Chiral Solvating Agents Research Articles

Phosphorylation as a method of tuning the enantiodiscrimination potency of quinine-An NMR study

Quinines phosphorylated at the C-9 hydroxyl group (diphenyl and diethyl phosphates) were synthesized and validated as novel effective chiral solvating agents in two alternative methods based on (1)H and (31)P NMR spectroscopy. Tested with a representative set of racemic analytes, the title compounds induced shift nonequivalence effects in (1)H NMR signals with values up to 0.1-0.2 ppm for 3,5-dinitrobenzoyl-substituted amino acids. In terms of enantiodifferentiation extent and application range, introduction of a phosphate group was proven to be superior compared to the action of nonmodified quinine. Interestingly, a temperature decrease to reach the slow exchange conditions also produced nonequivalences in the (31)P NMR spectra of the selectors. Comprehensive NMR analysis showed the existence of two conformations (closed 1 and 2) for both quinines in their free forms and the open 3 arrangement for the protonated ones. The crystal structure of diethylphosphorylquinine hydrochloride dichloromethane hemisolvate revealed a similar conformation to that observed in solution. Structures of complexes of phosphorylated quinines with selected ligands were determined with the use of NMR-based molecular modeling studies.

Chiral recognition in metal–organic frameworks studied by solid-state NMR spectroscopy using chiral solvating agents

Recently, we have described the synthesis of chiral metal-organic frameworks iPr-ChirUMCM-1 and Bn-ChirUMCM-1 and their use in enantioselective separation. Here, we demonstrate for the first time the use of a chiral solvating agent (1-phenyl-2,2,2-trifluoroethanol, TFPE) for chiral recognition in iPr-ChirUMCM-1 and Bn-ChirUMCM-1 by means of solid-state(13)C NMR spectroscopy.

Aza-Crown Macrocycles as Chiral Solvating Agents for Mandelic Acid Derivatives

A series of new chiral macrocycles containing the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and oligoethylene glycol-derived spacers has been prepared in enantiomerically pure form. Four of the macrocycles have been characterized by X-ray crystallography, which reveals a consistent mode of intramolecular N-H···N hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles were found to differentiate the enantiomers of mandelic acid (MA) by (1)H NMR spectroscopy in CDCl(3); within the series of macrocycles tested, enantiodiscrimination was promoted by (i) a meta-linkage geometry about the arene spacer, (ii) the presence of naphthalene- rather than phenylene-derived arene spacers, and (iii) increasing length of the oligoethylene glycol bridge. (1)H NMR titrations were performed with optically pure MA samples, and the data were fitted to a simultaneous 1:1 and 2:1 binding model, yielding estimates of 2:1 binding constants between some of the macrocycles and MA enantiomers. In several cases, NOESY spectra of the MA:macrocycle complexes show differential intramolecular correlations between protons adjacent to the amine and carboxylic acid groups of the macrocycles and MA enantiomers, respectively, thus demonstrating geometric differences between the diastereomeric intermolecular complexes. The three most effective macrocycles were employed as chiral solvating agents (CSAs) to determine the enantiomeric excess (ee) of 18 MA samples over a wide ee range and with very high accuracy (1% absolute error).

Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power

The application of different cyclodextrins (CDs) as NMR chiral solvating agents (CSAs) for the sodium salts of the proton-pump inhibitors omeprazole, pantoprazole (sesquihydrate) and rabeprazole was investigated. It was proved that the formation of diastereomeric host–guest complexes in D2O solution between the CDs and those substrates permitted the direct 1H NMR discrimination of the enantiomers of the sodium salts of these compounds without the need of previous working-up. Rotating frame nuclear overhauser effect spectroscopy (ROESY) was used to ascertain the solution geometries of the host–guest complexes. The results suggested a preferential binding of the benzimidazole moiety of the guest molecules within the macrocyclic cavity of α-CD, whereas the higher dimensions of β- and γ-CD also permitted the inclusion of the highly substituted pyridine moieties. Moreover, the solution stoichiometries and the binding constants of the complexes formed with pantoprazole at room temperature were determined by 1H and 19F NMR titration. Diffusion-filtered Spectroscopy was applied to obtain clean spectra without the interference of the HOD signal.

