Utility of crown ethers derived from methyl β-d-galactopyranoside and their lanthanide couples as chiral NMR discriminating agents

Two chiral crown ethers derived from methyl β-d-galactopyranoside are examined as chiral NMR discriminating agents for protonated primary amines, amino alcohols, and amino acids. In combination, the solubility and use of the two crown ethers span a range of common NMR solvents including chloroform, acetonitrile, and methanol, which are compatible with the solubilities of various protonated amines. Enantiomeric discrimination is observed in the spectra of most substrates in the presence of the crown ethers. In several cases, the enantiomeric discrimination is larger than observed with previously reported chiral crown ethers. The crown ether V contains a β-diol unit capable of forming a chelate bond with lanthanide(III) ions. Adding ytterbium(III)nitrate to NMR samples in acetonitrile containing V causes substantial enhancements in the enantiodiscrimination in the spectra of several substrates.     

Chiral recognition in NMR spectroscopy using crown ethers and their ytterbium(III) complexes

Chiral crown ethers 1 and 5 are useful enantiomeric discriminating agents in ¹H NMR spectroscopy for neutral and protonated primary amines, amino acids, and amino alcohols. The presence of the carboxylic acid groups in 1 and 5 provide sites at which ytterbium(III) can bind. Adding ytterbium(III) nitrate to crown–substrate mixtures in methanol-d₄ causes shifts in the spectra of substrates and often enhances the chiral discrimination in the ¹H NMR spectrum. The enhancement in enantiomeric discrimination that occurs in the presence of ytterbium(III) allows lower concentrations of the crown ether to be used in chiral recognition studies. Several amide derivatives of 1 were prepared and evaluated as chiral NMR discriminating agents, although except for 1e, these were less effective than 1.     

Chiral NMR discrimination of secondary amines using (18-crown-6)-2,3,11,12-tetracarboxylic acid

[reaction: see text] Enantiomeric discrimination is observed in the (1)H NMR spectra of chiral secondary amines in the presence of (R)-(+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Secondary amines are protonated by one of the carboxylic acid groups of the crown ether to produce the corresponding ammonium and carboxylate ions. The secondary ammonium ion likely forms two hydrogen bonds to crown ether oxygen atoms and an ion pair with the carboxylate anion.     

Chiral NMR discrimination of piperidines and piperazines using (18-crown-6)-2,3,11,12-tetracarboxylic acid

Enantiomeric discrimination is observed in the (1)H and (13)C NMR spectra of piperidines and piperazines in the presence of (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. The amines are protonated by the carboxylic acid groups of the crown ether to produce the corresponding ammonium and carboxylate ions. Association of the ammonium ion with the crown ether likely involves two hydrogen bonds with the crown ether oxygen atoms and an ion pair with the carboxylate anion. Methyl, hydroxymethyl, phenyl, carboxyl, pyridyl, and cyclohexyl substituent groups alpha to the nitrogen atom do not inhibit binding of the ammonium ion to the crown ether. The NMR spectra of piperidines with the stereogenic center alpha or beta to the nitrogen atom exhibit substantial enantiomeric discrimination. Dibasic substrates such as the piperizines are likely converted to their diprotonated form in the presence of the crown ether, and both nitrogen atoms appear to associate with the crown ether moiety.     

Chiral discrimination of aliphatic amines and amino alcohols using NMR spectroscopy

Two methods are compared for analyzing the enantiomeric purity of aliphatic amines and amino alcohols using NMR spectroscopy. The first employs (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid as a chiral NMR solvating agent in methanol‐d₄. The second involves a derivatization scheme in which the amine is reacted with naphtho[2,3‐c]furan‐1,3‐dione to form the corresponding amide. The naphthyl amide is then mixed with a chiral calix[4]resorcinarene in deuterium oxide. The crown ether only produces sufficient enantiomeric discrimination to determine enantiomeric purity for three of the nine substrates studied. The system with the naphthyl amide and a calix[4]resorcinarene produces enantiomeric discrimination of sufficient magnitude to determine enantiomeric purity for all nine substrates. The H1 and H4 resonances of the naphthyl ring are especially suitable to monitor for enantiomeric discrimination. The order of the (R)‐ and (S)‐enantiomers of the H1 and H4 resonances exhibit specific trends for aliphatic amines and amino alcohols that correlate with the absolute configuration. Copyright © 2012 John Wiley & Sons, Ltd.     

