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.     

A water-soluble calix[4]resorcinarene with L-pipecolinic acid groups as a chiral NMR solvating agent

A sulfonated calix[4]resorcinarene containing L-pipecolinic acid groups is investigated as a water-soluble chiral NMR solvating agent. Aromatic substrates with phenyl, indole, indane, naphthyl, and pyridyl rings are analyzed. The substrates, which are water soluble because of ammonium, hydroxyl, or carboxylate functional groups, form host-guest complexes by insertion of the aromatic ring into the cavity of the calix[4]resorcinarene. Enantiomeric discrimination with the calix[4]resorcinarene derivative with L-pipecolinic acid is compared with similar reagents with proline, hydroxyproline, and α-methylproline moieties that have previously been reported. The derivative with L-pipecolinic acid often produces the best enantiomeric discrimination for one or more hydrogen atoms of the 24 substrates examined herein.     

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 NMR signal separation behavior and mechanism of samarium(III) and neodymium(III) complexes with (S,S)‐ethylenediamine‐N,N'‐disuccinate

Enantiomeric ¹H and ¹³C NMR signal separation behaviors of various α‐amino acids and DL‐tartarate were investigated by using the samarium(III) and neodymium(III) complexes with (S ,S )‐ethylenediamine‐N ,N' ‐disuccinate as chiral shift reagents. A relatively smaller concentration ratio of the lanthanide(III) complex to substrates was suitable for the neodymium(III) complex compared with the samarium(III) one, striking a balance between relatively greater signal separation and broadening. To clarify the difference in the signal separation behavior, the chemical shifts of β‐protons for fully bound D‐ and L‐alanine (δ_b(D) and δ_b(L)) and their adduct formation constants (K s) were obtained for both metal complexes. Preference for D‐alanine was similarly observed for both complexes, while it was revealed that the difference between the δ_b(D) and δ_b(L) values is the significant factor to determine the enantiomeric signal separation. The neodymium(III) and samarium(III) complexes can be used complementarily for higher and smaller concentration ranges of substrates, respectively, because the neodymium(III) complex gives the larger difference between the δ_b(D) and δ_b(L) values with greater signal broadening compared to the samarium(III) complex.     

Synthesis and Utilization of Trialkylammonium‐Substituted Cyclodextrins as Water‐Soluble Chiral NMR Solvating Agents for Anionic Compounds

Cationic trialkylammonium‐substituted α‐, β‐, and γ‐cyclodextrins containing trimethyl‐, triethyl‐, and tri‐n‐propylammonium substituent groups were synthesized and analyzed for utility as water‐soluble chiral nuclear magnetic resonance (NMR) solvating agents. Racemic and enantiomerically pure (3‐chloro‐2‐hydroxypropyl)trimethyl‐, triethyl‐, and tri‐n‐propyl ammonium chloride were synthesized from the corresponding trialkyl amine hydrochloride and either racemic or enantiomerically pure epichlorohydrin. The ammonium salts were then reacted with α‐, β‐, and γ‐cyclodextrins at basic pH to provide the corresponding randomly substituted cationic cyclodextrins. The ¹H NMR spectra of a range of anionic, aromatic compounds was recorded with the cationic cyclodextrins. Cyclodextrins with a single stereochemistry at the hydroxy group on the (2‐hydroxypropyl)trialkylammonium chloride substituent were often but not always more effective than the corresponding cyclodextrin in which the C‐2 position was racemic. In several cases, the larger triethyl or tri‐n‐propyl derivatives were more effective than the corresponding trimethyl derivative at causing enantiomeric differentiation. None of the cyclodextrin derivatives were consistently the most effective for all of the anionic compounds studied. Chirality 28:299–305, 2016. © 2016 Wiley Periodicals, Inc.     

Amino acids as chiral derivatizing agents for antiproliferative substituted N‐benzyl isoindolinones

The absolute configurations of the diastereomers of novel amino acid ester derivatives of 2,3‐substituted isoindolinones, which are known as apoptosis activators due to their ability to inhibit the MDM2‐p53 PPI, were assigned using NMR and computational methods. Procedures for diastereomer separation and determining the absolute configuration were developed to perform the study. The high significance of N‐benzyl fragment for the determination of the diastereomer absolute configuration by NMR methods was established; it is determined by a number of factors inherent in this fragment and the structural features of the studied substrates. Analysis of the individual isomer activity showed that the target inhibitory effect of S‐ and R‐isoindolinone L‐valinates differs by less than 20%. It can be explained by the presence of a flexible linker between the isoindolinone core and amino acid fragment, which provides the optimal arrangement of the molecule in the hydrophobic cavity of MDM2 for both isomers.     

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.     