Chiral solvating agents for carboxylic acids based on the salen moiety

A series of chiral salen C 2- symmetric aminophenols 1–4, which were derived from (1 R,2 R)- or (1 S,2 S)-1,2-diphenylethane-1,2-diamine with the corresponding salicylic aldehyde through a [2+2] condensation reaction, have been prepared. The NMR studies demonstrated that they can function as chiral solvating agents for the determination of the enantiomeric purity of chiral carboxylic acids.

Imidazolinium sulfonate and sulfamate zwitterions as chiral solvating agents for enantiomeric excess calculations

The synthesis of enantiopure unsymmetrical N-heterocyclic based zwitterions incorporating imidazolinium and alkylsulfonate or sulfamate groups is described. The desired compounds were prepared in good yields from 1,3-propanesultone or cyclic sulfamidates and imidazolines. The imidazolinium based zwitterions proved to be versatile chiral solvating agents for Mosher’s acid, alcohols, cyanohydrins, amino alcohols, nitro alcohols, thiols, and carboxylic acids with very high shifts in the 1H and 19F NMR.

Enantiopure Ti(IV) amino triphenolate complexes as NMR chiral solvating agents

Enantiopure Ti(IV) complexes bearing pseudo-C(3) amino triphenolate ligands have been synthesized and characterized. The complexes bearing ortho phenyl groups act as (1)H NMR chiral solvating agent (CSA) for the stereochemical analysis of a series of sulfoxides. The coordination of a Lewis base coligand (sulfoxide) and the presence of aromatic rings are the key structural factors for the efficiency of the CSA.

A Practical Solvating Agent for the Chiral NMR Discrimination of Carboxylic Acids

AbstractA bisimidazoline compound has been prepared as a new chiral solvating agent starting from isophthalaldehyde and (S,S)‐1,2‐diphenylethylenediamine through a single‐step synthesis. In the presence of one equivalent of this reagent, carboxylic acid racemates show 1H NMR chemical shift nonequivalences large enough for the discrimination of the enantiomers. Studies with related compounds showed that the 1,3‐disubstituted structure is crucial for the acid‐solvating ability of the bisimidazoline compound.

Synthesis, stereochemistry and SAR of a series of minodronate analogues as RGGT inhibitors

Phosphonocarboxylate (PC) analogues of bisphosphonates are of interest due to their selective inhibition of a key enzyme in the mevalonate pathway, Rab geranylgeranyl transferase (RGGT). The dextrarotatory enantiomer of 2-hydroxy-3-(imidazo[1,2-a]pyridin-3-yl)-2-phosphonopropanoic acid (3-IPEHPC, 1) is the most potent PC-type RGGT inhibitor thus far identified. The absolute configuration of (+)- 1 in the active site complex has remained unknown due to difficulties in obtaining RGGT inhibitor complex crystals suitable for X-ray diffraction analysis. However, we have now succeeded in crystallizing (−)- 1 and here report its absolute configuration (AC) obtained by X-ray crystallography, thus also defining the AC of (+)- 1. An Autodock Vina 1.1 computer modeling study of (+)- 1 in the active site of modified RGGT binding GGPP (3DSV) identifies stereochemistry-dependent interactions that could account for the potency of (+)- 1 and supports the hypothesis that this type of inhibitor binds at the TAG tunnel, inhibiting the second geranylgeranylation step. We also report a convenient 31P NMR method to determine enantiomeric excess of 1 and its pyridyl analogue 2, using α- and β-cyclodextrins as chiral solvating agents, and describe the synthesis of a small series of 1 α- X ( X = H, F, Cl, Br; 7a– d) analogues to assess the contribution of the α-OH group to activity at enzyme and cellular levels. The IC 50 of 1 was 5–10× lower than 7a– d, and the LED for inhibition of Rab11 prenylation in vitro was 2–8× lower than for 7a– d. However, in a viability reduction assay with J774 cells, 1 and 7b had similar IC 50 values, ∼10× lower than those of 7a and 7c– d.

