Axially chiral N‐(o‐aryl)‐4‐hydroxy‐2‐oxazolidinone derivatives from diastereoselective reduction of N‐(o‐aryl)‐2,4‐oxazolidinediones: Thermally interconvertible atropisomers via ring‐chain‐ring tautomerization

The reduction of the axially chiral N‐(o‐aryl)‐5,5‐dimethyl‐2,4‐oxazolidinediones by NaBH₄ yielded axially chiral N‐(o‐aryl)‐4‐hydroxy‐5,5‐dimethyl‐2‐oxazolidinone enantiomers having a chiral center at C‐4, with 100% diastereoselectivity as has been shown by their ¹H and ¹³C NMR spectra and by enantioselective HPLC analysis. The resolved enantiomeric isomers were found to interconvert thermally through an aldehyde intermediate formed upon ring cleavage via a latent ring‐chain‐ring tautomerization. It was found that the rate of enantiomerization depended on the size and the electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen of the heterocycle. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Simple Resolution of Enantiomeric NMR Signals of α‐Amino Acids by Using Samarium(III) Nitrate With L‐Tartarate

Readily available L‐tartaric acid, which is a bidentate ligand with two chiral centers forming a seven‐membered chelate ring, was applied to the chiral ligand for the chiral nuclear magnetic resonance (NMR) shift reagent of samarium(III) formed in situ. This simple method does not cause serious signal broadening in the high magnetic field. Enantiomeric ¹³C and ¹H NMR signals and enantiotopic ¹H NMR signals of α‐amino acids were successfully resolved at pH 8.0 and the 1:3 molar ratio of Sm(NO₃)₃:L‐tartaric acid. It is elucidated that the enantiomeric signal resolution is attributed to the anisotropic magnetic environment for the enantiomers induced by the chiral L‐tartarato samarium(III) complex rather than differences in stability of the diastereomeric substrate adducts. The present ¹³C NMR signal resolution was also effective for the practical simultaneous analysis of plural kinds of DL‐amino acids. Chirality 27:353–357, 2015.© 2015 Wiley Periodicals, Inc.     

The determination of enantiomer composition of 1‐((3‐chlorophenyl)‐(phenyl)methyl) amine and 1‐((3‐chlorophenyl)(phenyl)‐methyl) urea (Galodif) by NMR spectroscopy,chiral HPLC,and polarimetry

For the first time, a method for enantiomer resolution of the anticonvulsant Galodif (1‐((3‐chlorophenyl)(phenyl)methyl) urea) by chiral HPLC was developed, whereas the enantiomeric composition of 1‐((3‐chlorophenyl)(phenyl)methyl) amine—precursor in Galodif synthesis—cannot be resolved by this method. However, starting 1‐((3‐chlorophenyl)(phenyl)methyl) amine quantitatively forms diastereomeric N‐((3‐chlorophenyl)(phenyl)methyl)‐1‐camphorsulfonamides in reaction with chiral (1R)‐(+)‐ or (1S)‐(?)‐camphor‐10‐sulfonyl chlorides. The diastereomeric ratio of obtained camphorsulfonamides can be easily determined by NMR ¹H and ¹³C spectroscopy. The DFT calculations of specific rotation of Galodif enantiomers showed good agreement with experimental data. The absolute configuration of enantiomers was proposed for the first time.     

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.     

Enantiomeric differentiation of atropine/hyoscyamine by 13C NMR spectroscopy and its application to Datura stramonium extract