A chemiluminescence method to detect hydroquinone with water‐soluble sulphonato‐(salen)manganese(III) complex as catalyst

A water‐soluble sulphonato‐(salen)manganese(III) complex with excellent catalytic properties was synthesized and demonstrated to greatly enhance the chemiluminescence signal of the hydrogen peroxide ? luminol reaction. Coupled with flow‐injection technique, a simple and sensitive chemiluminescence method was first developed to detect hydroquinone based on the chemiluminescence system of the hydrogen peroxide–luminol–sulphonato‐(salen)manganese(III) complex. Under optimal conditions, the assay exhibited a wide linear range from 0.1 to 10 ng mL^–1 with a detection limit of 0.05 ng mL^–1 for hydroquinone. The method was applied successfully to detect hydroquinone in tap‐water and mineral‐water, with a sampling frequency of 120 times per hour. The relative standard deviation for determination of hydroquinone was less than 5.6%, and the recoveries ranged from 96.8 to 103.0%. The ultraviolet spectra, chemiluminescence spectra, and the reaction kinetics for the peroxide–luminol–sulphonato‐(salen)manganese(III) complex system were employed to study the possible chemiluminescence mechanism. The proposed chemiluminescence analysis technique is rapid and sensitive, with low cost, and could be easily extended and applied to other compounds. Copyright © 2015 John Wiley & Sons, Ltd.     

Resolution,determination of enantiomeric purity and chiral recognition mechanism of new xanthone derivatives on (S,S)‐whelk‐O1 stationary phase

The enantioresolution and determination of the enantiomeric purity of 32 new xanthone derivatives, synthesized in enantiomerically pure form, were investigated on (S ,S )‐Whelk‐O1 chiral stationary phase (CSP). Enantioselectivity and resolution (α and R_S) with values ranging from 1.41–6.25 and from 1.29–17.20, respectively, were achieved. The elution was in polar organic mode with acetonitrile/methanol (50:50 v/v ) as mobile phase and, generally, the (R )‐enantiomer was the first to elute. The enantiomeric excess (ee ) for all synthesized xanthone derivatives was higher than 99%. All the enantiomeric pairs were enantioseparated, even those without an aromatic moiety linked to the stereogenic center. Computational studies for molecular docking were carried out to perform a qualitative analysis of the enantioresolution and to explore the chiral recognition mechanisms. The in silico results were consistent with the chromatographic parameters and elution orders. The interactions between the CSP and the xanthone derivatives involved in the chromatographic enantioseparation were elucidated.     

MalphaNP acid, a powerful chiral molecular tool for preparation of enantiopure alcohols by resolution and determination of their absolute configurations by the (1)H NMR anisotropy method

A novel methodology using a chiral molecular tool of MalphaNP acid (1), 2-methoxy-2-(1-naphthyl)propionic acid, useful for preparation of enantiopure secondary alcohols and determination of their absolute configurations by the (1)H NMR anisotropy method was developed; racemic MalphaNP acid (1) was enantioresolved with (-)-menthol, and the enantiopure MalphaNP acid (S)-(+)-(1) obtained was allowed to react with racemic alcohol, yielding a mixture of diastereomeric esters, which was clearly separated by HPLC on silica gel. By applying the sector rule of (1)H NMR anisotropy effect, the absolute configuration of the first-eluted MalphaNP ester was unambiguously determined. Solvolysis or reduction of the first-eluted MalphaNP esters yielded enantiopure alcohols.     

Quantitative 27Al NMR spectroscopic studies of Al (III) complexes with organic acid ligands and their comparison with GEOCHEM predicted values

The toxic inorganic monomeric forms of aluminium (Al) that limit plant growth have been shown to be effectively detoxified by complexation with organic acid ligands released by breakdown of added organic materials. The binding capacity of these acids is dependent on the degree of dissociation of their carboxyl groups and their ability to form bonds with Al. ²⁷Al NMR spectroscopy provides a non-invasive technique to study the bonding of Al with potential ligands without disturbing the equilibrium of the system. In single ligand systems containing oxalic acid, three ²⁷Al resonance peaks were observed at 6.4, 11.4 and 16.0 ppm downfield from the Al³⁺ reference peak at 0 ppm. These were assigned to Alox, Alox₂ and Alox₃ complexes respectively and were observable at pH values down to 3.5. In the presence of the citrate ligand, two ²⁷Al resonance peaks at 6.1 and 11.3 ppm, assigned respectively to the Alcit and Alcit₂ complexes, were observed at pH 3.4. At pH 4.3 and an Al:citrate molar ratio of 1:2, the 6.1 ppm peak was not visible, and the second peak further downfield was split into two unresolved peaks at 10.8 and 12.4 ppm indicating the presence of two forms of the Alcit₂ complex. Distribution of Al between the various species, based on integration of the resonance peaks and equilibrium calculations carried out using GEOCHEM, is discussed in light of the stability constants present in the database of GEOCHEM version (v.) 1.23 and GEOCHEM-PC v. 2.0. Large discrepancies between the computed values and the NMR measured values indicate the need to incorporate more recent literature values in the database for realistic equilibrium calculations in systems containing organic acid ligands. The potential of using quantitative ²⁷Al NMR measurements to calculate stability constants is discussed.     