Erratum to: Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

Erratum to: Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

The investigation of stereogenic properties of cyclotriphosphazene derivatives with two different chiral centres

Hexachlorocyclotriphosphazene N 3P 3Cl 6 and gem-disubstituted cyclotriphosphazene derivatives N 3P 3Cl 4X 2 (X = Ph, PhS, PhNH) were reacted with N-methyl-1,3-propanediamine and 3-amino-1-propanol to give compounds ( 9a– 12a, 9b– 12b) which exist as cis and trans geometric isomers and are two different racemic isomers, respectively to describe the stereogenic properties of a series of chiral cyclotriphosphazene compounds with two different centres of chirality. The geometric isomers were separated by column chromatography on silica gel and analysed by elemental analysis, mass spectrometry, and 31P and 1H NMR spectroscopies, and also the geometric forms ( cis or trans) of 9b, 10a, 11a, 11b and 12a have been determined by the X-ray crystallography. The enantiomers of all racemic compounds have been analysed by the changes in 31P NMR spectra on addition of a Chiral Solvating Agent (CSA), (R)-(+)-2,2,2-trifluoro-1-(9′-anthryl)ethanol. On the other hand, the racemic forms of chiral cyclotriphosphazene derivatives have been confirmed by contribution of chiral HPLC methods which have been developed for this study.

Stoichiometry, Association Constant, and Solvation Model of Chiral Hydroxyfuranones in the Presence of Pirkle's Alcohols

ABSTRACT (S)-(+)-Dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone, (R)-(-)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone, (S)-(-)-dihydro-4-hydroxy-2(3H)-furanone, and (S)-(-)-5-hydroxymethyl-2(5H)-furanone in the presence of pure enantiomers of 2,2,2-trifluoro-1-(9-anthryl)ethanol were studied by 1H NMR in deuterated chloroform solutions. Experimental Job's plots suggest that the resulting solvates are formed with one molecule of solute and one of the chiral solvating agent. From the magnitude of the association constant determined for (S)-(+)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone in the presence of (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol (1.26 ± 0.09 M−1), it is inferred that the solvate is weak and cannot be isolated at 298 K. The correlation between the magnitude of induced chemical shifts, NOESY maps, and the known configuration of solutes and chiral solvating agents suggests that intermolecular hydroxyl-hydroxyl interaction is the primary interaction. Accordingly, the secondary interaction might occur between benzylic-hydrogen of the chiral solvating agent and the carbonyl- or furan ring-oxygen atoms of the solute.

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, (1 R,2 S)- 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.

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.

Enantiomeric Discrimination and Quantification of the Chiral Organophosphorus Pesticide Fenamiphos in Aqueous Samples by a Novel and Selective 31P Nuclear Magnetic Resonance Spectroscopic Method Using Cyclodextrins as Chiral Selector

A rapid, selective, and accurate quantitative ³¹P nuclear magnetic resonance (³¹P NMR) spectroscopy method was used for the chiral recognition of the racemic organophosphorus pesticide fenamiphos using chiral solvating agents (CSAs). Six neutral cyclodextrins (CDs) (α-CD, β-CD, methyl-β-CD, hydroxyethyl-β-CD, hydroxypropyl-β-CD, and hydroxypropyl-γ-CD) and two anionic CDs (carboxymethyl-β-CD and carboxyethyl-β-CD) were selected for these experiments. The shift displacement values (Δδ), after addition of each of the eight CDs in the highest possible molar ratio to a guest, were recorded. The results showed that β-CD and hydroxypropyl-β-CD were the best chiral solvating agents for the enantiomeric discrimination of fenamiphos. Two-dimension rotating frame nuclear Overhauser spectroscopy (ROESY) was used to investigate the structure of the β-CD-fenamiphos inclusion complex in aqueous solution. To determine the fenamiphos enantiomers, a calibration curve was drawn for two enantiomers over the range of 0.05-0.25 mg mL⁻¹. The limits of detection (S/N = 3) were obtained as 0.0068 and 0.0060 mg mL⁻¹ for fenamiphos enantiomers. The recovery studies were performed on aqueous real samples ranging from 94 to 107% with coefficients of variation of ≤ 9%.

