19F and 1H NMR of aldimines of fluoroamino acids with pyridoxal-5′-phosphate

¹H and ¹⁹F NMR spectra were obtained for six Schiff bases (aldimines) formed by pyridoxal-5′-phosphate (PLP) with four fluorinated or their two parent non-fluorinated α-amino acids (phenylalanine and α-aminobutyric acid). pK_A Values were derived from ¹H and ¹⁹F titration curves. The imine nitrogen of the aldimines is very basic (～13) and sensitive to the electron withdrawing effect of fluorine. The pyridine nitrogen is less basic in the aldimines (～7) than in PLP (8.12) and is less sensitive to the electron withdrawing effect of the fluorine than is the imine nitrogen. The phosphate group has a pK in the same range (～6) and the chemical shifts of some nuclei are sensitive to both pK values. Protonation of the aldimine causes the ¹H signal to shift downfield at the methyl protons of the pyridine ring and at the aldehydic proton of the aldimine for the high pK value (except for the aldimines prepared from the β-fluorophenylalanine), but upfield at the aromatic proton and at the aldehydic proton of the aldimine for the low pK. Protonation of the aldimine causes the ¹⁹F signal of an aryl fluorine to shift downfield but gives an upfield shift at a β-fluorine. These data are related to the highly conjugated electronic structure of the Schiff bases.     

Herstellung enantiomerenreiner cis- oder trans-konfigurierter 2-(tert-Butyl)-3-methylimidazolidin-4-one aus den Aminosäuren (S)-Alanin, (S)-Phenylalanin, (R)-Phenylglycin, (S)-Methionin und (S)-Valin

Preparation of the Enantiomerically Pure cis- and trans-Configurated 2-(tert-Butyl)-3-methylimidazolidin-4-ones from the Amino Acids (S)-Alanine, (S)-Phenylalanine, (R)-Phenylglycine, (S)-Methionine, and (S)-Valine In contrast to α-hydroxy and α-mercapto carboxylic acids, simple α-amino acids do not form acetal-type derivatives ( 2 , X = NH) with pivalaldehyde. For the generation of amino-acid-derived chiral, nonracemic enolates (cf. 3 ), and hence, for the α-alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12–14 were prepared diastereoselectively. To this end, the methyl or ethyl esters of amino-acid hydrochlorides were first converted to N-methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides ( 11 ). These Schiff bases could be cyclized either to trans-or to cis-imidazolidinones ( 12, 14 and 13 , respectively), which were obtained in enantiomerically pure form after recrystallization. The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by ¹H-NMR spectroscopy in the presence of chiral shift reagents. The configurations (cis, trans) were assigned by NOE measurements on 300- or 360-MHz ¹H-NMR spectrometers.     

Structurally simple chiral thioureas as chiral solvating agents in the enantiodiscrimination of α-hydroxy and α-amino carboxylic acids

C₂-Symmetrical chiral thioureas (S,S)-1 and (S,S)-2 were prepared in good yield by the reaction of 2 equiv of inexpensive (S)-1-phenylethylamine, or the corresponding naphthyl analog, with 1 equiv of thiophosgene in the presence of excess triethylamine. The presence of asymmetric elements in (S,S)-1 and (S,S)-2, and their capacity to act as receptors for anionic species via hydrogen bonding were exploited in the development of ¹H NMR spectroscopic enantiodiscrimination of chiral carboxylic acids. In particular, the diastereomeric complexes derived from thioureas (S,S)-1 and (S,S)-2 with ammonium salts of the chiral acids gave rise to well separated signals of the α-hydrogens and simple integration provides the corresponding enantiomeric ratios. Furthermore, it was observed that C_α-H in the (R) enantiomers of the chiral α-hydroxy and α-amino carboxylic acids studied in this work consistently appears downfield relative to the same signals in the (S) enantiomers.     

High-performance liquid chromatographic separation of unusual amino acid enantiomers derivatized with (1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propyl-isothiocyanate

Summary A new chiral derivatizing agent (CDA), (1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propylisothiocyanate, (S,S)-DANI, was applied to the separation of the enantiomers of unusual amino acids containing two chiral centers. Different β-methyl-α-amino acids (β-MePhe, β-MeTyr and β-MeTrp) and β-amino acids with cycloalkane skeletons (2-aminocyclopentanecarboxylic acid and 2-aminocyclohexanecarboxylic acid) were derivatized and the thiourea derivatives produced were separated by reversed-phase high-performance liquid chromatography. The applicability of this new CDA in the separation of unusual amino acids is demonstrated. The four stereoisomers of the investigated amino acids (except β-MePhe) could be separated in one chromatographic run. Presented at Balaton Symposium on High Performance Separation Methods, Siófok, Hungary, September 1–3, 1999     

