Diastereomeric Sulfoxides Research Articles

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.

Oxidation‐Responsive Supramolecular Hydrogel Based on a Simple Fmoc‐Cysteine Derivative Capable of Showing Autonomous Gel–Sol–Gel Transitions

AbstractAqueous soft matter, including supramolecular hydrogels capable of exhibiting stimuli–responsive macroscopic phase transitions, has attracted increasing attention for the exploration of functional soft materials. However, the investigation of supramolecular hydrogels that undergo autonomous and multiple macroscopic phase transitions (e.g., gel–sol–gel, sol–gel–sol) in response to the surrounding environment without repeated additions of stimuli has remained largely unexplored. In this study, the oxidation‐responsive autonomous gel–sol–gel transitions of supramolecular hydrogels fabricated via the self‐assembly of a simple fluorenylmethyloxycarbonyl (Fmoc)‐protected, benzylated cysteine (Fmoc‐CBzl) is presented. During the evaluation of the oxidation process of Fmoc‐CBzl, it is revealed that the oxidized products, two diastereomeric sulfoxides (Fmoc‐CBzl‐(R)‐O and Fmoc‐CBzl‐(S)‐O), exhibit significantly different self‐assembly propensities under aqueous conditions. It may be noteworthy that the chirality of sulfoxide is largely overlooked and not effectively used to modulate supramolecular, self‐assembled nanostructures. The difference in the self‐assembly propensities and kinetics of self‐assembly/disassembly as well as co‐assembly will contribute to oxidation‐responsive autonomous gel–sol–gel transitions.

Eremophilanolide sulfoxides and eremophilanolides from the mangrove fungus TBRC-BCC 64093

Two unusual eremophilanolide sulfoxide diastereomers (1 and 2), seven eremophilanolides (3–7, 11, and 12) together with nine known eremophilanolides (8–10 and 13–18), anserinone A (19), and (−)-mellein-5-carboxylic acid (20) were isolated from the mangrove fungus TBRC-BCC 64093, a member of family Xylariaceae. The structures of these compounds were elucidated by extensive spectroscopic analysis of their NMR and MS data. The absolute configurations of the eremophilane sulfoxide diastereomers were determined by comparison of experimental and calculated electronic circular dichroism (ECD) data by TDDFT. Among the tested metabolites, eremophilane sulfoxide 1 showed weak cytotoxic activity against Vero cell lines with an IC50 value of 17.7 μg/mL.

Isobornanyl sulfoxides and isobornanyl sulfone: Physicochemical characteristics and the features of crystal structure

The physico-chemical characteristics and crystal structure of newly synthesized isobornanyl sulfoxides and sulfone are presented. After purification, diastereomeric sulfoxides were obtained in a 2:1 eutectic ratio, which did not allow either separation or enrichment of the mixture. Based on thermochemical data, the form of the phase diagram of the system was reconstructed, showing that diastereomers have significantly different melting points. According to the X-ray data, the same supramolecular open–chain S=O⋅⋅⋅H–O synthon is built up in the crystals of diastereomeric sulfoxides. The isobornanyl sulfone crystal is formed in a complex way – two crystallographically independent molecules playing different roles in the formation of H-bonds. The IR spectra of a diastereomeric sulfoxides mixture demonstrate the averaging of the synthon-forming functional groups bands. In a counterbalance, the IR spectrum of isobornanyl sulfone shows a doubling of the key bands of synthon-forming functional groups belonging to homochirally homogeneous but crystallographically nonequivalent molecules.

Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 – 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20 –51.61 µM) and enzalutamide (IC50 = 11.47 – 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15–30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

A systematic investigation on the impact of the level of oxidation at sulfur and the configuration of R/S-sulfoxide on the solid structure

In this work, the two aspects, different oxidation states of sulfur and diastereomeric sulfoxides, were combined to comprehend the role of crystal packing and different weak intermolecular interactions in the solid state.

Cover Feature: A Facile Method for the Separation of Methionine Sulfoxide Diastereomers, Structural Assignment, and DFT Analysis (Chem. Eur. J. 20/2020)

Cover Feature: A Facile Method for the Separation of Methionine Sulfoxide Diastereomers, Structural Assignment, and DFT Analysis (Chem. Eur. J. 20/2020)

A Facile Method for the Separation of Methionine Sulfoxide Diastereomers, Structural Assignment, and DFT Analysis.