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described.

ChemInform Abstract: A Chiral Solvating Agent for Direct NMR Assay of the Enantiomeric Purity of Carboxylic Acids.

Abstract The formation of diastereoisomeric salt complexes of 1,2-diphenyl-1,2-diaminoethane and chiral carboxylic acids (including α-arylpropionic, α-deuterio and α-halo-carboxylic acids) allows the direct NMR determination of the enantiomeric purity of mono- and di-carboxylic acids.

ChemInform Abstract: α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5- dimethanols (TADDOLs) for Resolutions of Alcohols and as Chiral Solvating Agents in NMR Spectroscopy.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Chiral Solvating Agents for Cyanohydrins and Carboxylic Acids

We have shown that a structure as simple as an ion pair of (R)- or (S)-mandelate and dimethylamminopyridinium ions possesses structural features that are sufficient for NMR enantiodiscrimination of cyanohydrins. Moreover, (1)H NMR data of cyanohydrins of known configuration obtained in the presence of the mandelate-dimethylaminopyridinium ion pair point to the existence of a correlation between chemical shifts and absolute configuration of cyanohydrins. Mandelate-DMAPH(+) ion pair and mandelonitrile form a 1:1 complex with an association constant of 338 M(-1) (DeltaG(0), -3.4 kcal/mol) for the (R)-mandelonitrile/(R)-mandelate-DMAPH(+) and 139 M(-1) (DeltaG(0), -2.9 kcal/mol) for the (R)-mandelonitrile/(S)-mandelate-DMAPH(+) complex. To understand the origin of enantiodiscrimination, the geometry optimization and energy minimization of the models of ternary complexes of (S)-mandelonitrile/(R)-mandelate/DMAPH(+) and (S)-mandelonitrile/(S)-mandelate/DMAPH(+) complexes was performed using DFT methodology (B3LYP) with the 6-31+G(d) basis set in Gaussian 3.0. Further, analysis of optimized molecular model obtained from theoretical studies suggested that (i) DMAP may be replaced with other amines, (ii) the hydroxyl group of mandelic acid is not necessary for stabilization of ternary complex and may be replaced with other groups such as methyl, (iii) the ion pair should form a stable ternary complex with any hydrogen-bond donor, provided its OH bond is sufficiently polarized, and (iv) alpha-H of racemic mandelic acid should also get resolved with optically pure mandelonitrile. These inferences were experimentally verified, which not only validated the proposed model but also led to development of a new chiral solvating agent for determination of ee of carboxylic acids and absolute configuration of aryl but not alkyl carboxylic acids.

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

Efficient use of the readily accessible chiral C 2-symmetric acyclic diamines (1–2) as well as macrocyclic amines (3–5) containing trans-1,2-diaminocyclohexyl moiety as chiral solvating agents (CSA) for the determination of enantiomeric excess of representative carboxylic acids (6–7) and an amino acid derivative (8) is illustrated. The enantiomeric composition of different carboxylic acids estimated here by the 1H NMR method, based on the integration of the corresponding methine proton signals are in good correlation with that determined using HPLC method. The data are in accordance with the formation of multimolecular diastereomeric complexes in solution, which render good splitting of NMR signals for the enantiomers of representative carboxylic acids as well as for N-Ts-phenylglycine (up to ΔΔδ = 0.295 ppm, 118 Hz).