Chiral Sulfur Research Articles

Formal Asymmetric (4+1) Annulation Reaction between Sulfur Ylides and 1,3-Dienes.

A highly enantioselective synthesis of functionalized cyclopentanoids by a formal asymmetric (4+1) annulation strategy was developed. The methodology consists of a stereoselective cyclopropanation reaction between chiral sulfur ylides and 1,3-dienes followed by a, in situ, stereospecific MgI2 -catalyzed rearrangement of vinylcyclopropanes. This method is distinguished by a remarkable compatibility with functional groups and a high stereocontrol.

ChemInform Abstract: Recent Applications of Chiral N‐tert‐Butanesulfinyl Imines, Chiral Diene Ligands and Chiral Sulfur‐Olefin Ligands in Asymmetric Synthesis

AbstractReview: 104 refs.

Acid catalyzed alcoholysis of sulfinamides: unusual stereochemistry, kinetics and a question of mechanism involving sulfurane intermediates and their pseudorotation.

The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. The steric course of the reaction depends mainly on the size of the dialkylamido group in the sulfinamides and of the alcohols used as nucleophilic reagents. It has been found that bulky reaction components preferentially form sulfinates with retention of configuration. It has been demonstrated that the stereochemical outcome of the reaction can be changed from inversion to retention and vice versa by adding inorganic salts to the acidic reaction medium. The unusual stereochemistry of this typical bimolecular nucleophilic substitution reaction, as confirmed by kinetic measurements, has been rationalized in terms of the addition-elimination mechanism, A-E, involving sulfuranes as intermediates which undergo pseudorotations.

The first application of C2-symmetric chiral sulfurous diamide as efficient sulfur–olefin hybrid ligands for Rh-catalyzed asymmetric 1,4-addition reactions

New C2-symmetric chiral sulfurous diamides were synthesized from (1R,2R)-(+)-1,2-diphenylethylenediamine and used as efficient chiral sulfur–olefin hybrid ligands for enantioselective rhodium-catalyzed asymmetric 1,4-addition reactions. High yields (up to 99%) and excellent enantioselectivities (up to 96%) were achieved for both cyclohexenone and cyclopentenone substrates.

Preclinical characterization of acyl sulfonimidamides: potential carboxylic acid bioisosteres with tunable properties.

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa , lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

Recent applications of chiral N-tert-butanesulfinyl imines, chiral diene ligands and chiral sulfur–olefin ligands in asymmetric synthesis

The highly efficient asymmetric reactions of chiral sulfinyl auxiliary, diene ligands and sulfur–olefin ligands are presented.

Application of Chiral Olefin Ligands in Asymmetric Catalysis

As a novel class of potential ligands, chiral olefin ligands have attracted much attention. Chiral olefin ligands exhibit higher activity and selectivity than the traditional nitrogen, phosphine, oxide ligands in some reactions, and solved some problems that other ligands could not do. To enhance the coordination of the olefin ligands and the metal, heteroatoms were introduced to its backbone, several hybrid olefin ligands have been developed to increase the diversity of the ligands for further expanding the application of chiral olefin ligands. In this review, the recent advances in the development of chiral diene ligands, chiral phosphine olefin ligands and chiral sulfur olefin ligands, and their application in transition-metal catalyzed asymmetric reactions are reviewed.

ChemInform Abstract: Rh(I)‐Catalyzed Asymmetric 1,2‐Additions of Arylboronic Acids to Isatins with Chiral Sulfur—Alkene Hybrid Ligands.

AbstractThe title reaction provides a variety of 3‐aryl‐3‐hydroxy‐2‐oxindoles in moderate to excellent yields with enantioselectivities up to 85%.

ChemInform Abstract: Enantio‐ and Diastereoselective Synthesis of Spiro‐Epoxyoxindoles.

AbstractHighly enantioenriched spiro‐epoxyoxindoles are obtained from isatins and chiral sulfur ylides generated in situ from camphor‐derived sulfonium salts.