(18-Crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent for determining the enantiomeric purity and absolute configuration of β-amino acids

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids and acyclic derivatives with aliphatic, aromatic, and heterocyclic aromatic moieties. The β-amino acids are mixed with the crown ether in methanol-d₄ in either their neutral or protonated form. Substantial enantiomeric discrimination typically occurs for the resonances of the α-methylene and β-methine hydrogen atoms. Resonances of the substituent group of the β-amino acid often exhibit enantiomeric discrimination. The enantiomeric discrimination of the α-methylene and β-methine resonances of specific groups of compounds shows consistent patterns that correlate with the absolute configuration.     

Enantiomeric discrimination of cyclic β-amino acids using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids with cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, bicyclo[2.2.1]heptane, and bicyclo[2.2.1]heptene rings. The crown ether was added to the neutral β-amino acids in methanol-d₄. A neutralization reaction between the crown ether and β-amino acid forms the ammonium ion needed for favorable association. Enantiomeric discrimination of the two hydrogen atoms α to the amine and carboxylic acid moieties of the β-amino acid was observed with every substrate studied. Trends in the order of the enantiomeric discrimination of certain hydrogen atoms for substrates of similar structures correlate with the absolute configuration.     

Chiral NMR discrimination of pyrrolidines using (18-crown-6)-2,3,11,12-tetracarboxylic acid

The compound (18-crown-6)-2,3,11,12-tetracarboxylic acid is shown to be an effective chiral NMR solvating agent for determining the enantiomeric excess of chiral pyrrolidines. Enantiomeric discrimination is observed in both the ¹H and ¹³C NMR spectra. The neutral amine is mixed with the crown ether in an NMR tube and a neutralization reaction between the two produces the corresponding ammonium and carboxylate ions. An association of these ions accounts for the chiral recognition. Pyrrolidines with one or two substituent groups α to the nitrogen atom are not inhibited from binding to the crown ether. Chiral discrimination was observed in the NMR spectra of pyrrolidines that have a stereogenic center α or β to the nitrogen atom. Dibasic substrates are likely converted to their diprotonated form in the presence of the crown ether, and both ammonium sites appear to associate with the crown ether moiety.     

Enantiomeric separation of hydroxy acids and carboxylic acids by diamino-beta-cyclodextrins (AB,AC,AD) in capillary electrophoresis

Selectively modified 6,6'-dideoxy-6,6'-L-diamino-beta-cyclodextrins (AB, AC, AD) were successfully used as chiral selectors for the enantiomeric separation of hydroxy acids and carboxylic acids (in particular, phenoxyalkanoic acid herbicides) in capillary electrophoresis (CE). Chiral separations were obtained at a low selector concentration (1 mM) with good enantioselectivity and resolution factors. Separations were optimized as a function of pH. The different position of the charged groups on the upper rim greatly influenced the separation, accounting for electrostatic interactions between the protonated amino groups of the cyclodextrins (CDs) and the carboxylate of the selectands. The best enantiomeric separation of hydroxy acids was obtained with the AC regioisomer, whereas carboxylic acids were well resolved only by the AB regioisomer. A recognition model is proposed, based on two-dimensional nuclear magnetic resonance (2-D NMR) experiments, in which the orientation of the guest in the inclusion complex is determined by the electrostatic interactions between the selectand and the CD upper rim.     

Improvement of chiral stationary phases based on cinchona alkaloids bonded to crown ethers by chiral modification

To improve the chiral recognition capability of a cinchona alkaloid crown ether chiral stationary phase, the crown ether moiety was modified by the chiral group of (1S, 2S)‐2‐aminocyclohexyl phenylcarbamate. Both quinine and quinidine‐based stationary phases were evaluated by chiral acids, chiral primary amines and amino acids. The quinine/quinidine and crown ether provided ion‐exchange sites and complex interaction site for carboxyl group and primary amine group in amino acids, respectively, which were necessary for the chiral discrimination of amino acid enantiomers. The introduction of the chiral group greatly improved the chiral recognition for chiral primary amines. The structure of crown ether moiety was proved to play a dominant role in the chiral recognitions for chiral primary amines and amino acids.     

