Synthesis and application of 3‐substituted (S)‐BINOL as chiral ligands for the asymmetric ethylation of aldehydes

A series of (S)‐BINOL ligands substituted at the 3 position with some five‐membered nitrogen‐containing aromatic heterocycles were effectively prepared and their catalytic abilities were evaluated in the asymmetric addition of diethylzinc to benzaldehyde in the presence of titanium tetraisopropoxide. Under the optimized reaction conditions, titanium complex of (S)‐3‐(1H‐benzimidazol‐1‐yl)‐1,1′‐bi‐2‐naphthol was found to be the most efficient catalyst for asymmetric ethylation of various aldehydes to generate the corresponding secondary alcohols in up to 99% yield and 91% ee. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

New Lignans from the Flower of Forsythia koreana and Their Suppression Effect on VCAM‐1 Expression in MOVAS Cells

Six lignans including two new lignans were obtained as the principal components of the Forsythia koreana flowers via silica gel (SiO₂), octadecyl SiO₂ (ODS) as well as Sephadex LH‐20 column chromatography. In addition to two new lignans, named koreanaside A ((7R,8S,7′R,8′S)‐7,7′‐diepoxy‐5′‐hydroxy‐3,3′‐dimethoxylignan 4‐O‐β‐d ‐glucopyranoside) and koreanaside B ((7R,8S,7′S,8′R)‐7,9′‐epoxy‐9,5′,7′‐trihydroxy‐3,3′‐dimethoxylignan 4‐O‐β‐d ‐glucopyranoside), four known lignans were identified to be (+)‐phylligenin, (?)‐epipinoresinol, pinoresinol, and tinosposide A. The structures and absolute configurations of koreanasides A and B were established by means of analysis of spectroscopic data (NMR, IR, FAB‐MS, and CD), whereas the structures of known lignans were identified by comparison their NMR and MS values with those in the reported literature. Their chemical structures including configuration were established by means of analysis of spectroscopic data (NMR, IR, FAB‐MS, and CD) but also comparison of their NMR and MS values with those in the reported literature. This is the first article for isolation of six lignans of F. koreana flowers. Koreanasides A and B showed high radical scavenging activity with oxygen radical absorbance capacity (ORAC) values of 0.97 ± 0.01 and 1.02 ± 0.01, respectively. Koreanaside A also prohibited expressing VCAM‐1 in MOVAS cells with 80.5% at 25 mg/mL.     

Use of (S)‐BINOL as NMR chiral solvating agent for the enantiodiscrimination of omeprazole and its analogs

The application of (S)‐1,1′‐binaphthyl‐2,2′‐diol as NMR chiral solvating agent (CSA) for omeprazole, and three of its analogs (lanso‐, panto‐, and rabe‐prazole) was investigated. The formation of diastereomeric host–guest complexes in solution between the CSA and the racemic substrates produced sufficient NMR signal splitting for the determination of enantiomeric excesses by ¹H‐ or ¹⁹F‐NMR spectroscopy. Using of hydrophobic deuterated solvents was mandatory for obtaining good enantiodiscrimination, thus suggesting the importance of intermolecular hydrogen bonds in the stabilization of the complexes. The method was applied to the fast quantification of the enantiomeric purity of in‐process samples of S‐omeprazole. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Recent advances in asymmetric oxidative coupling of 2‐naphthol and its derivatives

The enantiomeric atropoisomers of 1,1′‐binaphthyl‐2,2′‐diol (BINOL) have become one of the most widely used chiral ligands and auxiliaries for asymmetric synthesis. This review provides an overview of enantioselective synthesis of optical active BINOLs by straightforward asymmetric oxidative coupling of identical 2‐naphthol and its substituted derivatives. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

A surface molecularly imprinted polymer as chiral stationary phase for chiral separation of 1,1′‐binaphthalene‐2‐naphthol racemates

