions. The reaction involves a sulfoxide bearing two aldehyde moieties as the substrate that, according to structural analysis and DFT calculations, exists as a racemic mixture due to the presence of an intramolecular chalcogen bond. This chalcogen bond formed between aldehyde (oxygen atom) and sulfoxide (sulfur atom), induces a conformational locking effect, thus making the symmetric sulfoxide as a racemate. In the presence of N–heterocyclic carbene (NHC) as catalyst, the aldehyde moiety activated by the chalcogen bond selectively reacts with an alcohol to afford the corresponding chiral sulfoxide products with excellent optical purities. This reaction involves a dynamic kinetic resolution (DKR) process enabled by conformational locking and facile isomerization by chalcogen bonding interactions.

Multienzyme Redox System with Cofactor Regeneration for Cyclic Deracemization of Sulfoxides

AbstractOptically pure sulfoxides are noteworthy compounds applied in a wide range of industrial fields; however, the biocatalytic deracemization of racemic sulfoxides is challenging. Herein, a high‐enantioselective methionine sulfoxide reductase A (MsrA) was combined with a low‐enantioselective styrene monooxygenase (SMO) for the cyclic deracemization of sulfoxides. Enantiopure sulfoxides were obtained in >90 % yield and with >90 % enantiomeric excess (ee) through dynamic “selective reduction and non‐selective oxidation” cycles. The cofactors of MsrA and SMO were subsequently regenerated by the cascade catalysis of three auxiliary enzymes through the consumption of low‐cost D‐glucose. Moreover, this “one‐pot, one‐step” cyclic deracemization strategy exhibited a wide substrate scope toward various aromatic, heteroaromatic, alkyl and thio‐alkyl sulfoxides. This system proposed an efficient strategy for the green synthesis of chiral sulfoxide.

Multienzyme Redox System with Cofactor Regeneration for Cyclic Deracemization of Sulfoxides.

Optically pure sulfoxides are noteworthy compounds applied in a wide range of industrial fields; however, the biocatalytic deracemization of racemic sulfoxides is challenging. Herein, a high-enantioselective methionine sulfoxide reductase A (MsrA) was combined with a low-enantioselective styrene monooxygenase (SMO) for the cyclic deracemization of sulfoxides. Enantiopure sulfoxides were obtained in >90 % yield and with >90 % enantiomeric excess (ee) through dynamic "selective reduction and non-selective oxidation" cycles. The cofactors of MsrA and SMO were subsequently regenerated by the cascade catalysis of three auxiliary enzymes through the consumption of low-cost D-glucose. Moreover, this "one-pot, one-step" cyclic deracemization strategy exhibited a wide substrate scope toward various aromatic, heteroaromatic, alkyl and thio-alkyl sulfoxides. This system proposed an efficient strategy for the green synthesis of chiral sulfoxide.

A novel 4-hydroxyacetophenone monooxygenase featuring aromatic substrates preference for enantioselective access to sulfoxides

Baeyer-Villiger monooxygenases are recognized as valuable tools for biooxidative synthesis of chiral sulfoxides. In this work, a novel HAPMO ortholog from Pseudomonas fluorescens (HAPMOPf) was identified by genome mining. Evolutionary relationship and sequence analysis revealed that HAPMOPf belongs to the family of typical type I BVMOs. HAPMOPf has a low KM value (0.025 mM) toward 4-hydroxyacetophenone, and a half-life of 24 h at 30 °C and pH 9.0. HAPMOPf exhibited distinct activity toward aromatic ketones as well as various thioethers, such as methyl phenyl sulfide and bromo‑methyl phenyl sulfide. The highest activities of HAPMOPf was 1.47 U·mg−1 toward 4-hydroxyacetophenone among tested ketone and thioether substrates. Furthermore, over 95% enantioselectivity was determined toward methyl phenyl sulfides with ortho, meta, and para-substituents (Cl, Br, CHO, NH2). Therefore, HAPMOPf is a promising biocatalyst for the synthesis of aromatic esters and chiral sulfoxides.

Colorimetric High-Throughput Screening Method for Directed Evolution of Prazole Sulfide Monooxygenase.