Synthesis and characterization of tetraphenylporphyrin iron(III) complexes with substituted phenylcyanamide ligands

Several five coordinate complexes of [(TPP)Fe^III(L)] in which TPP is the dianion of tetraphenylporphyrin and L is the monoanion of phenylcyanamide (pcyd) (1), 2,5-dichlorophenylcyanamide (2,5-Cl₂pcyd) (2), 2,6-dichlorophenylcyanamide (2,6-Cl₂pcyd) (3), and 2,3,4,6-tetrachlorophenylcyanamide (2,3,4,6-Cl₄pcyd) (4) have been prepared by the reaction of [(TPP)Fe^IIICl] with appropriate thallium salt of phenylcyanamide. Each of the complexes has been characterized by IR, UV-Vis and ¹H NMR spectroscopic data. Dark red-brown needles of [(TPP)Fe^III(2,6-Cl₂pcyd)] (C₅₁H₃₁Cl₂FeN₆ · CHCl₃) crystallize in the triclinic system. The crystal structure of Fe(III) compound shows a slight distortion from square pyramidal coordination with the 2,6-dichlorophenylcyanamide anion in the axial position through nitrile nitrogen atom. Iron atom is 0.47(1) Å out of plane of the porphyrin toward phenylcyanamide ligand. In non-coordinating solvents, such as benzene or chloroform, these complexes exhibit ¹H NMR spectra that are characteristic of high-spin (S = 5/2) species. The X-ray crystal structure parameters are also consistent with high-spin iron(III) complexes. The iron(III) phenylcyanamide complexes are not reactive toward molecular oxygen; however, these complexes react with HCl and produce TPPFe^IIICl.     

The synthesis and characterisation of Rh(III) complexes with pyridyl triazole ligands

A series of Rh(III) mixed ligand polypyridine type complexes have been prepared. Complexes of the form [Rh(L)₂(L^′)]ⁿ⁺, where n=2/3, L=2,2^′-bipyridine (bpy)/1,10-phenanthroline (phen) and L^′=3-(pyridin-2-yl)-1,2,4-triazole (Hpytr), 1-methyl-3-(pyridin-2-yl)-1,2,4-triazole (1M3pytr), 4-methyl-3-(pyridin-2-yl)-1,2,4-triazole (4Mpytr), 3,5-bis(pyridin-2-yl)-1,2,4-triazole (Hbpt), 4-amino-3,5-bis(pyridin-2-yl)-1,2,4-triazole (NH₂bpt) and 3-(pyridin-2-yl)-5-phenyl-1,2,4-triazole (HPhpytr), have been prepared and their synthesis and characterisation are reported. Crystals of [Rh(bpy)₂(Phpytr)](PF₆)₂ and [Rh(phen)₂(NHbpt)](PF₆)₂ were obtained and their structures determined. Analysis of X-ray crystallographic data showed that coordination of the metal centre in [Rh(phen)₂(NHbpt)](PF₆)₂ occurs via the amine moiety and a nitrogen of the pyridine ring. NMR studies illustrated that coordination to the NH₂bpt ligand was also possible via a nitrogen of the triazole ring and the pyridine ring forming the complex [Rh(phen)₂(NH₂bpt)](PF₆)₃. The absorption and emission properties of the complexes studied were found to be π-π^* in nature and preliminary evidence suggests that all complexes with the exception of [Rh(phen)₂(NHbpt)](PF₆)₂ and [Rh(bpy)₂(NHbpt)](PF₆)₂ are dual emitting at 77 K.     

Shewanella oneidensis MR‐1 mutants selected for their inability to produce soluble organic‐Fe(III) complexes are unable to respire Fe(III) as anaerobic electron acceptor

Summary Recent voltammetric analyses indicate that Shewanella putrefaciens strain 200 produces soluble organic‐Fe(III) complexes during anaerobic respiration of sparingly soluble Fe(III) oxides. Results of the present study expand the range of Shewanella species capable of producing soluble organic‐Fe(III) complexes to include Shewanella oneidensis MR‐1. Soluble organic‐Fe(III) was produced by S. oneidensis cultures incubated anaerobically with Fe(III) oxides, or with Fe(III) oxides and the alternate electron acceptor fumarate, but not in the presence of O₂, nitrate or trimethylamine‐N‐oxide. Chemical mutagenesis procedures were combined with a novel MicroElectrode Screening Array (MESA) to identify four (designated Sol) mutants with impaired ability to produce soluble organic‐Fe(III) during anaerobic respiration of Fe(III) oxides. Two of the Sol mutants were deficient in anaerobic growth on both soluble Fe(III)‐citrate and Fe(III) oxide, yet retained the ability to grow on a suite of seven alternate electron acceptors. The rates of soluble organic‐Fe(III) production were proportional to the rates of iron reduction by the S. oneidensis wild‐type and Sol mutant strains, and all four Sol mutants retained wild‐type siderophore production capability. Results of this study indicate that the production of soluble organic‐Fe(III) may be an important intermediate step in the anaerobic respiration of both soluble and sparingly soluble forms of Fe(III) by S. oneidensis.     