Methionine (Met) oxidation is an important biological redox node, with hundreds if not thousands of protein targets. The process yields methionine oxide (MetO). It renders the sulfur chiral, producing two distinct, diastereomerically related products. Despite the biological significance of Met oxidation, a reliable protocol to separate the resultant MetO diastereomers is currently lacking. This hampers our ability to make peptides and proteins that contain stereochemically defined MetO to then study their structural and functional properties. We have developed a facile method that uses supercritical CO2 chromatography and allows obtaining both diastereomers in purities exceeding 99 %. 1 H NMR spectra were correlated with X-ray structural information. The stereochemical interconversion barrier at sulfur was calculated as 45.2 kcal mol-1 , highlighting the remarkable stereochemical stability of MetO sulfur chirality. Our protocol should open the road to synthesis and study of a wide variety of stereochemically defined MetO-containing proteins and peptides.

Synthesis and Isolation of Diastereomeric Anomeric Sulfoxides from a d-Mannuronate Thioglycoside Building Block

Methyl [S-phenyl 4-O-acetyl-2,3-di-O-benzyl-1-thio-α-d-mannopyranoside (R/S)S-oxide] uronate was synthesised from a thioglycoside mannosyl uronate donor in a 98% yield. By using one equivalent of meta-chloroperbenzoic acid (m-CPBA) as the sulphur oxidant, a smooth conversion to the diastereomeric sulfoxide products was achieved. The product was fully characterized by 1H, 13C and 2D NMR alongside MS analysis.

Synthesis of Sulfones and Sulfoxides Based on (+)-usnic Acid

Sulfones were produced by meta-chloroperbenzoic-acid oxidation of the corresponding thioethers prepared from (+)-usnic acid. Reaction of the thioethers with H2O2 in the presence of VO(acac)2 formed a mixture of sulfoxide diastereomers. Possible chiral oxidation of the thioethers into sulfoxides was studied.

Oryzamides A-E, Cyclodepsipeptides from the Sponge-Derived Fungus Nigrospora oryzae PF18.

Three new cyclohexadepsipeptides, oryzamides A-C (1-3), two isolation artifacts, oryzamides D (4) and E (5), and the known congener scopularide A (6), all possessing a rare 3-hydroxy-4-methyldecanoic acid (HMDA) substructure, were isolated from the mycelial extract of the sponge-derived fungus Nigrospora oryzae PF18. Their planar structures were elucidated by spectroscopic analysis and comparison with the literature data. The absolute configurations were determined using the advanced Marfey's method and single-crystal X-ray diffraction analysis. Among them, oryzamides D (4) and E (5) were a pair of diastereomers at the sulfur atom of the l-methionine sulfoxide residue, which showcased the possible separation of a pair of methionine sulfoxide diastereomers. The X-ray crystal structure of scopularide A (6) was obtained for the first time, thereby establishing its relative and absolute configuration at C-4 of the HMDA residue. Oryzamides A-C (1-3) did not display cytotoxic, antibacterial, antiparasitic, and NF-κB inhibitory activities.

Facile Diastereoseparation of Glycosyl Sulfoxides by Chiral Stationary Phase.

Separation of the diastereomers of glycosyl sulfoxides differing in the sulfur chirality has been difficult. This article presents a fast and scalable method for their diastereoseparation using a chiral stationary phase. The usefulness of this method was demonstrated in a 500-mg scale separation within 20 min, and in the separation of trisaccharyl sulfoxide diastereomers. Chirality 28:534-539, 2016. © 2016 Wiley Periodicals, Inc.

S=o…s=o Interactions as a Driving Force for Low-Temperature Conformational Rearrangement of Stable H-Bonding {S(O)-Ch2-Ch2-OH···}2 Synthon in two Modifications of Diastereomeric Pinanyl Sulfoxides Co-Crystal

GRAPHICAL ABSTRACTFor the triclinic and monoclinic modifications of diastereomeric pinanyl sulfoxides co-crystal, remarkable alterations in unit cell parameters by transition from 293 to 150 К were ascertained. Such alterations are accompanied by conformational restructuring of a stable hydrogen-bonded synthon from an “unfolded” to a “folded” form. The driving force of this restructuring is the tendency to form S=O…S=O interactions, which show up in the low-temperature phases of both polymorphs. These are well-supported by the methods of quantum chemistry (DFT, B97-D/6-31G(d,p), AIM All).