Baeyer-Villiger monooxygenases (BVMOs) are important biocatalysts for the enzymatic synthesis of chiral sulfoxides, including chiral sulfoxide-type proton pump inhibitors for the treatment of gastrointestinal diseases. However, native BVMOs are not yet suitable for practical application due to their unsatisfactory activity and thermostability. Although protein engineering approaches can help address these issues, few feasible high-throughput methods are available for the engineering of such enzymes. Herein, a colorimetric detection method to distinguish sulfoxides from sulfides and sulfones was developed for prazole sulfide monooxygenases. Directed evolution enabled by this method has identified a prazole sulfide monooxygenase CbBVMO variant with improved activity and thermostability that catalyzes the asymmetric oxidation of lansoprazole sulfide. A 71.3 % increase in conversion and 6 °C enhancement in the melting point were achieved compared with the wild-type enzyme. This new method is feasible for high-throughput screening of prazole sulfide monooxygenase variants with improved activity, thermostability, and/or substrate specificity.

Enantioseparation of chiral (benzylsulfinyl)benzamide sulfoxides by capillary electrophoresis using cyclodextrins as chiral selectors

Sulfur as a stereogenic center can be found in synthetic compounds and natural products. The current study evaluated the enantioseparation of 16 chiral (benzylsulfinyl)benzamide compounds by capillary electrophoresis using charged cyclodextrins (CDs) as chiral selectors in 50 mM sodium acetate buffer, pH 5.5. The sulfoxides varied in the type and position of the substituent of the benzyl moiety as well as the position and methylation of the amide group. Typically, randomly substituted CDs separated the majority of the model analytes in contrast to single isomer CDs. In case of random substitution, γ-CD derivatives displayed higher resolution ability toward the set of model compounds followed by β-CD and α-CD derivatives. Except for a few examples, the (+)-enantiomer of the analytes migrated before the (–)-isomer irrespective of the type of the CD so that the chiral recognition appeared to be also mostly independent on the structure of the sulfoxides. Evaluation of complexation constants and complex mobilities of selected CD-analyte pairs revealed that the separations were based on the stereoselective complexation by the CD expressed as complexation constants but examples for complex mobilities as the determining factor for the enantiomer migration order were also found. In case of 2-(4-bromobenzylsulfinyl)-N-methyl benzamide in the presence of heptakis(2,3-di-O-methyl-6-O-sulfo)-α-CD reversal of the enantiomer migration order as a function of the CD concentration was observed. Using neutral CD derivatives in the presence of sodium dodecyl sulfate-based micelles at pH 9.0 only few sulfoxides could be enantioseparated.

Rapid Photoracemization of Chiral Alkyl Aryl Sulfoxides.

The photoracemization of chiral alkyl aryl sulfoxides with a photosensitizer has not been sufficiently investigated thus far. Therefore, in this study, a rapid photoracemization reaction of enantiopure alkyl aryl sulfoxides using 1 mol % 2,4,6-triphenylpyrylium tetrafluoroborate (TPT+) was developed. Various substitution patterns were tolerated and every racemization reaction proceeded extremely fast (k2 = 1.77 × 104–6.08 × 101 M–1 s–1, t1/2 = 0.4–114 s). Some chiral sulfoxides with easily oxidizable functional groups are not appropriate for this photoisomerization. The electrochemical potentials of the functional groups, determined via cyclic voltammetry, are useful for predicting the reactive or nonreactive groups in this photoracemization reaction. A theoretical study was conducted to clarify the sp2-like nature of S of the sulfoxide cation radical, which makes photoracemization easier.

Advances of Sulfenate Anions in Catalytic Asymmetric Synthesis of Sulfoxides.

In recent years, sulfenate anions as key intermediates in enantioselective synthesis have attracted considerable attention. Typically, development of novel synthetic methods to generate sulfenate anions allows for the preparation of various enantiopure sulfoxides, which are prevalently used as auxiliaries, ligands, organocatalysts, and biologically active compounds. This review presents the in situ preparation methods and the recent applications of sulfenate anions in catalytic asymmetric synthesis of chiral sulfoxides.

