2-Cyano-2-indolylpropanoic acid as a chiral derivatizing agent for the absolute configuration assignment of secondary alcohols and primary amines by 1H NMR and VCD

A convenient approach for the absolute configuration assignment of secondary alcohols in the (8R,1′R,2′S,5′R)-15,25, (8S,1′R,2′S,5′R)-15,25, (8R,1′R)-21–24, and (8S,1′R)-21–24 ester series, and of primary amines in the (8R,1′R)-32–37 and (8S,1′R)-32–37 amide series, by means of ¹H NMR and VCD spectroscopy, using 2-cyano-2-indolylpropanoic acid as a chiral derivatizing agent is presented. DFT calculations were carried out to demonstrate the anisotropic effect of the indole skeleton on the chiral alcohol or the amine fragment. Vibrational circular dichroism (VCD) measurements of the above series indicated a VCD bisignated couplet resulting from the interaction of the ester carbonyl group and the CN group. The absolute configuration assignments were further tested by X-ray diffraction analysis.     

Tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid: a chiral derivatizing agent for the determination of the absolute configuration of secondary alcohols

A new chiral derivatizing agent, tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid (THENA), with a represented syn-periplanar disposition of O-C_α-CO as a part of the bicyclic system to lock the aromatic residue conformation and the availability of an internal reference proton for ¹H NMR spectral alignment, is introduced. In the determination of the absolute configuration of chiral secondary alcohols, THENA offered good uniformity of Δδ with high reliability, resulting in unambiguous assignment of the absolute configuration.     

A very reliable method for determination of absolute configuration of chiral secondary alcohols by 1H NMR spectroscopy

Surprisingly stable synperiplanar conformers of CFTA esters have led us to develop a new and very reliable method for assigning absolute configurations of even secondary alcohols having minimal structural differences, such as chiral benzhydrols and alpha-monodeuterated benzyl alcohols.     

Determination of the absolute configuration of chiral cyclic alcohols using diamine derivatizing agents by 31P NMR spectroscopy

The absolute configuration and enantiomeric excess of chiral cyclic alcohols can be predicted from the ³¹P NMR spectra of the two diastereoisomers obtained with organophosphorus diamino-derivatizing agents (CDAs) and the chiral secondary alcohol, according to a simplified model taking into account the spatial location of the substituents of the chiral alcohol center and the ³¹P NMR signals of the two diastereoisomers.     

The assignment of the absolute configuration of diethyl hydroxy- and aminophosphonates by 1H and 31P NMR using naproxen as a reliable chiral derivatizing agent

The assignment of the absolute configuration of hydroxy- and aminophosphonates by their double derivatization with commercially available naproxen is presented. The correlation between the spatial arrangement around the stereogenic carbon center and the signs of the DeltadeltaRS allows determination of the absolute configuration of hydroxy- and aminophosphonates by simple comparison of the 1H and 31P NMR spectra of the (R)- and (S)-naproxen ester or amide derivatives. Extensive conformational analysis (theoretical calculations, low-temperature experiments) supported by the NMR studies of structurally diverse naproxen esters and amides of hydroxy- and aminophosphonates proved that a simplified model can be successfully used.     

Determining the absolute configuration of secondary alcohols by means of a chiral auxiliary and NOESY

The absolute configuration of secondary alcohols can be determined by NOE between the diastereotopic protons of the lactam and the protons of the alcohol moieties in some 1-(alkoxymethyl)-methyl-2-pyrrolidone-5-carboxylate derivatives. Two simple methods based on conformational analysis and ¹H NMR data have been developed. The main conformer, in all cases, was established by means of MM, semi-empirical, and ab initio calculations.     

Synthesis of 1-fluoroindan-1-carboxylic acid (FICA) and its properties as a chiral derivatizing agent

1-Fluoroindan-1-carboxylic acid (FICA) (1) was designed and synthesized as its methyl ester (FICA Me ester) (4) in order to develop an efficient chiral derivatizing agent (CDA) which excels α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) in capability. FICA Me ester (4) was prepared by fluorination of methyl 1-hydroxyindan-1-carboxylate (3) with (diethylamino)sulfur trifluoride (DAST) and derived to the esters of racemic secondary alcohols by ester exchange reaction. The resulting Δδ_F value was large in the case of 2-butyl ester of FICA (5a), whereas not detectable in the case of the corresponding MTPA ester (6a). The magnitude of the Δδ_H values was similar to that of MTPA esters. The diastereomers of (R)-(−)-8-phenylmenthyl ester of FICA (5i) was separated and their ¹H NMR analyses revealed that the concept of the modified Mosher's method was successfully applied to 5i.     

Application of deuterated THENA for assigning the absolute configuration of chiral secondary alcohols

The structure of a constrained bicyclic chiral derivatizing agent (CDA), 1,2,3,4-tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid, THENA 1, was modified by replacing both exo-methylene protons with deuterium atoms. The modified CDA, THENA-d₂2, could be used to assign the absolute configuration of chiral secondary alcohols with good reliability. Compared with THENA, the multiplicity of the methylene proton signals in the ¹H NMR spectra of THENA-d₂ derivatives is less complicated and the new CDA thus offers simpler NMR spectra for data interpretation.     

Toward the creation of NMR databases in chiral solvents: bidentate chiral NMR solvents for assignment of the absolute configuration of acyclic secondary alcohols

The absolute configuration of acyclic secondary alcohols can be established from analysis of the chemical shift behaviors of the adjacent carbons in bidentate chiral solvents (R,R)- and (S,S)-1d as formulated in the boxed illustration.     