Chiral Dicarboxamide Scaffolds Containing a Sulfiliminyl Moiety as Potential Ryanodine Receptor Activators

To search for new environmentally benign insecticides with high activity, low toxicity, and low residue, novel chiral configurations introduced into dicarboxamide scaffolds containing N-cyano sulfiliminyl moieties were first studied. Four series of phthalamides with sulfur-containing side chains were designed, synthesized, and evaluated against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)) for their insecticidal activities. All structures were characterized by (1)H NMR, (13)C NMR, and HRMS (or elemental analysis), and their configurations were confirmed by optical polarimetry. The biological assessment indicated that some title compounds exhibited significant insecticidal activities. For oriental armyworm, these stereoisomers exerted different impacts on biological activity following the sequence (Sc, Ss) ≥ (Sc, Rs) ≫ (Rc, Ss) > (Rc, Rs), and carbon chirality influenced the activities more strongly than sulfur. Compounds Ia and IIa reached as high an activity as commercial flubendiamide, with LC50 values of 0.0504 and 0.0699 mg L(-1), respectively, lower than that of flubendiamide (0.1230 mg L(-1)). For diamondback moth, the sequence of activity was (Sc, Ss) > (Sc, Rs), and the sulfur chirality influenced the activities more greatly than carbon. Compound IIe exhibited even higher activity than flubendiamide, whereas Ie and Ic,d reached the activity of the latter. The results indicated that the improvement of insecticidal activity probably required a coordination of both carbon and sulfur chirality. Comparative molecular field analysis calculation indicated that stereoisomers with Sc configurations containing strong electron-withdrawing groups such as as CN are important in maintaining the high activity. The chiral scaffolds containing the N-cyano sulfiliminyl moiety are also essential for high larvicidal activity. Some title compounds could be considered as potential candidates for ryanodine receptor activators.

Rh(I)-catalyzed asymmetric 1,2-additions of arylboronic acids to isatins with chiral sulfur–alkene hybrid ligands

A rhodium-catalyzed asymmetric 1,2-addition of arylboronic acids to isatins with chiral sulfur–alkene hybrid ligands was achieved, and a variety of 3-aryl-3-hydroxy-2-oxindoles were obtained in moderate to good yields with up to 85% ee and a biologically active compound was synthesized with this strategy.

Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines.

Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes. We performed gene reporter assays for transcriptional activity of AhR, RT-PCR analyses for CYP1A1/2 mRNAs, western blots for CYP1A1/2 proteins and EROD assay for CYP1A1/2 catalytic activity. Lansoprazole and omeprazole enantiomers displayed differential effects on AhR-CYP1A1/2 pathway. In general, S-enantiomers were stronger activators of AhR and inducers of CYP1A genes as compared to R-enantiomers in lower concentrations, i.e. 1–10 µM for lansoprazole and 10–100 µM for omeprazole. In contrast, R-enantiomers were stronger AhR activators and CYP1A inducers than S-enantiomers in higher concentrations, i.e. 100 µM for lansoprazole and 250 µM for omeprazole. In conclusion, we provide the first evidence of enantiospecific effects of omeprazole and lansoprazole on AhR signaling pathway.

Enantio- and diastereoselective synthesis of spiro-epoxyoxindoles.

An asymmetric synthesis of epoxyoxindoles from isatins has been developed by employing chiral sulfur ylides generated in situ from camphor-derived sulfonium salts. This reaction allows an efficient access to enantioenriched spiro-epoxyoxindoles under mild reaction conditions, featuring high yields and excellent enantio- and diastereoselectivities.

Enantioseparation of selected chiral sulfoxides in high-performance liquid chromatography with polysaccharide-based chiral selectors in polar organic mobile phases with emphasis on enantiomer elution order

The separation of the enantiomers of 17 chiral sulfoxides was studied on polysaccharide-based chiral columns in polar organic mobile phases. Enantiomer elution order (EEO) was the primary objective in this study. Two of the six chiral columns, especially those based on amylose tris(3,5-dimethylphenylcarbamate) and cellulose tris(4-chloro-3-methylphenylcarbamate) (Lux Cellulose-4) proved to be most successful in the separation of the enantiomers of the studied sulfoxides. Interesting examples of EEO reversal were observed depending on the chiral selector or the composition of the mobile phase. For instance, the R-(+) enantiomer of lansoprazole eluted before the S-(-) enantiomer on Lux Cellulose-1 in both methanol or ethanol as the mobile phase, while the elution order was opposite in the same eluents on amylose tris(3,5-dimethylphenylcarbamate) with the S-(-) enantiomer eluting before the R-(+) enantiomer. The R-(+) enantiomer of omeprazole eluted first on Lux Amylose-2 in methanol but it was second when acetonitrile was used as the mobile phase with the same chiral selector. Several other examples of reversal in EEO were observed in this study. An interesting example of the separation of four stereoisomers of phenaminophos sulfoxide containing chiral sulfur and phosphor atoms is also reported here.