Enantioselective separation of racemic secondary amines on a chiral crown ether-based liquid chromatography stationary phase

The first general enantioselective separation of racemic secondary amines on a crown ether-based liquid chromatography chiral stationary phase (CSP) is presented. The CSP is based on (+)- or (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel. A mobile phase containing methanol, acetonitrile, triethylamine and acetic acid was employed in these separations of secondary amines with crown ether CSPs. The separation mechanism is believed to be the secondary amine forming a complex which includes crown ether coordination and electrostatic interaction of the positively charged amine with a carboxylate anion of the immobilized crown ether.     

Resorcinarene-based cavitands with chiral amino acid substituents for chiral amine recognition

Resorcinarene-based deep cavitands alanine methyl resorcinarene acid (), alanine undecyl resorcinarene acid () and glycine undecyl resorcinarene acid (), which contain chiral amino acids, have been synthesized. The upper rim of the resorcinarene host is elongated with four identical substituents topped with alanine and glycine groups. The structures of the new resorcinarenes were elucidated by nuclear magnetic resonance (NMR), mass spectrometry (MS) and the sustained off-resonance irradiation collision induced dissociation (SORI-CID) technique in FTICR-MS. These studies revealed that eight water molecules associate to the cavitand, two for each alanine group. The alanine substituent groups are proposed to form a kite-like structure around the resorcinarene scaffold. The binding of , , and with chiral R- and S-methyl benzyl amines was studied by (1)H NMR titration, and compared to that of a binary l-tartaric acid and the monoacid phthalyl alanine (). The results show that these compounds interact with amine guests; however, with four carboxylic acid groups, they bind several amine molecules strongly while the binary l-tartaric acid only binds one amine guest strongly. The simple compound , which contains one carboxylic group, shows weak binding to the amines. The (1)H NMR titration of with primary, secondary, and tertiary chiral amines showed that it can discriminate between these three types of amines and showed chiral discrimination for chiral secondary amines.     

A novel generation of coupling reagents. Enantiodifferentiating coupling reagents prepared in situ from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and chiral tertiary amines

Coupling of racemic N-protected amino acids with amino components by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in the presence of chiral tertiary amines such as strychnine, brucine, and sparteine proceeds enantioselectively, affording appropriate amides or dipeptides in 69-85% yield. The configuration of the preferred enantiomer and enantiomeric enrichment depend on the structures of the amine and carboxylic acid. Calculated Kagan enantioselectivity parameters (s) are in the range 1.6-195. Chiral triazinylammonium chlorides formed in situ from CDMT and chiral tertiary amines are postulated as reactive intermediates involved in the process of enantioselective activation of N-protected amino acids.     

Chiral imines prepared from 1-(2-aminoalkyl)aziridines as novel chiral shifts reagents for efficient recognition of acids

Optically pure, chiral imines synthesized from the corresponding aldehydes and 1-(2-aminoalkyl)aziridines in good chemical yields, have been assessed as an NMR chiral shift reagents for effective discrimination of the signals of some acids (mandelic acid and its derivatives and N-protected amino acid). The title compounds have proven to be very useful for the determination of enantiomeric purity and absolute configuration of the aforementioned acid derivatives.     

Enantiodifferentiating Photodimerization of a 2,6-Disubstituted Anthracene Assisted by Supramolecular Double-Helix Formation with Chiral Amines

A novel 2,6-anthrylene-linked bis(m-terphenylcarboxylic acid) strand ( 1 ) self-associates into a racemic double-helix. In the presence of chiral mono- and diamines, either a right- or left-handed double-helix was predominantly induced by chiral amines sandwiched between the carboxylic acid strands with accompanying stacking of the two prochiral anthracene linker units in an enantiotopic face-selective way, as revealed by circular dichroism and NMR spectral analyses. The photoirradiation of the optically active double helices complexed with chiral amines proceeded in a diastereo- (anti or syn) and enantiodifferentiating way to afford the chiral anti-photodimer with up to 98 % enantiomeric excess when (R)-phenylethylamine was used as a chiral double-helix inducer. The resulting optically active anti-photodimer can recognize the chirality of amines and diastereoselectively complex with chiral amines.     

