C-hexaphenyl-substituted trianglamine as a chiral solvating agent for carboxylic acids

Chiral hexaazamacrocycles with a trianglamine structure and C(3)-symmetry, containing six ring substituents and twelve stereocenters have been tested as chiral solvating agents (CSAs) for α-substituted carboxylic acids. Excellent results have been obtained with a hexaphenyl-substituted macrocycle. The optimal ratio between the macrocycle and racemic acid, allowing for baseline separation of the enantiomers' signals in the (1)H NMR spectrum, was dependent on the type of acid, in particular on its degree of acidity. The analyte and the CSA could be separated and recovered by a simple acid-base extraction and reused without purification. The conformations of the free and protonated hexaamino macrocycles were inferred by CD spectroscopic studies and DFT calculations.     

An azamacrocyclic receptor as efficient polytopic chiral solvating agent for carboxylic acids

The efficient use of a polyazamacrocycle as chiral solvating agent (CSA) for the determination of the enantiomeric excess of different carboxylic acids has been studied. All the data agree with the formation of multimolecular diastereomeric complexes in solution, which render good splitting of the NMR signals for the enantiomers of the acids (up to ΔΔδ = 0.20 ppm) using a small amount (even 0.125 equiv) of the receptor.     

Amphiphilic chiral receptor as efficient chiral solvating agent for both lipophilic and hydrophilic carboxylic acids

Two amphiphilic chiral receptors 2a and 2b were designed and synthesized. Both are efficient chiral solvating agents for chiral carboxylic acids. In particular, 2a is an excellent CSA not only for lipophilic guests, but also for some hydrophilic guests. It is the first CSA for the direct determination of the enantiomeric composition of hydrophilic chiral hydroxylated acid in protic polar solvent.     

Application of a new chiral derivatizing agent to the enantioseparation of secondary amino acids

A new chiral derivatizing agent, (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE, was applied for the high-performance liquid chromatographic separation of enantiomers of 19 unnatural secondary amino acids: proline, pipecolic acid analogues, piperazine-2-carboxylic acid, morpholine-3-carboxylic acid, thiomorpholine-3-carboxylic acid and analogues containing the 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydronorharmane, 1,2,3,4-tetrahydro-2-carboline and 2-benzazepine skeletons. Excellent resolutions were achieved for most of the investigated compounds by using a reversed-phase mobile phase system. The conditions of separation were optimized by variation of the mobile phase composition.     

A new strategy for chiral recognition of amino acids

A new strategy is established for detecting chiral amino acids based on the electron transfer from hemoglobin Fe(II) to Cu(II) in copper complexes of the amino acids. The sensor shows a highly selective recognition of arginine enantiomers.     

Development of new isothiocyanate-based chiral derivatizing agent for amino acids

Summary (1S,2S)-1,3-Diacetoxy-1-(4-nitrophenyl)-2-propylisothiocyanate [(S,S)-DANI] has been developed as a new chiral derivatizing agent for resolution of compounds containing an amino group. The reagent is readily available in both enantiomeric forms. Its applicability was demonstrated by the resolution of representative α-amino acids. The diastereomeric thiourea derivatives produced were separated by reversed-phase (C₁₈) high-performance liquid chromatography, with mixtures of 0.1% aqueous trifluoroacetic acid (pH∼2) and methanol as eluents.     

Use of allysilanes as a new type of silylating agent for alcohols and carboxylic acids

A new convenient route to silyl ethers and esters from alcohols and carboxylic acids using allylsilanes in the presence of an acid catalyst in acetonitrile was developed. The present method is also applicable to t-butyldimethylsilylation.     

Enantiodifferentiation of multifunctional tertiary alcohols by NMR spectroscopy with a Whelk-O type chiral solvating agent

A Whelk-O type chiral solvating agent (CSA) allows NMR enantioresolution of multifunctional tertiary alcohols. Crystallographic analysis of the CSA revealed two conformers, which can be expected to coexist in solution. One conformation affords a chiral cleft that can engage a single enantiomer in simultaneous hydrogen bonding, π–π stacking, and CH/π interactions. This chiral recognition process yields nonequivalent NMR signals for the enantiomers of eighteen substrates even when substoichiometric amounts of the CSA are used.     

New chiral solvating agents for carboxylic acids: discrimination of enantiotopic nuclei and binding properties

New chiral hosts for carboxylic acids have been synthesized and their capacity for discrimination of enantiotopic nuclei explored by NMR. In addition, binding properties were examined by ¹H NMR titration experiments and molecular mechanics calculations.     