ChemInform Abstract: Oxazolidine Sulfur Ylides Derived from Phenylglycinol for the Specific and Highly Diastereoselective Synthesis of Aryl and Alkyl trans‐Epoxyamides.

AbstractCoupling of chiral sulfur ylides of type (VII) with aldehydes provides an efficient and highly diastereoselective approach to aryl and alkyl trans‐epoxyamides.

ChemInform Abstract: Construction of Optically Active Indolines by Formal [4 + 1] Annulation of Sulfur Ylides and N‐(ortho‐Chloromethyl)aryl Amides.

AbstractAsymmetric [4 + 1] annulation of axial chiral sulfur ylides (I) and N‐(ortho‐chloromethyl)aryl amides represents a direct procedure to access chiral 2‐substituted indolines.

ChemInform Abstract: Methods for the Synthesis of Chiral Sulfur Heterocycles and Their Application in the Asymmetric Baylis—Hillman Reactions.

AbstractDimesylates of chiral diols cyclize in the presence of sodium sulfide to provide sulfur heterocycles (III) and (VII).

Noninteracting, Vicinal Frustrated P/B-Lewis Pair at the Norbornane Framework: Synthesis, Characterization, and Reactions

Hydroboration of dimesitylnorbornenylphosphane with Piers' borane [HB(C6F5)2] gave the frustrated Lewis pair (FLP) 4 in good yield. It has the -PMes2 Lewis base attached at the 2-endo position and the -B(C6F5)2 group 3-exo oriented at the norbornane framework. The vicinal FLP 4 was shown by X-ray diffraction and by spectroscopy to be a rare example of an intramolecular noninteracting pair of a Lewis acid and Lewis base functionality. The FLP 4 rapidly splits dihydrogen heterolytically at ambient temperature to yield the phosphonium/hydrido borate zwitterion 5. It adds to the carbonyl group of benzaldehyde and to carbon dioxide to yield the adducts 6 and 7, respectively. Compounds 5-7 were characterized by X-ray diffraction. Compound 4 adds to the S═O function of sulfur dioxide to give a pair of diastereomeric heterocyclic six-membered ring products due to the newly formed sulfur chirality center, annulated with the norbornane skeleton, which were investigated by (31)P/(11)B single and double resonance solid state NMR experiments. Compound 8 was also characterized by X-ray diffraction. The FLP 4 undergoes a clean N,N-addition to nitric oxide (NO) to give a norbornane annulated five-membered heterocyclic persistent FLP-NO aminoxyl radical 12 (characterized, e.g., by X-ray diffraction and EPR spectroscopy). Additionally, the FLP radical was characterized by (1)H solid state NMR spectroscopy. The radical 12 undergoes a H-atom abstraction reaction with 1,4-cyclohexadiene to yield the respective diamagnetic FLP-NOH product 13, which was also characterized by X-ray diffraction and solid state NMR spectroscopy.

Construction of Optically Active Indolines by Formal [4+1] Annulation of Sulfur Ylides and N‐(ortho‐Chloromethyl)aryl Amides

Get asymmetric! Asymmetric [4+1] annulation of sulfur ylides and N-(ortho-chloromethyl)aryl amides allowed the formation of the desired cycloadduct with moderate to high yields and enantioselectivities (see scheme). The described strategy, taking advantage of chiral sulfur ylides, represents a direct procedure to access chiral 2-substituted indolines.

Methods for the synthesis of chiral sulfur heterocycles and their application in the asymmetric Baylis–Hillman reactions

Enantiomerically pure (2S,6S)-2,6-diphenyltetrahydro-2H-thiopyran, (2S)-2-phenyltetrahydro thiophene, and (2S)-2-phenyltetrahydro-2H-thiopyran were prepared in 70–72% yields and with 86–99% ee via cyclization of the corresponding dimesylate in an SN2 cyclization reaction using sodium sulfide nonahydrate. The results on the application of various chiral sulfides in asymmetric Baylis–Hillman reactions are also described.