Acrylamide (AM) was copolymerized with ethylene glycol dimethacrylate (EGDMA) in the presence of (R )‐1,1′‐binaphthalene‐2‐naphthol (BINOL) as the template molecules on the surface of silica gel by a free radical polymerization to produce a chiral stationary phase based on the surface molecularly imprinted polymer (SMIP‐CSP). The SMIP‐CSP showed a much better separation factor (α = 4.28) than the CSP based on the molecularly imprinted polymer (MIP‐CSP) without coating on the silica gel (α = 1.96) during the chiral separation of BINOL enantiomers by high‐performance liquid chromatography. The influence of the pretreatment temperature and the content of the template molecule ((R )‐BINOL) of the SMIP‐CSP, and the mobile phase composition on the separation of the racemic BINOL were systematically investigated.     

The Syntheses of new Camphorsulfonylated Ligands Derived from 2-Amino-2'-Hydroxy-1,1'-Binaphthyl and Their Enantioselectivities in the Addition of Dialkylzinc Reagents to Aldehydes

A series of new camphorsulfonylated ligands derived from chiral 2‐amino‐2′‐hydroxy‐1,1′‐binaphthyl (NOBIN) and (+)‐camphorsulfonic acid were synthesized by a short and simple synthetic sequence, and their enantioselective catalytic activities were assessed in the nucleophilic addition reaction of dialkylzinc reagents to aldehydes in the presence of titanium tetraisopropoxide. The most efficient ligand, N‐hydroxycamphorsulfonylated (S)‐NOBIN, gave (S)‐addition products with good yields and up to 87% of ee value. The ¹H nuclear magnetic resonance (NMR) and ¹³C NMR results of the titanium titration experiments on this ligand indicate that the most likely catalytic reactive species involved in this catalytic asymmetric addition is a bimetallic titanium complex. A possible catalytic reaction mechanism is proposed. Chirality 24:825–832, 2012. © 2012 Wiley Periodicals, Inc.     

Synthetic Method for 2,2'‐Disubstituted Fluorinated Binaphthyl Derivatives and Application as Chiral Source in Design of Chiral Mono‐Phosphoric Acid Catalyst

A practical synthetic method for 2,2'‐disubstituted fluorinated binaphthyl derivatives was achieved using magnesium bis(2,2,6,6‐tetramethylpiperamide) [Mg(TMP)₂], prepared from LiTMP (2 equiv) and MgBr₂ (1 equiv), which allows for access to a variety of fluorinated binaphthyl compounds. The utility of the fluorinated binaphthyl backbone was evaluated in F₁₀BINOL derived chiral mono‐phosphoric acid (R)‐ 19 as the chiral Brønsted acid catalyst. The catalyst (R)‐ 19 performs exceptionally well in the catalytic enantioselective imino‐ene reaction, demonstrating the potential of a fluorinated binaphthyl framework. Chirality 27:464–475, 2015. © 2015 Wiley Periodicals, Inc.     

Enantioselective toxic effects of hexaconazole enantiomers against Scenedesmus obliquus

Enantioselectivity in ecotoxicity of chiral pesticides in the aquatic environment has been a subject of growing interest. In this study, the toxicological impacts of hexaconazole enantiomers were investigated with freshwater algae Scenedesmus obliquus. After 96 h of exposure, the EC₅₀ values for rac‐hexaconazole, (+)‐hexaconazole, and (?)‐hexaconazole were 0.178, 0.355, and 0.065 mg l^?1, respectively. Therefore, the acute toxicities of hexaconazole enantiomers were enantioselective. In addition, the different toxic effects were evaluated when S. obliquus were exposed to 0.2, 0.5, and 1.0 mg l^?1 of rac‐hexaconazole, (+)‐hexaconazole, and (?)‐hexaconazole during 96 h, respectively. The chlorophyll a and chlorophyll b contents of S. obliquus treated by (?)‐hexaconazole were lower than those exposed to (+)‐hexaconazole, whereas the malondialdehyde contents of S. obliquus treated by (?)‐form were higher than those exposed to (+)‐form at higher concentrations. In general, catalase activities were significantly upregulated by exposure to (?)‐enantiomer than (+)‐enantiomer at all three concentrations. However, superoxide dismutase activities exposed to (?)‐hexaconazole were lower than that exposed to (+)‐hexaconazole at 0.2 mg l^?1 and 0.5 mg l^?1. On the basis of these data, the acute toxicity and toxic effects of hexaconazole against S. obliquus were enantioselective, and such enantiomeric differences must be taken into consideration in pesticide risk assessment. Chirality 24:610–614, 2012. © 2012 Wiley Periodicals, Inc.     