Liquid chromatographic methods for separation,determination, and bioassay of enantiomers of etodolac: A review

The control of enantiomeric purity and determination of individual enantiomeric drug molecules remains the subject of importance for clinical, analytical, and regulatory purposes and to facilitate an accurate evaluation of the risks posed by them to human health. A large number of pharmaceuticals are marketed and administered as racemates. Etodolac is among such nonsteroidal anti‐inflammatory drugs. Overall literature reports on its enantioseparation are scanty. Liquid chromatography (LC) methods of enantioseparation of (±)‐etodolac, including certain unconventional ones, are well covered and discussed in this paper. Methods of direct approach without using chiral columns or chiral thin‐layer chromatography plate and of indirect approach using certain chiral derivatizing agents such as (S)‐naproxen and (S)‐levofloxacin are described. Most interesting aspects include establishment of structure and molecular asymmetry of chemically different types of diastereomeric derivatives using liquid chromatography with mass spectrometry (LC–MS), ¹H NMR spectroscopy and by drawing conformations in three dimensional views by using certain software. The methods provide chirality recognition even in the absence of pure enantiomers. Besides, recovery of pure enantiomers by detagging or via solubility difference of chiral inducing reagent and the analyte, without racemization at any stage, has been achieved. The limits of detection and quantification are much lower than the industry benchmarks.     

NMR study of monophthalocyaninatolanthanide (III) compounds

The variation of ¹H NMR shifts of monophthalocyaninatolanthanide (III) compounds of nine rare earth elements from Sm³⁺ to Lu³⁺ (except Gd³⁺) was studied. It was found that a “triad effect” appears in the sign alteration of the induced chemical shifts of α, β protons in the phthalocyanine rings for the second half of the rare earth series, that is, ¹H NMR spectra shift upfield for Tb³⁺, Dy³⁺ and Ho³⁺ compounds, while for Er³⁺, Tm³⁺ and Yb³⁺ the spectra shift downfield. The largest alteration of the chemical shifts appears in the compound with Tb³⁺. This is in agreement with the regularity obtained theoretically by Bleaney. The ¹³C NMR spectra of several monophthalocyaninatolanthanide compounds have also been recorded. The variation of the chemical shifts was discussed.     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Über die Enantiomerentrennung durch Verteilung zwischen flüssigen Phasen. 4. Mitteilung. Enantioselektivität der diastereoisomeren Weinsäure-dimenthylester gegenüber α-Aminoalkohol-Salzen

Separation of Enantiomers by Partition between Liquid Phases. Enantioselectivity of Diastereoisomeric Dimenthyl Tartarates towards α-Aminoalcohol Salts The enantioselectivity of the easily obtainable diastereoisomeric dimenthyl tartarates I and II towards the salts of a series of α-aminoalcohols 1 - 10 was investigated by partition between aqueous and lipophilic phase. The measured enantiomer distribution constants Q (=K_A/K_B) confirm the previously observed configurational relationships between the lipophilic tartarates and the preferentially extracted enantiomer of the hydrophilic ammonium slat. However, the (R,R)-ester I is appreciably more selective than its (S,S)-diastereoisomer II or other previously investigated esters. The tartarates I - III transport norephedrin salts through bulk lipophilic membranes with enantioselectivity comparable to that observed in partition experiments. The most enantioselective ester I can be used as an efficient mobile phase for preparative separation of norephedrine enantiomers by flash partition chromatography.     

The conformation of (1R,2S,4R,5S)-2,4-dimethoxybicyclo[3.3.1]nonan-9-one and some related compounds

A mixture of stereoisomers of 2,4-dimethoxybicyclo[3.3.1]nonan-9-one was prepared, separated by column chromatography and characterized by 60 MHz ¹H NMR spectroscopy using Eu(fod)₃. A double chair conformation with axial methoxyl groups is established for (1R,2S,4R,5S)-2,4-dimethoxybicyclo[3.3.1]-nonan-9-one on the basis of the J(12), J(2,H-3 exo) and J(2,3 endo) values and the chemical shifts for H-2(4). The conformation of some related compounds is subsequently inferred.     