Enantioseparation of novel anti-inflammatory chiral sulfoxides with two cellulose dichlorophenylcarbamate-based chiral stationary phases and polar-organic mobile phase(s)

Chiral sulfoxides represent a class of substances of great importance in many fields, including medicinal chemistry dealing with the synthesis of novel cyclooxygenase-2 (COX-2) inhibiting/NO donors. In the present study, two nitrooxyethyl sulfoxides along with their metabolites, hydroxyethyl derivatives have been successfully enantioresolved with two cellulose tris(3,5-dichlorophenylcarbamate)-based chiral stationary phases (CSPs), one with a coated (CSP 1) and the other (CSP 2) with an immobilized chiral selector. The immobilized selector in CSP 2 produced comparable-to-better performances than the coated one in CSP 1 (with α and RS values up to 1.94 and 6.32, respectively) running the analysis with a polar-organic phase made up with an ethanol/2-propanol (80:20, v/v) mobile phase. Electronic circular dichroism studies coupled to ab initio time-dependent density functional theory simulations allowed us to determine the elution order of three out of four compounds. For the two hydroxyethyl derivatives the same enantiomeric elution order [(S)<(R)] was obtained with both CSPs, while the compounds containing the −ONO2 group experienced a different elution order depending on the coated or immobilized nature of the chiral selector [(S)<(R) with CSP 1 and (R)<(S) with CSP 2]. A molecular modeling study based on docking simulations was performed to gain a deeper insight into the enantioseparation mechanism of the hydroxyethyl derivatives on both CSPs.

Synthesis of Chiral Sulfoxides via Pd(II)-Catalyzed Enantioselective C-H Alkynylation/Kinetic Resolution of 2-(Arylsulfinyl)pyridines.

A Pd(II)-catalyzed enantioselective C-H alkynylation of 2-(arylsulfinyl)pyridines via kinetic resolution using cheap and commercially available l-pGlu-OH as a chiral ligand is reported. A wide range of 2-(arylsulfinyl)pyridines were compatible with this protocol, giving the alkynylation products and recovered sulfoxides in high yields with high enantioselectivities (up to 99% ee). Furthermore, the enantioenriched products can be easily transformed to several other types of chiral sulfoxide scaffolds with the retention of enantiopurity.

Enantiopure Double ortho‐Oligophenylethynylene‐Based Helical Structures with Circularly Polarized Luminescence Activity

AbstractIn this paper, we describe the optical and chiroptical properties of an enantiopure multipodal ortho‐oligophenylethynylene (S,S,S,S)‐1 presenting four chiral sulfoxide groups at the extremes. The presence of these groups together with alkynes allows the coordination with carbophilic Ag(I), and/or oxophilic Zn(II) cations, yielding double helical structures in an enantiopure way. In this sense, different behaviors in absorption, fluorescence, ECD and CPL spectra have been found depending on the stoichiometry and nature of the metal. We have observed that Zn(II) coordination favors an intensity increase of the electronic circular dichroism (ECD) spectra of compound (S,S,S,S)‐1 yielding an M‐helicity in the ortho‐oligophenylene ethynylene (o‐OPE) backbone. On the other hand, ECD spectra of final Ag(I) complex shows two different bands with an opposite sign to the free ligand, thus giving the P‐helical isomer. In addition, circularly polarized luminescence (CPL) exhibit an enhanced intensity and negative sign in both complexes. Computational studies were also carried out, supporting the experimental results.

Sulfoxide Reductases and Applications in Biocatalytic Preparation of Chiral Sulfoxides: A Mini-Review.

Chiral sulfoxides are valuable organosulfur compounds that have been widely used in medicinal and organic synthesis. Biocatalytic approaches for preparing chiral sulfoxides were developed in the past few years, mainly through asymmetric oxidation of prochiral sulfides. Recently, the application of sulfoxide reductase to prepare chiral sulfoxides through kinetic resolution has emerged as a new method, exhibiting extraordinary catalytic properties. This article reviews the chemical and biological functions of these sulfoxide reductases and highlights their applications in chiral sulfoxide preparation.