Effects of solvent on inclusion complexation of a chiral dipeptide toward racemic BINOL

The effects of reaction solvent on inclusion complexation of a chiral dipeptide (3S,6S)‐ 1 derived from (S)‐proline toward racemic BINOL was investigated, discovering that the reaction solvent played a crucial role in determining the inclusion complexation behavior of dipeptide (3S,6S)‐ 1 toward rac‐BINOL. (3S,6S)‐ 1 did not show any chiroselective or achiroselective complexation toward rac‐BINOL in polar protic solvents such as methanol and ethanol, polar aprotic solvents including trichloromethane and THF, while in polar aprotic solvent ethyl acetate and apolar aprotic solvents benzene, (3S,6S)‐ 1 displayed achiroselective complexation toward rac‐BINOL. However, the resulting heterocomplex HC‐ 2 from benzene and HC‐ 3 from ethyl acetate have a different composition. Single crystal X‐ray diffraction analysis demonstrates that the two heterocomplexes are formed via different H‐bond interaction patterns, in which the reaction solvent has a dramatic effect. Furthermore, this work provides a relatively green method for quantitative enantiomeric enrichment of nonracemic BINOL, in which unacceptable and toxic benzene was replaced by ethyl acetate.     

Solid‐phase extraction with metal–organic frameworks for the analysis of chiral compounds

Metal–organic frameworks (MOFs) are excellent porous materials with nanoscale cavities and high surface areas, which make them promising as novel adsorbents in solid‐phase extraction (SPE). In this article we report a new application of the chiral MOF [Zn₂(D‐Cam)₂(4,4′‐bpy)]_n in SPE used for the measurement of the enantiomeric excess (ee) of (±)‐1,1′‐bi‐2‐naphthol. Several important experimental parameters that may influence the extraction efficiency were investigated and optimized. Under the optimum conditions, a good linearity (R² > 0.999) was found between the ee value and the reciprocal of the peak areas. When compared with the actual ee measured using chiral HPLC, the SPE‐based assay also showed good accuracy and precision. The results showed that SPE based on chiral MOFs as adsorbents is a simple and effective method for the determination of the ee values of chiral compounds.     

Asymmetric catalysis of homo‐coupling of 3‐substituted naphthylamine and hetero‐coupling with 3‐substituted naphthol leading to 3,3′‐dimethyl‐2,2′‐diaminobinaphthyl and ‐2‐amino‐2′‐hydroxybinaphthyl

Optically active 3,3′‐dimethyl‐2,2′‐diamino‐1,1′‐binaphthyl (DM‐DABN) and 3,3′‐dimethyl‐2‐amino‐2′‐hydroxybinaphthyl (DM‐NOBIN) derivatives were synthesized by Cu‐(?)‐sparteine complex‐catalyzed enantioselective homo‐ and hetero‐coupling of 2‐naphthylamine, respectively. The difference in enantioselectivity was observed by changing the concentration of oxygen. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Optically Active α‐Phenylethylamine as Efficient Organocatalyst in the Solvent‐free Reactions Between 2,3‐Butanedione and Conjugated Nitroolefins

(R)‐(+) and (S)‐(?)‐1‐phenylethylamine have been shown to promote highly diastereoselective and complementary enantioselective formal [3 + 2]carbocyclization reactions between 2,3‐butanedione and conjugated nitroalkenes with formation of enantiomerically rich 2‐hydroxy‐3‐nitrocyclopentanone derivatives. The reactions were carried out both in solvent and under solvent‐free conditions. The absolute configurations of the products were assigned by X‐ray and circular dichroism spectra analyses. Chirality 24:1005–1012, 2012. © 2012 Wiley Periodicals, Inc.     