Synthesis and oxidation of thioglicosides underlain by neomenthanethiol, D-glucose, and D-fructose

Synthesis of sulfides proceeding from neomenthanethiol, 1,2-O-isopropylidene-α-D-glucofuranose and 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose was performed to get 65 and 54% yield respectively. Oxidation of the sulfides afforded diastereomeric sulfoxides in the yields from 40 to 53%, and diastereomeric excess (de) up to 36%. After removing the isopropylidene protection from 1-deoxy-1-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose a water-soluble sulfide was obtained.

Stereospecific electrophoretically mediated microanalysis assay for methionine sulfoxide reductase enzymes

An electrophoretically mediated microanalysis assay (EMMA) for the determination of the stereoselective reduction of L-methionine sulfoxide diastereomers by methionine sulfoxide reductase enzymes was developed using fluorenylmethyloxycarbonyl (Fmoc)-L-methionine sulfoxide as substrate. The separation of the diastereomers of Fmoc-L-methionine sulfoxide and the product Fmoc-L-methionine was achieved in a successive multiple ionic-polymer layer-coated capillary using a 50 mM Tris buffer, pH8.0, containing 30mM sodium dodecyl sulfate as background electrolyte and an applied voltage of 25kV. 4-Aminobenzoic acid was employed as internal standard. An injection sequence of incubation buffer, enzyme, substrate, enzyme, and incubation buffer was selected. The assay was optimized with regard to mixing time and mixing voltage and subsequently applied for the analysis of stereoselective reduction of Fmoc-L-methionine-(S)-sulfoxide by human methionine sulfoxide reductase A and of the Fmoc-L-methionine-(R)-sulfoxide by human methionine sulfoxide reductase B. The Michaelis-Menten constant, K m, and the maximum velocity, v max, were determined. Essentially identical data were determined by the electrophoretically mediated microanalysis assay and the analysis of the samples by CE upon offline incubation. Furthermore, it was shown for the first time that Fmoc-methionine-(R)-sulfoxide is a substrate of human methionine sulfoxide reductase B.

Stereospecific micellar electrokinetic chromatography assay of methionine sulfoxide reductase activity employing a multiple layer coated capillary

A micellar electrokinetic chromatography method for the analysis of the l-methionine sulfoxide diastereomers employing a successive multiple ionic-polymer layer coated fused-silica capillary was developed and validated in order to investigate the stereospecificity of methionine sulfoxide reductases. The capillary coating consisted of a first layer of hexadimethrine and a second layer of dextran sulfate providing a stable strong cathodic EOF and consequently highly repeatable analyte migration times. The methionine sulfoxide diastereomers, methionine as product as well as β-alanine as internal standard were derivatized by dabsyl chloride and separated using a 35 mM sodium phosphate buffer, pH 8.0, containing 25 mM SDS as BGE and a separation voltage of 25 kV. The method was validated in the range of 0.15-2.0 mM with respect to linearity and precision. The LODs of the analytes ranged between 0.04 and 0.10 mM. The assay was subsequently applied to determine the stereospecificity of methionine sulfoxide reductases as well as the enzyme kinetics of human methionine sulfoxide reductase A. Monitoring the decrease of the l-methionine-(S)-sulfoxide Km = 411.8 ± 33.8 μM and Vmax = 307.5 ± 10.8 μM/min were determined.

Selective and Practical Oxidation of Sulfides to Diastereopure Sulfoxides: A Combined Experimental and Computational Investigation

AbstractWe describe an effective oxidation of diltiazem (DTZ)‐like molecules (a class of prochiral sulfides with potential pharmacological properties) using m‐chloroperbenzoic acid (MCPBA) as oxidant either in dichloromethane or methanol. An excellent diastereomeric excess of one sulfoxide has been observed “in the absence of any chiral auxiliary”. The stereochemistry of the two diastereomeric sulfoxides has been determined by TDDFT simulations of the experimental electronic circular dichroism (ECD) spectra. A computational DFT study of the reaction mechanism shows that the attack of MCPBA on the two sulfide enantiotopic faces affords two preliminary complexes M1 and M1′. M1 is more stable than M1′ by 3.3 and 3.5 kcal mol−1 in dichloromethane and methanol, respectively, and after equilibration its population must be dominant. Two diastereomeric pathways originate from M1 and M1′ and give two diastereomeric sulfoxides with R and S configurations at the new chiral sulfur, respectively. Since TS (the transition state originating from M1) is more stable than TS′ (the energy gap is 0.7 kcal mol−1 in dichloromethane or methanol), following the Curtin–Hammett principle, the favoured path is the pro‐R channel (M1→TS→M2) affording the (Rc,Rs)‐2a′ product species in agreement with the observed diastereoselectivity. The M1–M1′ and TS–TS′ energy gaps are actually determined by the difference in the hydrogen bond network that features the two species even if the approaching orientation of the two molecules is governed by the interactions between the π systems of oxidant and substrate aromatic rings. The diastereomeric ratio computed on the basis of the energy difference between TS and TS′ (0.7 kcal mol−1) is 63:37, which must be compared to the experimental value 9:1. When we consider free energy differences (2.4 kcal mol−1 in vacuum and 2.9 kcal mol−1 in solution) this theoretical ratio becomes 85:15 and 89:11, respectively, in excellent agreement with the experimental value 9:1.