Chiral separation of N-methyl-dl-aspartic acid in rat brain tissue as N-ethoxycarbonylated (S)-(+)-2-octyl ester derivatives by GC-MS

A selective and sensitive analytical method was developed for enantiomeric separation and determination of N‐methyl‐DL‐aspartic acid (NMA). The method involved the conversion of each enantiomer into N‐ethoxycarbonylated (S)‐(+)‐2‐octyl ester derivative for the direct separation by gas chromatography–mass spectrometry (GC‐MS). The diastereomeric derivatives showed characteristic mass spectral properties for analysis by selected ion monitoring mode (SIM) and enabling enantioseparation on an achiral capillary column. Two enantiomers were baseline separated, and the detection limits for N‐methyl‐L‐aspartic acid (NMLA) and N‐methyl‐D‐aspartic acid (NMDA) were 0.07 and 0.03 ng/g, respectively. When applied to rat brain tissues for absolute configuration of NMA, only NMDA was determined, while NMLA was monitored as lower than the limit of detection. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of rigid and C2-symmetric pyridino-15-crown-5 type macrocycles bearing diamide–diester functions: enantiomeric recognition for chiral primary organoammonium perchlorate salts

Four novel C₂-symmetric macrocyclic compounds with a pyridine function and possessing amide and ester lingeages were prepared. The enantiomeric discrimination abilities of these macrocycles against α-phenylethylammonium and α-(1-naphthyl)ethylammonium perchlorate salts were measured by standard ¹H NMR titration techniques in DMSO-d₆. A binding constant ratio of 31 (Kbind(S)/Kbind(R)) for two enantiomers of α-(1-naphthyl)ethylammonium salt with the macrocyclic host (S,S)-4 bearing phenyl arms was observed, which corresponds to an enantiomeric discrimination of approximately 94%. Molecular dynamic calculations were performed for some of the supramolecular complexes to in order to gain insight into the mode of molecular recognition between the macrocyclic compounds and ammonium salts; these results were consistent with experimental observations, which may be relevant to those in biochemical processes occurring in organisms.     

Spectroscopic studies of water-soluble superstructured iron(III) porphyrin. Interaction with the bovine serum albumin protein

Abstract

Acid-base equilibrium of the “one-face”-hindered sulfonated porphyrin, α5,15-[2,2′(dodecamethyleneoxy),(5-sulfonato)diphenyl]-10,20-bis(2-hydroxy,5-sulfonatophenyl)porphyrinato iron(III), has been studied by paramagnetic ¹H NMR. The isotropically shifted signals change in a fast exchange regime on the NMR time-scale. ¹H longitudinal relaxation times and temperature dependence of the chemical shifts were measured and analyzed. The electronic structure of hydroxo specie is characteristic of a six- or five-coordinate high-spin iron(III) porphyrin with an S = 5/2 ground state. The ¹H NMR titration allowed determination of the acidity constant, pK_a 6.2 (0.1 M KNO₃, 25 °C). In addition, we also report the interaction between the monohydroxo iron(III) porphyrin and the bovine serum albumin protein. From a ¹H NMR titration, we have determined the affinity apparent constant, log K_ap 3.2 (pH 7, KNO₃ 0.1 M, 25 °C). The formation of superstructured iron porphyrin-albumin protein adduct was confirmed by electronic absorption spectroscopy and electron paramagnetic resonance.     

An approach to the synthesis and assignment of the absolute configuration of all enantiomers of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate

Ethyl butyryloxy(phenyl)methane(P-phenyl)phosphinate was hydrolyzed using four bacterial species as biocatalysts. In all cases the reaction was stereoselective and isomers bearing an α-carbon atom with an (S)-configuration were hydrolyzed preferentially. Also a lack of stereoselectivity toward the phosphorus atom was observed. Hydrolysis of one enantiomeric mixture, namely mixture of (S_P,R) and (R_P,S) configuration afforded enantiomerically pure ethyl (R_P,S)-hydroxy(phenyl)methane(P-phenyl)phosphinate, configuration of which was established by X-ray crystallography. The observed ¹H and ³¹P NMR chemical shifts of Mosher esters of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate were correlated with the configurations of both stereogenic centers of all four stereoisomers.     

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.     

Chemical shifts as a novel measure of interactions between two binding sites of symmetric dialkyldimethylammonium bromides to α-cyclodextrin