Novel C2-symmetric chiral 18-crown-6 derivatives with two aromatic sidearms as chiral NMR discriminating agents

Novel C₂-symmetric chiral 18-crown-6 derivatives with two aromatic sidearms 2-4 were prepared, and their enantiomeric recognition abilities as chiral NMR discriminating agents towards primary ammonium salts were examined. Among these chiral crown ethers, the most effective enantiomeric discrimination of racemic ammonium salts in the ¹H NMR spectra was attained by the derivative with two pyrenylmethyl sidearms.     

手性溶解剂在NMR法测定对映体比率和绝对构型的研究进展

综述了手性溶解剂在NMR法测定对映体比率及绝对构型的研究进展.按照手性溶解剂的结构类型,包括胺、酰胺、羧酸、醇、氨基醇、大环化合物,对手性溶解剂的结构特点与手性识别性能进行了详细的介绍.     

Chiral bis(amino amides) as chiral solvating agents for enantiomeric excess determination of α-hydroxy and arylpropionic acids

A family of bis(amino amides) derived from natural amino acids has been synthesized and tested for the NMR enantiodiscrimination, as chiral solvating agents, for enantiomeric excess determination of some carboxylic acids. Those bis(amino amide) receptors contain different structural modifications and the splitting of the signals of the acids, after addition of the corresponding CSAs, depends on those structural variables. The influence of aminoacid side chain and the nature of the aliphatic spacer are important parameters to obtain good chiral discriminations. The results obtained clearly show the chiral recognition abilities of these bis(amino amide) ligands and suggest their advantageous use as chiral solvating agents for carboxylic acids. The binding between bis(amino amides) and carboxylic acids has been studied by ESI-MS, NMR, DSC, and molecular modeling. The data suggest that enantiodiscrimination involves the formation of an ionic pair after proton transfer from the carboxylic substrate to the bis(amino amides).     

Comparison of the chiral resolution on cis-trans isomeric chiral stationary phases derived from (S)-1-(1-naphthyl)ethylamine

A pair of cis-trans isomeric chiral stationary phases (CSPs) derived from (S)-1-(1-naphtyl)ethylamine was prepared. The chromatographic behaviours on both CSPs with regard to the resolution of enantiomeric amino acids, amino alcohols, amines, and carboxylic acid were studied. According to separation factors, the trans-CSP showed better chiral recognition ability for the separation of most analytes chosen in this study. Three homologous series of the alkyl esters of racemic amino acids were resolved on both CSPs using n-hexane-2-propanol and n-hexane-dichloromethane as mobile phases. The trans-CSP also showed better enantioselectivity for the resolution of homologues. A reverse of elution order was observed for the resolution of the homologous series of phenylglycine alkyl esters on both CSPs. It was found that the relationship between the separation factor and the alkyl chain length of the ester homologous series depended upon the components of mobile phase. A higher magnitude of difference between the two CSPs in enantioselectivity for the resolution of a given homologue was obtained when n-hexane-dichloromethane was used as a mobile phase. A chiral recognition process, in which steric repulsion, face-to-face π-π interaction, face-to-edge π-π interaction and hydrogen bonding interaction were involved, was also suggested to describe the separation of enantiomeric homologues on both CSPs. This study clearly indicates that the chiral resolution is influenced by the geometry of the double bond in a CSP.     

Enantiodifferentiating Photodimerization of a 2,6‐Disubstituted Anthracene Assisted by Supramolecular Double‐Helix Formation with Chiral Amines

A novel 2,6‐anthrylene‐linked bis(m‐terphenylcarboxylic acid) strand ( 1 ) self‐associates into a racemic double‐helix. In the presence of chiral mono‐ and diamines, either a right‐ or left‐handed double‐helix was predominantly induced by chiral amines sandwiched between the carboxylic acid strands with accompanying stacking of the two prochiral anthracene linker units in an enantiotopic face‐selective way, as revealed by circular dichroism and NMR spectral analyses. The photoirradiation of the optically active double helices complexed with chiral amines proceeded in a diastereo‐ (anti or syn) and enantiodifferentiating way to afford the chiral anti‐photodimer with up to 98 % enantiomeric excess when (R)‐phenylethylamine was used as a chiral double‐helix inducer. The resulting optically active anti‐photodimer can recognize the chirality of amines and diastereoselectively complex with chiral amines.