Circularly polarized luminescence of Sm (III) and Eu (III) complexes with chiral ligand (R/S)‐BINAPO

Luminescent lanthanide (III) ions have been exploited for circularly polarized luminescence (CPL) for decades. However, very few of these studies have involved chiral samarium (III) complexes. Complexes are prepared by mixing axial chiral ligands (R/S))‐2,2’‐bis(diphenylphosphoryl)‐1,1′‐binaphthyl (BINAPO) with europium and samarium Tris (trifluoromethane sulfonate) (Eu (OTf)₃ and Sm (OTf)₃). Luminescence‐based titration shows that the complex formed is Ln((R/S)‐BINAPO)₂(OTf)₃, where Ln = Eu or Sm. The CPL spectra are reported for Eu((R/S)‐BINAPO)₂(OTf)₃ and Sm((R/S)‐BINAPO)₂(OTf)₃. The sign of the dissymmetry factors, g_em, was dependent upon the chirality of the BINAPO ligand, and the magnitudes were relatively large. Of all of the complexes in this study, Sm((S)‐BINAPO)₂(OTf)₃ has the largest g_em = 0.272, which is one of the largest recorded for a chiral Sm³⁺ complex. A theoretical three‐dimensional structural model of the complex that is consistent with the experimental observations is developed and refined. This report also shows that (R/S)‐BINAPO are the only reported ligands where g_em (Sm³⁺) > g_em (Eu³⁺).     

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.     

Synthesis,spectral properties and antimicrobial activity of a new cationic water‐soluble pH‐dependent poly(propylene imine) dendrimer modified with 1,8‐naphthalimides

A three‐step synthesis was implemented to prepare a quaternary ammonium functionalized blue fluorescent poly(propylene imine) dendrimer modified with pyridinium salt of 4‐acylamino‐1,8‐naphthalimide. The new cationic dendrimer absorbs in the ultraviolet light region and emits blue fluorescence. Its spectral characteristics in organic solvents and in an aqueous solution were studied. The influence of pH on the fluorescence intensity of the dendrimer was established with regard to its use as a pH sensor. The effect of hydroxyl ions on the absorption and fluorescence spectra in dry N,N‐dimethylformamide was also investigated. The antimicrobial activity of the dendrimer was assessed against model pathogenic microorganisms in agar, liquid medium, and after its deposition on cotton fabric.     

Method for determination of optical purity of 2‐arylpropanoic acids using urea derivatives based on a 1,1′‐binaphthalene skeleton as chiral NMR solvating agents: Advantages and limitations thereof

Five optically active urea derivatives ( 1 ‐ 5 ) were used as NMR solvating agents for analysis of the optical purity of different 2‐arylpropanoic acids commonly used as nonsteroidal anti‐inflammatory drugs. These novel chiral solvating agents were more efficient at discriminating the respective enantiomers of targets than the chiral solvating agents known so far, without the need to add a base for achieving the signal splitting. The advantages and limits of the use of these novel chiral solvating agents were studied.     

Synthesis and application of N‐[1‐(4‐(4‐fluorophenyl)‐2,6‐dioxocyclohexylidene)ethyl] (Fde)‐protected amino acids for optimization of solid‐phase peptide synthesis using gel‐phase 19F NMR spectroscopy

N‐[1‐(4‐(4‐fluorophenyl)‐2,6‐dioxocyclohexylidene)ethyl] (Fde) protected amino acids have been prepared and applied in solid‐phase peptide synthesis monitored by gel‐phase ¹⁹F NMR spectroscopy. The Fde protective group could be cleaved with 2% hydrazine or 5% hydroxylamine solution in DMF as determined with gel‐phase ¹⁹F NMR spectroscopy. The dipeptide Ac‐L ‐Val‐L ‐Val‐NH₂ 12 was constructed using Fde‐L ‐Val‐OH and no noticeable racemization took place during the amino acid coupling with N,N′‐diisopropylcarbodiimide and 1‐hydroxy‐7‐azabenzotriazole or Fde deblocking. To extend the scope of Fde protection, the hydrophobic nonapeptide LLLLTVLTV from the signal sequence of mucin MUC1 was successfully prepared using Fde‐L ‐Leu‐OH at diagnostic positions. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.