Asymmetric epoxidation of cinnamyl alcohol with optically active titanium complexes

A family of titanium(IV) alkoxo compounds [{Ti(O‐i‐Pr)₂(OR)₂}₂] 1–4 prepared by alcohol exchange of Ti(O‐i‐Pr)₄ and a chiral higher‐boiling alcohol [ROH = 1,2:3,4‐di‐O‐isopropylidene‐α‐d ‐galactopyranose, 1,2:5,6‐di‐O‐isopropylidene‐α‐d ‐glucofuranose, (1R,2S,5R)‐(?)‐menthol, (1S‐endo)‐(?)‐borneol, (1S,2R,5S)‐(+)‐menthol, and (+)‐borneol] has been tested to evaluate their catalytic activity and stereoselectivity in the asymmetric epoxidation of cinnamyl alcohol. © 2005 Wiley‐Liss, Inc. Chirality     

Pharmacokinetics of Terazosin Enantiomers in Healthy Chinese Male Subjects

The purpose of this study was to elucidate the pharmacokinetics of terazosin enantiomers in healthy Chinese male subjects. After a single oral dose of 2‐mg terazosin, the plasma concentrations of terazosin enantiomers were measured over the course of 48 h in 12 healthy subjects. The plasma concentrations of (+)‐(R)‐terazosin at all time points were higher than those of (?)‐(S)‐terazosin. The area under the plasma concentration–time curve (AUC_0–∞) and maximum plasma concentration of (+)‐(R)‐terazosin were significantly greater than those of the (?)‐(S)‐terazosin (P < 0.01, respectively). The R/S ratio of AUC_0–∞ of terazosin was 1.68. For the first time, it was proven that the pharmacokinetics of terazosin was stereoselective in healthy Chinese male subjects. Chirality 24:1047–1050, 2012. © 2012 Wiley Periodicals, Inc.     

Enantioselective recognition of carboxylic acids by novel fluorescent triazine‐based thiazoles

Hydrogen bonding and π‐π interactions take special part in the enantioselectivity task. In this regard, because of having both hydrogen acceptor and hydrogen donor groups, melamine derivatives become more of an issue for enantioselectivity. In the light of such information, triazine‐based chiral, fluorescence active novel thiazole derivatives L1 and L2 were designed and synthesized from (S)‐(?)‐2‐amino‐1‐butanol and (1S,2R)‐(+)‐2‐amino‐1,2‐diphenylethanol. The structural establishment of these compounds was made by spectroscopic methods such as FTIR, ¹H, and ¹³C NMR. While the solution of these compounds in DMSO did not show any fluorescence emission, it was observed that the emission increased 44‐fold for L1 and 55‐fold for L2 in 95% water, similar to the aggregation‐induced emission (AIE) characterized compounds. In this regard, enantioselective capabilities of these compounds against carboxylic acids were tested, and in experiments carried out at a ratio of 40/60 DMSO/H₂O, it was determined that R‐2ClMA increased the fluorescence emission of L1 chiral receptor by 2.59 times compared to S‐isomer.     

(S)‐(−)‐(2‐MeBu)N(Pr)2MeI Salt as Template in the Enantioselective Synthesis of the Enantiopure Two‐dimensional (S)‐(−)‐(2‐MeBu)N(Pr)2Me[ΛMnΔCr(C2O4)3] Ferromagnet

We describe herein the synthesis of (rac)‐ or enantiopure (S)‐(?)‐(2‐MeBu)N(Pr)₂MeI ammonium salts. These racemic and enantiopure ammonium salts were used as cationic templates to obtain new two‐dimensional (2D) ferromagnets [(rac)‐(2‐MeBu)N(Pr)₂Me][MnCr(C₂O₄)₃] and [(S)‐(?)‐(2‐MeBu)N(Pr)₂Me][ΔMnΛ nCr(C₂O₄)₃]. The absolute configuration of the hexacoordinated Cr(III) metallic ion in the enantiopure 2D network was determined by a circular dichroism measurement. The structure of [(2‐MeBu)N(Pr)₂Me][MnCr(C₂O₄)₃], established by single crystal X‐ray diffraction, belongs to the chiral P6₃ space group. According to direct current (dc) magnetic measurements, these compounds are ferrromagnets with a temperature Tc = 6°K. Chirality 25:444–448, 2013. © 2013 Wiley Periodicals, Inc.     