Atroposelective Synthesis of Conjugated Diene-Based Axially Chiral Styrenes via Pd(II)-Catalyzed Thioether-Directed Alkenyl C-H Olefination.

The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd(II)-catalyzed thioether-directed alkenyl C-H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.

Aspects of albendazole metabolism in western lowland gorillas (Gorilla gorilla gorilla) compared to humans and other species assessed by HPLC, LC‐MS, and chiral electrokinetic chromatography

AbstractThe benzimidazole anthelmintic drug albendazole becomes metabolized to chiral albendazole sulfoxide, albendazole sulfone, albendazole 2‐aminosulfone, and other metabolites. High‐performance liquid chromatography with UV absorbance and fluorescence detection, liquid chromatography with mass spectrometry, and chiral electrokinetic chromatography were used to analyze albendazole metabolites in extracts of western lowland gorilla (Gorilla gorilla gorilla) plasma of patients with alveolar echinococcosis and the data are compared to those obtained with human patient samples and to those reported for other species in the literature. The data revealed that the albendazole sulfoxide to albendazole sulfone concentration ratio in gorilla plasma is significantly smaller compared to that in samples of men, rats, dogs, and cattle. It is, however, similar to what was observed in sheep and goats. The (+)‐albendazole sulfoxide to (−)‐albendazole sulfoxide enantiomeric ratio in gorilla blood determined by chiral electrokinetic chromatography was found to be &gt;1 which is comparable to what was observed in humans, dogs, sheep, goats, and cattle but different to mice and rats. Furthermore, the electrokinetic chromatography data suggest that small amounts of albendazole 2‐aminosulfone may be present in plasma of gorillas and humans. The data gathered with the various separation‐based assays illustrate the value of technology featuring different analyte separation and detection principles. This is the first account describing aspects of the albendazole metabolism in gorillas.

Chiral separation in the class of proton pump inhibitors by chromatographic and electromigration techniques: An overview.

Proton pump inhibitors (PPIs) are benzimidazole-derivative chiral sulfoxides, frequently used in the treatment of gastric hyperacidity-related disorders. Due to their stereoselective metabolism, the eutomeric forms of PPIs can present a more advantageous pharmacokinetic profile by comparison with the distomers or racemates. Moreover, two representatives of the class are used in therapy both as racemates and as pure enantiomers (esomeprazole, dexlansoprazole). A relatively large number of enantioseparation methods employed for the stereoselective determination of PPIs from pharmaceutical, biological, and environmental matrices were published in the past three decades. The purpose of the current overview is to provide a systematic survey of the available chiral separation methods published since the introduction of PPIs in the therapy up to the present. Analytical and bioanalytical methods using different chromatographic and electromigration techniques reported for the enantioseparation of omeprazole, lansoprazole, pantoprazole, rabeprazole, ilaprazole, and tenatoprazole are included. The analytical conditions of the presented methods are summarized in three comprehensive tables, while a critical discussion of the applied techniques, possible mechanism of enantiorecognition, and future perspectives on the topic are also presented.

Protein engineering of thioether monooxygenase to improve its thermostability for enzymatic synthesis of chiral sulfoxide

• Consensus analysis and random mutagenesis were conducted to engineer a cyclohexanone monooxygenase from the Acinetobacter calcoaceticus (AcCHMO-M6) for improving its thermostability as well as specific activity. • The half-lives of the resultant mutants at 40 °C were increased up to 8.5 h as well as with up to 4-fold enhance in specific activity. • By employing the best mutant AcCHMO-M10, complete conversion (>99% conversion, >99% ee) asymmetric Kagan oxidation of omeprazole sulfide was achieved in 16 h, while the AcCHMO-M6 only afford 39% conversion. Esomeprazole, the S -enantiomer of omeprazole, is the best-selling proton pump inhibitor. In our previous work, a mutant of cyclohexanone monooxygenase from the Acinetobacter calcoaceticus (named Ac CHMO-M6) was successfully obtained through protein engineering which could catalyze the oxidation of omeprazole sulfide. However, its practical application is still hindered by the poor thermostability, especially in the up-scaled reaction process. In this work, site mutagenesis based on consensus analysis and directed evolution were used to engineer this enzyme in order to improve the stability of Ac CHMO-M6. The half-lives of the resultant mutants Ac CHMO-M9 (F29L/R444E) and Ac CHMO-M10 (F29L/R444E/A145S/G430T) at 40 °C were increased from 2.2 h to 8.5 h and 5.9 h respectively, while the corresponding T m values were increased by 7 °C and 5.3 °C in comparison to Ac CHMO-M6. The specific activity of Ac CHMO-M9 was comparable to that of Ac CHMO-M6, and the specific activity of Ac CHMO-M10 was about 4-fold that of Ac CHMO-M6. The Ac CHMO-M10 catalyzed sulfide oxidation reaction reached 100% conversion after 16 hours at 30 °C, in contrast to 39.4% conversion in the case of Ac CHMO-M6. These results show that the potential of this thioether monooxygenase can be significantly improved by protein engineering.