Determination of enantiomeric excess and concentration of unprotected amino acids, amines, amino alcohols, and carboxylic acids by competitive binding assays with a chiral scandium complex

A practical UV-vis sensing method for enantioselective microanalysis of unprotected amino acids, amines, amino alcohols, and carboxylic acids in aqueous solution has been developed. Both concentration and enantiomeric composition of a wide range of chiral substrates can be determined with high accuracy by two simple competitive binding assays using a scandium complex derived from 1,8-bis(3-(3',5'-dimethylphenyl)-9-acridyl)naphthalene N,N'-dioxide.     

Cycloalkane-1,2-diamine derivatives as chiral solvating agents. Study of the structural variables controlling the NMR enantiodiscrimination of chiral carboxylic acids

A family of pincer-like receptors (2-5) has been synthesized and tested for the NMR enantiodiscrimination (CSA) of chiral carboxylic acids. Starting from a previous design (1), different structural variables have been mapped on the receptor frame. The splitting of the signals of the acids upon the addition of the CSAs largely depends on these structural variables. Thus, we concluded that the C₂ symmetrical pyridine-2,6-biscarboxamide moiety is a key structural feature for the efficiency of the CSA. Structural studies by NMR and molecular modeling showed that this moiety promotes the U-shape-folded pincer-like conformation by intramolecular H-bonds. On the other hand, we also observed that the cyclohexane-1,2-diamine derivative 5 is a more versatile CSA than its cyclopentane analogue 1, as 5 shows a better performance for more structurally different acids. However, the original cyclopentane derivative (1) remained the best for the arylpropionic acids. Finally, combination of NMR and modeling studies allowed us to propose a reasonable model for the interaction and, accordingly, for the observed NMR enantiodiscrimination.     

Synthesis of new chiral calix[4]azacrowns for enantiomeric recognition of carboxylic acids

Two novel chiral calix[4]azacrown ethers 4 and 5 bearing a furfuryl group on the nitrogen atom were developed by the reaction of dibromo- or ditosyl derivatives of p-tert-butylcalix[4]arenes 2 and 3 with a chiral diol, 1. The enantioselective recognition of these receptors towards the enantiomers of racemic carboxylic acids has been studied by ¹H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds 4 and 5 with each of the enantiomers of guest molecules were determined by using Job plots and a nonlinear least-squares fitting method, respectively. The Job plots indicate that both of the hosts form 1:1 instantaneous complexes with (R)- or (S)-mandelic acid and (l)- or (d)-dibenzoyltartaric acid. The receptors exhibited different chiral recognition abilities towards the enantiomers of racemic guests.     

Novel NMR chiral solvating agents derived from (1R,2R)-diaminocyclohexane: synthesis and enantiodiscrimination for chiral carboxylic acids

A series of new compounds, (1R,2R)-1-(1′,8′-naphthalimide)-2-aminocyclohexane 1 and its 4′-derivatives 2 and 3 derived from (1R,2R)-1,2-diaminocyclohexane have been synthesized conveniently and efficiently. ¹H NMR spectroscopy was employed to investigate their enantiodiscriminating ability. Compared with α-phenylethylamine, a commercially available chiral solvating agent (CSA), these compounds exhibited better enantiodiscriminating ability toward the chiral carboxylic acids we had chosen, distinguishing them as promising and practical CSAs.     

Amino alcohol based chiral solvating agents: synthesis and applications in the NMR enantiodiscrimination of carboxylic acids

Four optically active amino alcohols were synthesized via the ring opening of (R)-N-(2,3-epoxypropyl)phthalimide with (R)-2-phenyl glycinol, (1R,2S)-cis-1-amino-2-indanol, (R)-2-amino-1-butanol and (S)-phenyl ethylamine in 73-93% yields. The enantioselective recognition of these receptors towards the enantiomers of racemic carboxylic acids was studied by ¹H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of the guests were determined by using Job plots and a non-linear least-squares fitting method, respectively. Large non-equivalent chemical shifts (up to 30.0 Hz) can be achieved in the presence of chiral amino alcohols 2 and 5. Amongst the chiral receptors used, compound 5 was found to be the best chiral shift reagent, and was effective in the determination of the enantiomeric excess of chiral carboxylic acids.     