Introduction – The two enantiomers of hyoscyamine, an alkaloid found in many plant species, have distinct pharmacological and biological properties. Methods for the discrimination of both enantiomers are almost exclusively based on chiral HPLC/UV. Determination of the enantiomeric ratio (e.r.) of hyoscyamine is a challenging problem since this compound tends to racaemise, forming atropine during acid–base extraction. Objective – To develop a protocol for the calculation of enantiomeric ratio of hyoscyamine in a plant extract using a ¹³C NMR method. Methodology – Samples were prepared by extraction of dried Datura stramonium seeds. Observation of C12 and C15 NMR signals of hyoscyamine in the presence of one equivalent of TFA and sub‐stoichiometric amount of Yb(hfc)₃ allowed the calculation of the e.r. of S‐(?) and R‐(+)‐hyoscyamine. Results – The method was optimised with various mixtures of (+) and (?)‐hyoscyamine ranging from 50:50 (racaemic mixture, i.e. atropine) to 98.5:1.5. The e.r. measured by NMR on the signals of aromatic C12 and C15 were in agreement with the gravimetrically prepared samples. The method was then applied to an extract of Datura stramonium and S‐(?)‐hyoscyamine was the unique enantiomer. Conclusion – The study showed that the e.r. determination of atropine/hyoscyamine was achieved with a routine NMR spectrometer, using CLSR/TFA on pure compounds as well as on the crude extract of Datura stramonium. Copyright © 2010 John Wiley & Sons, Ltd.     

Zwitterionic Phosphorylated Quinines as Chiral Solvating Agents for NMR Spectroscopy

Because of their unique 3D arrangement, naturally occurring Cinchona alkaloids and their synthetic derivatives have found wide‐ranging applications in chiral recognition. Recently, we determined the enantioselective properties of C‐9‐phosphate mixed triesters of quinine as versatile chiral solvating agents in nuclear magnetic resonance (NMR) spectroscopy. In the current study, we introduce new zwitterionic members of this class of molecules containing a negatively charged phosphate moiety (i.e., ethyl, n‐butyl and phenyl hydrogen quininyl phosphate). An efficient approach for synthesizing these compounds is elaborated, and full characterization, including conformational and autoaggregation phenomena studies, was performed. Therefore, their ability to induce NMR anisochrony of selected enantiomeric substrates (i.e., primarily N‐DNB‐protected amino acids and their methyl esters) was analyzed compared to uncharged diphenyl quininyl phosphate and its positively charged quaternary ammonium hydrochloride salt. In addition, ¹H and ¹³C NMR experiments revealed their enantiodiscrimination potential toward novel analytes, such as secondary amines and nonprotected amino acids. Chirality 27:752–760, 2015. © 2015 Wiley Periodicals, Inc.     

Synthesis and odor of chiral partial structures of β‐vetivone,Part 2

Several stereoisomeric, monocyclic analogs of (−)‐β‐vetivone (1), one of the main constituents of vetiver oil, were studied to examine if the olfactory properties of (−)‐β‐vetivone (1) could be reproduced from these structurally simpler, synthetically accessible compounds. The effects of diastereomeric and enantiomeric structural differences on the odor of the partial vetivone structure were studied. A chiral phenyl sulfoximine was used for separation of the racemic mixtures. Detailed nuclear magnetic resonance (NMR)‐spectroscopic studies (¹H, ¹³C) were used to determine relative configurations whereas absolute configurations were determined by circular dichroism (CD) methods. Chirality 11:133–138, 1999. © 1999 Wiley‐Liss, Inc.     

1H NMR studies of drugs with achiral and chiral lanthanide shift reagents: Applications to the anticonvulsant pheneturide

The anticonvulsant pheneturide, PNT, has been studied by 300 MHz ¹H NMR in CDCl₃ at ambient temperatures with the achiral lanthanide shift reagent (LSR) Eu(FOD)₃, and with the chiral LSR, Eu(HFC)₃. Both LSRs produced spectral simplification of the aryl proton signal region, and substantial lanthanide‐induced shifts (LIS). With added Eu(HFC)₃, enantiomeric shift differences (ΔΔδ) were induced for most nuclei of PNT, indicating substantial potential for direct determination of enantiomeric excess. Valley heights between corresponding signals in the PNT enantiomers as low as 3.6% were achieved for the meta resonance. Least squares line‐fitting was applied to the variation of chemical shift vs. [LSR]/[PNT] molar ratios for both LSRs. Tentative assignments were made for the NH absorptions based on two‐dimensional NMR (COSY45), as well as their relative magnitudes of LIS, ΔΔδ, and lanthanide‐induced line broadening. The PNT conformation reported in the crystal is believed to be retained in solution with added LSR. The relative senses of magnetic nonequivalence were found to be the same among the three sets of aryl protons, and among the three kinds of protons in the ethyl moiety, with high levels of added chiral LSR, using 2D NMR. Chirality 11:529–535, 1999. © 1999 Wiley‐Liss, Inc.     