Thermodynamic Resolution of Pharmaceutical Precursor Modafinil Acid on the Basis of Chiral‐at‐Metal Strategy

Main observation and conclusionChiral‐at‐metal strategy was developed to resolve the essential sulfoxide pharmaceutical intermediates R‐modafinil acid and its analogues with high yields and ee values. The efficient resolution process was achieved based on the diastereoselective discrimination caused by hydrogen bond and intramolecular π‐π interaction between chiral‐at‐metal center and the coordinated chiral sulfoxide ligands. Moreover, the chiral Ir(III) receptor can be reused with complete retention of their configurations and without the loss of reaction activity and enantioselectivity. This work provides a new access to synthesize R‐modafinil acid as well as its analogues and develops the application of chiral‐at‐metal strategy in chiral resolution.

Optimum synthesis of esomeprazole catalyzed by Rhodococcus rhodochrous ATCC 4276 through response surface methodology

Enantiopure esomeprazole is an important drug in the treatment of gastric ulcer. The asymmetric sulfoxidation of omeprazole thioether was catalyzed by immobilized cells of a mutant of Rhodococcus rhodocrous ATCC 4276 to synthesize esomeprazole. The bioreaction was carried out in a biphasic system (chloroform-water), at a high substrate concentration (200 mM), and optimized using response surface methodology (RSM). The optimal yield of esomeprazole obtained was 94.8% with e.e. (>99%) without the formation of the sulfone form as a byproduct, under the optimal conditions: the concentration of immobilized cells, 283.5 g/L, the incubation temperature, 37.05 °C, and pH of phosphate buffer, 7.35, respectively. A quadratic polynomial model was developed with R2 of 0.9998, which indicates that the model predicts the observed data with very high accuracy. The mutant exhibited a high enantioselective activity and substrate and product tolerance. The small size of immobilized cell beads (0.5–1 mm) creates a large reaction interface. The aerated flask provides enough oxygen for a high concentration of cells. The significant improvement of substrate tolerance may mainly be attributed to employing the chloroform-water biphasic system because organic substrates may be partitioned in the organic phase, eliminating potential damage and inhibition to cells. Based on the above, the asymmetric sulfoxidation catalyzed by immobilized bacterial cells is therefore more promising for efficient synthesis of chiral sulfoxides.

Efficient Synthesis of Sulfur-Stereogenic Sulfoximines via Ru(II)-Catalyzed Enantioselective C-H Functionalization Enabled by Chiral Carboxylic Acid.

Ru(II)-catalyzed enantioselective C-H functionalization involving an enantiodetermining C-H cleavage step remains undeveloped. Here we describe a Ru(II)-catalyzed enantioselective C-H activation/annulation of sulfoximines with α-carbonyl sulfoxonium ylides using a novel class of chiral binaphthyl monocarboxylic acids as chiral ligands, which can be easily and modularly prepared from 1,1'-binaphthyl-2,2'-dicarboxylic acid. A broad range of sulfur-stereogenic sulfoximines were prepared in high yields with excellent enantioselectivities (up to 99% yield and 99% ee) via desymmetrization, kinetic resolution, and parallel kinetic resolution. Furthermore, the resolution products can be easily transformed to chiral sulfoxides and key intermediates for kinase inhibitors.