Resin-bound chiral derivatizing agents for assignment of configuration by NMR spectroscopy

A general methodology for assigning the configuration of chiral mono- and polyfunctional compounds by NMR is presented. The approach is based on the use of polystyrene-bound chiral derivatizing agents (CDA-resins) specifically designed to achieve the high-yield formation of the covalent linkages (amide or ester bonds) between the substrate and the chiral auxiliary within the NMR tube, without the need for other manipulations, on a microscale level and in a short time. The deuterated NMR solvents (CDCl3, CD3CN, CS2/CD2Cl2) are also the reaction solvents and separations, purifications or workups of any kind are not necessary prior to recording the spectra. The CDA-resins prepared included MPA, 9-AMA, BPG, MTPA, and 2-NTBA as auxiliary agents incorporated either as single enantiomers or as mixed combinations of the (R)- and the (S)-enantiomers at unequal and known ratios. The high versatility of these systems was successfully demonstrated in a variety of ways based on double and single derivatization, low temperature experiments, or the formation of metal complexes. The approach allowed the absolute configurations of chiral primary amines, primary and secondary alcohols, cyanohydrins, thiols, diols, triols, and amino alcohols to be determined. Extensive high-resolution magic angle spinning (HR-MAS) NMR experiments allowed the characterization of the new CDA-resins and enabled the study of their stability and regioselectivity.     

Determination of absolute configuration of secondary alcohols using new chiral auxiliary and chemical shift calculation

A new chiral carboxylic acid 1 was synthesized for determination of absolute configuration of secondary alcohols. Several chiral alcohols were converted to esters with 1. Their experimental esterification shift changes were successfully reproduced by the chemical shift simulation method combined with molecular dynamic simulation.     

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.     

An efficient chiral phosphorus derivatizing agent for the determination of the enantiomeric excess of chiral alcohols and amines by 31P NMR spectroscopy

The chiral phosphorus derivatizing agent (CDA) 1 was prepared from optically pure (S)‐1,1‐bis‐2‐naphthol. It was first used in the determination of the enantiomeric excess of chiral alcohols and amines by means of ³¹P NMR spectroscopy. It showed that, for the chiral aromatic alcohols, no apparent kinetic resolution was noted and good base‐line separation was observed. Furthermore, the chemical shift difference (Δδ) of ³¹P NMR spectroscopy was much larger than those determined by the use of other chiral phosphorus derivatizing agents reported previously. However, for aliphatic alcohols, it showed not only obvious kinetic resolutions but incomplete base‐line separation. Moreover, we also found that the use of CDA 1 was suitable for the determination of enantiomeric excess of chiral primary amines. © 2002 John Wiley & Sons, Inc. Heteroatom Chem 13:93–95, 2002; DOI 10.1002/hc.10018     

Application of chiral bidentate NMR solvents for assignment of the absolute configuration of alcohols: scope and limitation

The ¹³C NMR behaviors of several cyclic and biaryl secondary alcohols as well as acyclic tertiary alcohols have been studied in the chiral bidentate NMR solvent BMBA-p-Me (1). An empirical rule has been advanced to correlate the absolute configuration of each type of alcohols with the ¹³C chemical shift behaviors in (R,R)- and (S,S)-BMBA-p-Me.     

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.     

Chlorodinitrophenylhydrazine, a useful crystalline agent for absolute configuration determination of various chiral ketones

For the determination of absolute configuration of various chiral ketones, we examined some hydrazines having a heavy atom as crystalline auxiliaries, and found that 2-chloro-4,6-dinitrophenylhydrazine is a useful crystalline agent for carbonyl compounds. Chiral hydrazones prepared from the hydrazine and various chiral ketones gave suitable single crystals for X-ray crystallographic analysis. The absolute configurations of the hydrazones were determined by X-ray crystallographic analysis using anomalous dispersion effect of the chlorine atom. The hydrazine is a useful crystalline agent for absolute configuration determination of various chiral ketones.     

Selective excitation 1D-NMR experiments for the assignment of the absolute configuration of secondary alcohols

Routine selective excitation experiments, easy to set up on modern NMR spectrometers, allow for the determination of the absolute configuration of chiral secondary alcohols by double derivatization directly in the NMR tube. As a general method, TOCSY1D with selective excitation of the α proton in the MPA esters and with a short mixing time reveals only the nearby protons in the coupling network. Typically, the analysis takes less than 30 min. A longer mixing time, selective excitation of other signals, or NOESY1D experiments can be used for measuring ΔδRS of other protons.     

Some new protocols for the assignment of absolute configuration by NMR spectroscopy using chiral solvating agents and CDAs

The utility of enantiopure BINOL (1,10-Bi-2-naphthol), in a ternary ion-pair complex, which is obtained using a carboxylic acid and an organic base, as a versatile chiral solvating agent (CSA) has been demonstrated for chiral analysis and the absolute configuration assignment of hydroxy acids. Another protocol where the utility of NOBIN as a CSA has been developed for discrimination and absolute configuration assignment of acids, hydroxy acids and their derivatives with a distinct strategy where a third ingredient, p-toluenesulfonic acid (p-TsOH) serves as a linker. In addition some three component chiral derivatization protocols have been introduced, such as the use of 2-formylphenylboronic acid and enantiopure mandelic acid or a primary amine for the determination of the configuration of primary amines and hydroxy acids, respectively. A simple, rapid and highly efficient three component chiral derivatizing protocol has also been discussed which was developed for assigning the absolute configuration of chiral α-hydroxy acids and their derivatives, which involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and (S)-[1,1-binaphthalene]-2,2-diamine separately. In a few examples, the DFT based theoretical calculations have been carried out to determine the geometry optimized structures of the complexes.     

Chiral thiols: the assignment of their absolute configuration by 1H NMR

A general NMR spectroscopy protocol for determination of absolute configuration of thiols, that includes the introduction of new aryl-tert-butoxyacetic acids as chiral derivatizing agents (CDAs), is described.