Molecular tweezers for enantiodiscrimination in NMR: Di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl benzenedicarboxylates

A series of new chiral molecular tweezers, di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Water‐soluble calix[4]resorcinarenes as chiral NMR solvating agents for bicyclic aromatic compounds

Water‐soluble calix[4]resorcinarenes with proline, 3‐hydroxyproline, and 4‐hydroxyproline substituent groups are evaluated as chiral NMR solvating agents on a series of bicyclic aromatic compounds with naphthyl, indole, dihydroindole, and indane rings. The substrates interact with the calixresorcinarene through insertion of the aromatic ring into the cavity. Most of the substrates are analyzed as cationic species, although one anionic species is analyzed. All of the substrates exhibit enantiomeric discrimination in the ¹H‐NMR spectrum with one or more of the calixresorcinarenes. In most cases, the hydroxyproline derivatives are more effective at causing enantiodifferentiation than the corresponding proline derivative. Presumably, the hydroxyl group on the proline moieties is involved in interactions with the substituent groups of the substrate that are important in creating chiral recognition. The enantiomeric discrimination in the ¹H‐NMR spectrum is large enough for many resonances to permit the analysis of enantiomeric purity. Chirality 2009. © 2009 Wiley‐Liss, Inc.     

Synthesis and odor of chiral partial structures of β‐vetivone. I.

Several, stereoisomeric, monocyclic analogs of (−)‐β‐vetivone (1), one of the main constituents of vetiver oil, were studied to determine whether the olfactory properties of (−)‐β‐vetivone (1) could be reproduced from these structurally simpler, synthetically accessible compounds. The effects of diastereomeric and enantiomeric structural differences on the odor of the partial vetivone structure were determined. A chiral phenyl sulfoximine was used for separation of the racemic mixtures. Detailed nuclear magnetic resonance (NMR) spectroscopic studies (¹H, ¹³C) were used to determine relative configurations while absolute configurations were determined by circular dichroism (CD) methods. Chirality 11:14–20, 1999. © 1999 Wiley‐Liss, Inc.     

Comparison of Chiral Separations of Aminophosphonic Acids and Their Aminocarboxylic Acid Analogs Using a Crown Ether Column

Crown ethers are capable of complexing with primary amines and have been utilized in chromatography to separate amino acid racemates. This application has been extended to resolve (1‐amino‐1‐phenylmethyl)phosphonic acid and (1‐aminoethyl)phosphonic acid racemates, along with their aminocarboxylic acid analogs (2‐phenylglycine and alanine, respectively), via a ChiroSil RCA crown ether based chiral stationary phase. Effects of the organic modifier, temperature, and acid type and concentration on retention and selectivity were also investigated. Trends in retention and selectivity varied between aminophosponic acids and their aminocarboxylic analogs. Computer modeling and ¹H NMR analyses were performed to potentially gain a better understanding of interactions of the aforementioned molecules with the ChiroSil RCA chiral stationary phase. Theoretical predictions of the most stable conformations for (R)‐ and (S)‐enantiomers were compared to elution order; it was found that the elution order agreed with molecular modeling such that the longest retention correlated with the predicted most stable complex between the enantiomer and crown ether. ¹H NMR demonstrated interactions of aminophosphonic and aminocarboxylic racemates with (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid in solution and was utilized to determine enantiomeric excess of (1‐amino‐1‐phenylmethyl)phosphonic acid after its enantioenrichment via crystallization through diastereomeric salt formation with the crown ether followed by filtration. Chirality 25:369–378, 2013. © 2013 Wiley Periodicals, Inc.     