Stereospecific Syntheses and Structures of Planar Chiral Bidentate η5:κS-Indenyl-Sulfanyl and -Sulfinyl Complexes of Rhodium(III)

Axially chiral rac-1-(2-methyl-1H-inden-3-yl)-2-(methylsulfanyl)naphthalene (rac-3) was synthesized from methyl 2-(methylsulfanyl)-1-naphthoate through reaction with the di-Grignard reagent derived from 1-bromo-2-(2-bromopropyl)benzene, followed by acid-catalyzed dehydration of the intermediate indanol. Oxidation of rac-3 with m-CPBA gave the diastereomeric sulfoxides (aR*,RS*)-5 and (aR*,SS*)-6, with the relative configuration of 5 established using single-crystal X-ray diffraction. The dichloro[η5:κS-indenyl-sulfanyl and -sulfinyl]rhodium complexes rac-4, (pR*,SS*)-7, and (pR*,RS*)-8 were synthesized through reaction of the ligands rac-3, (aR*,RS*)-5, and (aR*,SS*)-6, respectively, with rhodium trichloride in 9:1 methanol/water solution heated under reflux. The use of water as a cosolvent was found to be critical for obtaining good yields in the complexation reactions. Solid-state structures for the racemic rhodium complexes were determined through single-crystal X-ray diffraction. The enantiomers of th...

Asymmetric Synthesis of (S)-(−)-Xylopinine. Use of the Sulfinyl Group as an Ipso Director in Aromatic SE

Optically pure (S)-(-)-xylopinine 2 was prepared in three steps in 52% overall yield. Thus, condensation of the carbanion derived from (S)-4 with the (S)-(E)-sulfinylimine 5 gave a 2:1 mixture of tetrahydroisoquinolines 6a and 6b, differing only in configuration at sulfur. N-Desulfinylation of this mixture gave the diastereomeric sulfoxides which, without separation, were converted into (S)-(-)-xylopinine (2) with loss of the sulfinyl moieties under Pictet-Spengler conditions. This unprecedented ipso electrophilic substitution of a sulfinyl group may have synthetic implications beyond that described in this work.

Identification and Quantitation of theN-Acetyl-L-cysteineS-Conjugates of Bendamustine and Its Sulfoxides in Human Bile after Administration of Bendamustine Hydrochloride

We recently reported the detection of mercapturic acid pathway metabolites of bendamustine, namely, cysteine S-conjugates in human bile, which are supposed to subsequently undergo further metabolism. In this study, we describe the identification and quantitation of consecutive bendamustine metabolites occurring in human bile using authentic reference standards and the synthesis and structural confirmation of these compounds. Mass spectrometry data along with high-performance liquid chromatography retention data (fluorescence detection) of the synthetic reference standards were consistent with those of the metabolites found in human bile after administration of bendamustine hydrochloride to cancer patients. Analysis of the purified synthetic reference compounds showed a purity of at least 95%. Structural confirmation was achieved by one- and two-dimensional proton as well as carbon-13 NMR spectroscopy and mass spectrometry. A total of 16 bendamustine-related compounds were detected in the bile of patients, 11 of them were recovered as conjugates. Eight conjugates have been structurally confirmed as novel mercapturic acids and sulfoxides. Biliary excretion of the sulfoxides was twice that of the mercapturate precursors. Glutathione S-conjugates of bendamustine have not been detected in bile samples, indicating rapid enzymatic cleavage in humans. Both the lack of glutathione (GSH) conjugates and occurrence of diastereomeric sulfoxides emphasize species-related differences in the GSH conjugation of bendamustine between humans and rats. The total amount recovered in the bile as the sum of all conjugates over the period of 24 h after dosing averaged 5.2% of the administered dose. The question of whether the novel metabolites contribute to urinary excretion should be a target of future investigations.