Synthesis of enantiomers of exo‐2‐norbornyl‐N‐n‐butylcarbamate and endo‐2‐norbornyl‐N‐n‐butylcarbamate for stereoselective inhibition of acetylcholinesterase

The acetylcholinesterase inhibition by enantiomers of exo‐ and endo‐2‐norbornyl‐N‐n‐butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐exo‐2‐norbornyl‐N‐n‐butylcarbamates, the R‐enantiomer is more potent than the S‐enantiomer. But, for the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates, the S‐enantiomer is more potent than the R‐enantiomer. Optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates are synthesized from condensations of optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norborneols with n‐butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Enantioselective vinylation of aldehydes with the vinyl Grignard reagent catalyzed by magnesium complex of chiral BINOLs

Enantioselective vinylation of aldehydes via direct catalytic asymmetric Grignard reaction of aldehdyes and the vinyl Grinard reagent is a long‐standing challenge. This work demonstrated that the magnesium (S)‐3,3′‐dimethyl BINOLate enantioselectively catalyze the direct vinylation of aldehydes with the deactivated vinylmagnesium bromide by bis(2‐[N,N′‐dimethylamino]ethyl) ether (BDMAEE) in the addition of n‐butylmagnesium chloride. The highest ee of 63% was achieved up to date.     

A Forgotten Chiral Spiro Compound Revisited: 3,3'‐Dimethyl‐3H,3'H‐2,2'‐spirobi[[1,3]benzothiazole]

The title compound was obtained as a side product during dimerization‐oxidation steps of the carbene generated from N‐methylbenzothiazolium iodide. Chromatography on (S,S)‐Whelk O1 column showed on cooling a typical plateau shape chromatogram indicating an exchange between two enantiomers on the column. The thermal barrier to racemization was determined (85 kJ.mol^?1 at 10 °C) by dynamic high‐performance liquid chromatography (DHPLC).The absolute configuration of the first (M) and second eluted (P) enantiomers on the (S, S)‐Whelk O1 column was established by comparing the reconstructed circular dichroism (CD) spectra from the CD detector signal and the calculated CD spectrum of the (P) enantiomer. Mass spectrometry revealed that 3,3'‐dimethyl‐3H,3'H‐2,2'‐spirobi[[1,3]benzothiazole] can be viewed as a masked thiophenate attached to a benzothiazolium framework. Chirality 27:716–721, 2015. © 2015 Wiley Periodicals, Inc.     

Enantioselective synthesis and antioxidant activity of 3‐(3,4‐dihydroxyphenyl)‐glyceric acid—Basic monomeric moiety of a biologically active polyether from Symphytum asperum and S. caucasicum

The racemic and enantioselective synthesis of a novel glyceric acid derivative, namely, 2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid as well as the antioxidant activities is described. The virtually pure enantiomers, (+)‐(2R,3S)‐2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid and (?)‐(2S,3R)‐2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid were synthesized for the first time via Sharpless asymmetric dihydroxylation of trans‐caffeic acid derivatives using the enantiocomplementary catalysts, (DHQD)₂‐PHAL and (DHQ)₂‐PHAL. The determination of enantiomeric purity of the novel chiral glyceric acid derivatives was performed by high‐performance liquid chromatographic techniques on the stage of their alkylated precursors. The novel glyceric acid derivatives show strong antioxidant activity against hypochlorite and N,N‐diphenyl‐N‐picryl‐hydrazyl free radical. Their antioxidant activity is about 40‐fold higher than that of the corresponding natural polyether and three‐fold higher of trans‐caffeic acid itself. Chirality, 2010. © 2010 Wiley‐Liss, Inc.