The synthesis and X-ray structure of a chiral rhodium-NHC complex: Implications for the use of NHCs in asymmetric hydroformylation catalysis

An optically active N-heterocyclic carbene (NHC) has been metallated with [RhCl(COD)]₂ to give a rhodium(I) monocarbene substituted complex. This complex has been fully characterized by ¹H and ¹³C NMR spectroscopy and by single-crystal X-ray analysis. Preliminary tests of hydroformylation of styrene catalyzed with this compound have shown that branched to linear aldehyde ratio was rather low 0.67 (40%) and that the enantiomeric excess measured on the corresponding alcohols was only 10%. In the presence of an excess of triphenylphosphine, the ratio of branched to linear aldehyde increased markedly (91%) whereas the enantioselectivity of the reaction remained almost unchanged (12.5%).     

Highly Enantioselective Production of Chiral Secondary Alcohols with Candida zeylanoides as a New Whole Cell Biocatalyst

The increasing demand for biocatalysts in synthesizing enantiomerically pure chiral alcohols results from the outstanding characteristics of biocatalysts in reaction, economic, and ecological issues. Herein, fifteen yeast strains belonging to three food originated yeast species Candida zeylanoides, Pichia fermentans, and Saccharomyces uvarum were tested for their capability for asymmetric reduction of acetophenone to 1‐phenylethanol as biocatalysts. Of these strains, C. zeylanoides P1 showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high yields. The preparative scale asymmetric bioreduction of 4‐nitroacetophenone ( 1m ) by C. zeylanoides P1 gave (S)‐1‐(4‐nitrophenyl)ethanol ( 2m ) with 89% yield and > 99% enantiomeric excess. Compound 2m has been obtained in an enantiomerically pure and inexpensive form. Additionally, these results indicate that C. zeylanoides P1 is a promising biocatalyst for the synthesis of chiral alcohols in industry.     

Enantioseparation of Mandelic Acid Enantiomers With Magnetic Nano‐Sorbent Modified by a Chiral Selector

In this study, R(+)‐α‐methylbenzylamine‐modified magnetic chiral sorbent was synthesized and assessed as a new enantioselective solid phase sorbent for separation of mandelic acid enantiomers from aqueous solutions. The chemical structures and magnetic properties of the new sorbent were characterized by vibrating sample magnetometry, transmission electron microscopy, Fourier transform infrared spectroscopy, and dynamic light scattering. The effects of different variables such as the initial concentration of racemic mandelic acid, dosage of sorbent, and contact time upon sorption characteristics of mandelic acid enantiomers on magnetic chiral sorbent were investigated. The sorption of mandelic acid enantiomers followed a pseudo‐second‐order reaction and equilibrium experiments were well fitted to a Langmuir isotherm model. The maximum adsorption capacity of racemic mandelic acid on to the magnetic chiral sorbent was found to be 405 mg g^?1. The magnetic chiral sorbent has a greater affinity for (S)‐(+)‐mandelic acid compared to (R)‐(?)‐mandelic acid. The optimum resolution was achieved with 10 mL 30 mM of racemic mandelic acid and 110 mg of magnetic chiral sorbent. The best percent enantiomeric excess values (up to 64%) were obtained by use of a chiralpak AD‐H column. Chirality 27:835–842, 2015. © 2015 Wiley Periodicals, Inc.     

Carboxymethylated cyclodextrins and their complexes with Pr(III) and Yb(III) as water‐soluble chiral NMR solvating agents for cationic compounds

Cyclodextrins that are indiscriminately carboxymethylated at the 2‐, 3‐, and 6‐positions are used as chiral NMR solvating agents for cationic substrates with phenyl, naphthyl, pyridyl, indoline, and indole rings. Enantiodifferentiation with the α‐, β‐, and γ‐cyclodextrin derivatives is compared. The carboxymethylated derivatives are almost always more effective as chiral NMR solvating agents for cationic substrates than native cyclodextrins. The most effective carboxymethylated cyclodextrin varies for different substrates, and at times even different resonances of the substrate. Addition of paramagnetic praseodymium(III) or ytterbium(III) to mixtures of the carboxymethylated cyclodextrin and substrate often causes enhancements in enantiomeric discrimination and facilitates measurements of enantiomeric purity. The lanthanide ion bonds to the carboxymethyl groups and causes perturbations in the chemical shifts in the NMR spectra of substrate molecules in the cyclodextrin cavity. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Synthesis and Quantitative Analysis of Diastereomeric Linked Ester Conjugates With Remote Stereocenters Using High‐Field NMR and Chiral HPLC