Chiral ionic liquids based on nicotine for the chiral recognition of carboxylic acids

The synthesis of enantiopure ionic liquids based on (?)-nicotine is discussed. The desired compounds were prepared in good yields from (?)-nicotine via quaternization of the pyridine ring of (?)-nicotine with MeI and EtBr. After anion metathesis the ionic liquids were investigated as chiral solvating agents and showed a splitting of the signals of Mosher’s acid and mandelic acid in the ¹H and ¹⁹F NMR spectra. In addition to aprotic solvents it was also possible to use methanol in the experiments.     

Enantioselective fluorescent recognition of amino alcohols by a chiral tetrahydroxyl 1,1'-binaphthyl compound

The tetrahydroxyl derivative of BINOL, (S)- or (R)-1, and its analogues are synthesized. (S)- or (R)-1 can be used to conduct the enantioselective recognition of chiral amino alcohols. In comparison with BINOL, the two additional hydroxyl groups of (S)- or (R)-1 have increased the binding of this compound with the amino alcohols and significantly improved the fluorescence quenching efficiency. The fluorescence responses of (S)- or (R)-1 toward amino alcohols are compared with those of its analogues (R)-4 and (R)-6. It shows that the interaction of the central naphthyl hydroxyl groups of (S)- or (R)-1 with the substrates is responsible for the observed fluorescence quenching, and the two additional alkyl hydroxyl groups increase the quenching efficiency.     

A simple method for the determination of enantiomeric excess and identity of chiral carboxylic acids

The association between an achiral copper(II) host (1) and chiral carboxylate guests was studied using exciton-coupled circular dichroism (ECCD). Enantiomeric complexes were created upon binding of the enantiomers of the carboxylate guests to the host, and the sign of the resultant CD signal allowed for determination of the configuration of the studied guest. The difference in magnitudes and shapes of the CD signals, in conjunction with linear discriminant analysis (LDA), allowed for the identity of the guest to be determined successfully. A model was created for the host-guest complexes which successfully predicts the sign of the observed CD signal. Further, Taft parameters were used in the model, leading to rationalization of the observed magnitudes of the CD signals. Finally, the enantiomeric excess (ee) of unknown samples of three chiral carboxylic acid guests was determined with an average absolute error of ±3.0%.     

Synthesis of new chiral imidazolium salts derived from amino acids: their evaluation in chiral molecular recognition

A family of new imidazolium salts derived from natural amino acids has been synthesized and tested for NMR enantiodiscrimination, as chiral shift reagents, of carboxylic acids. These imidazolium receptors contain different structural modifications and the splitting of the signals of the acids, after addition of the corresponding CSRs, depends on these structural variables. Compound 8b exhibited the strongest chiral solvating properties for racemic Mosher acid and was recognized as a suitable CSR for the determination of its enantiomeric composition.     

Enantioselective recognition of carboxylates: a receptor derived from alpha-aminoxy acids functions as a chiral shift reagent for carboxylic acids

Enantioselective recognition of carboxylates has important implications in asymmetric synthesis and drug discovery. We have prepared a novel C2-symmetric receptor 1 from alpha-aminoxy acids in a high overall yield. A series of chiral recognition studies indicate that receptor 1 not only can bind to carboxylate ions tightly but also has a good ability to recognize enantiomers of a broad variety of carboxylic acids in the 1H NMR spectra. Thus, the receptor 1 can be used as a chiral shift reagent for the determination of enantiomeric purities of chiral carboxylic acids by 1H NMR directly and rapidly.     

Asymmetric transfer hydrogenation of ferrocenyl ketones: a new simple route to chiral ferrocenyl alcohols

The asymmetric transfer hydrogenation (ATH) of ferrocenyl ketones, such as FcC(O)CH₂Y [Fc = ferrocenyl, Y = H (1a), CH₃ (1b), Cl (1c) or N₃ (1d)] has been carried out using the Noyori/Ikariya catalysts [(−)-(1R,2S)-ephedrine] or N-tosyl-(1R,2R)-diphenylethylenediamine [(R,R)-TsDPEN] as chiral ligands combined with [RuCl₂(η⁶-benzene)]₂ and 2-PrOH or HCO₂H–Et₃N as the hydrogen sources, respectively. The best results were achieved with the [(R,R)-TsDPEN–Ru^IIHCO₂H–Et₃N] catalytic system, which produced the ferrocenylalcohols (R)-2a, (R)-2c, and (R)-2d in good yields and excellent enantiomeric excesses (>98% ee).