A stereochemically safe high‐yielding procedure for linking unprotected as well as protected hydroxycarboxylic acids to chiral secondary alcohols via glycolic acid linker is proposed. L‐menthol has been linked with both enantiomers of mandelic, malic, and methoxyphenylacetic acid using bromo‐ or iodoacetyl group as a precursor of the glycolic acid linker. High‐field nuclear magnetic resonance (NMR) and chiral high‐performance liquid chromatography (HPLC) determination of high diastereomeric ratio (dr) (>99%) of the products bearing remote stereocenters was explored. Chiral HPLC allowed quantitation of the diastereomers up to dr 99.9/0.1. High‐field NMR quantitation of the diastereomeric and parent alcoholic impurities in esters was demonstrated at the molar 0.3% and 0.03% levels, respectively. These analyses were done via comparison of integral intensities from major component ¹³C satellites in ¹H or even in ¹³C spectra to the ¹H or ¹³C signals of impurities. Despite lower sensitivity, the last option generally has much better selectivity. In this way the dynamic resolution is brought down by two orders. Chirality 25:793–798, 2013. © 2013 Wiley Periodicals, Inc.     

Utilization of (18‐Crown‐6)‐2,3,11,12‐tetracarboxylic Acid as a Chiral NMR Solvating Agent for Diamines and β‐Amino Acids

The compound (18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid was evaluated as a chiral nuclear magnetic resonance (NMR) solvating agent for a series of diamines and bicyclic β‐amino acids. The amine must be protonated for strong association with the crown ether. An advantage of (18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid over many other crown ethers is that it undergoes a neutralization reaction with neutral amines to form the protonated species needed for binding. Twelve primary diamines in neutral and protonated forms were evaluated. Diamines with aryl and aliphatic groups were examined. Some are atropisomers with equivalent amine groups. Others have two nonequivalent amine groups. Association equilibria for these systems are complex, given the potential formation of 2:1, 1:1, and 1:2 crown‐amine complexes and given the various charged species in solution for mixtures of the crown ether with the neutral amine. The crown ether produced enantiomeric differentiation in the ¹H NMR spectrum of one or more resonances for every diamine substrate. Also, a series of five bicyclic β‐amino acids were examined and (18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid caused enantiomeric differentiation in the ¹H NMR spectrum of three or more resonances of each compound. Chirality 27:708–715, 2015. © 2015 Wiley Periodicals, Inc.     

NMR chiral discrimination of chalcogen containing secondary alcohols

Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatizing agents. The BINOL/DMAP ternary complex demonstrated a simple and fast protocol for determining enantiopurity. The drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral derivatizing agent (CDA) for NMR chiral discrimination of chalcogen containing secondary alcohols. The chiral recognition by CDA and chiral solvating agent (CSA) was assessed using ¹H, ⁷⁷Se‐{1H}, and ¹²⁵Te‐{1H} NMR spectroscopy. A simple model for the assignment of the absolute configuration from NMR data is presented.     

Chiral Amine Enantiomeric Excess Determination Using Self‐Assembled Octahedral Fe(II)‐Imine Complexes

A receptor assembly composed of iron(II) triflate and pyridine‐2,6‐dicarbaldehyde was used to determine the enantiomeric excess (ee) of alpha‐chiral primary amines using circular dichroism spectroscopy. The alpha chiral amines condense with the dialdehyde to form a diimine, which forms a 2:1 octahedral complex with iron(II). The ee values of unknown concentrations of alpha‐chiral amines were determined by constructing calibration curves for each amine and then measuring the ellipticity at 600 nm. This improves our previously reported assay for ee determination of chiral primary amines by further increasing the wavelength at which CD is measured and reducing the absolute error of the assay. Chirality 27:294–298, 2015. 2015 Wiley Periodicals, Inc.