Complex formation of α-cyclodextrin (α-CD) with decyltrimethylammonium (DeTAB), N,N-dioctyldimethylammonium (DOAB), and N,N-didecyldimethylammonium bromides (DDeAB) was investigated by proton NMR spectroscopy. Analysis of chemical shifts yielded macroscopic 1:1 and 1:2 binding constants (K₁ and K₂) and chemical shift differences (Δδ_SD and Δδ_SD2) for the 1:1 and 1:2 complexes of DeTAB, DOAB, and DDeAB with α-CD. The K₁ and K₂ values of DDeAB were quantitatively explained on the basis of the assumption that the microscopic 1:1 binding constant of DDeAB is identical to the observed K₁ value of DeTAB. The K₂ value of DDeAB was also explained in terms of its observed K₁ value and the independent binding of two alkyl chains. Furthermore, the Δδ_SD and Δδ_SD2 values for protons of DDeAB and α-CD were quantitatively explained on the basis of the assumption that the geometry of the decyl group of DDeAB in an α-CD cavity is identical to that of DeTAB. The Δδ_SD value was also explicable on the basis of the same geometric assumption and the observed Δδ_SD2 value for this system. Similar results were obtained for the 1:1 and 1:2 DOAB-α-CD complexes.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol and its propionate,the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol (diprionol) and its propionate, the sex pheromones of pine sawflies (Neodiprion sp. and other), in high enantiomeric purity was achieved from (1R,3S)-2,2-dichloro-3-methylcyclopropanecarboxylic acid. The carbon skeleton of diprionol was formed via copper-catalyzed cross-coupling reactions and diastereoselective methylation of the intermediate chiral α-methylbranched aldehyde with MeTi(Oi-Pr)₃ in the presence of [(R,R)-TADDOL]Ti(Oi-Pr)₂. The latter transformation leads to a syn-adduct with high stereoselectivity, which depends on the presence and configuration of the α-stereogenic center in the aldehyde. The diastereomeric purity of (2S,3S,7S)-diprionol can be substantially increased via crystallization of its 3,5-dinitrobenzoate.     

One‐dimensional TOCSY 1H NMR experiments on adducts of amino acid esters with cobalt(III) tetramethylchiroporphyrin. Prospects for the analysis of amino acid mixtures

Cobalt(III) tetramethylchiroporphyrin, CoCl(TMCP), is a useful chiral shift reagent for structure attribution, absolute configuration assignment and enantiomeric excess determination of amino acid methyl esters by ¹H NMR spectroscopy. However, it has two axial sites available for amine coordination, a structural feature which generates n(n + 1)/2 diastereomeric species and n² distinct spin systems from a mixture of n amino ester enantiomers, making the analysis of complex amino acid samples exceedingly difficult by classical 1‐D or 2‐D NMR methods when n > 3. The 1‐D TOCSY experiment is shown to be a powerful tool for the selective excitation and detection of every single component of a mixture of four amino acid methyl esters bound to CoCl(TMCP): those of(S)‐Leu, (S)‐Asp, (R)‐Asp and (S)‐Glu, for example. The potential utility of this methodology for the determination of amino acid enantiomers in carbonaceous meteorites or other extraterrestrial samples is suggested. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing diamide–diester groups: enantiomeric recognition for α-(1-naphthyl)ethylammonium perchlorate salts

A series of rigid and chiral C₂-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 bearing diamide–ester groups were synthesized. The binding properties of these macrocycles were examined for α-(1-naphthyl)ethylammonium perchlorates salts by an ¹H NMR titration method. Taking into account the host employed, important differences were observed in the K_a values of (R)- and (S)-enantiomers of guests for macrocycles (S,S)-4 and (S,S)-6, K_S/K_R = 3.6, and K_S/K_R = 0.1 (K_R/K_S = 10.3) ΔΔG = 3.19 and ΔΔG = ?5.77 kJ mol^?1, respectively. The results indicated excellent enantioselectivity of macrocyclic (S,S)-6 towards the enantiomers of α-(1-naphthyl)ethylammonium perchlorate salts.     

Enantiodifferentiation of aminophosphonic and aminophosphinic acids with α- and β-cyclodextrins

Cyclodextrins were used as chiral selectors for the ³¹P NMR determination of the enantiomeric excess of aminoalkanephosphonic and aminoalkanephosphinic acids. Most of these acids form inclusion complexes with α- and/or β-cyclodextrin and upon increasing the cyclodextrin to aminophosphonic acid molar ratio ³¹P NMR signals for (R)- and (S)-enantiomers separate. ROESY spectra allowed the determination of structures of the inclusion complexes.     

NMR-aided differentiation of enantiomers: Signal enantioresolution

NMR-aided enantiodiscrimination using chiral auxiliaries (CAs) is a recognized method for differentiating enantiomers and for measuring enantiomeric ratios (er). Up to the present, the study, optimization, and comparison of such methods have been performed based on the enantiodifferentiation of NMR signals via analyzing non-equivalent chemical-shift values (ΔΔδ) of the diastereoisomeric species formed. However, a poor and non-reliable comparison of results is often obtained via the analysis of ΔΔδ exclusively. In here, the concept of enantioresolution of an individual NMR signal and its importance for NMR-aided enantiodifferentiation studies is introduced and discussed. In addition, the enantioresolution quotient, E, is proposed as the parameter to describe its quantification. Complementary to measuring ΔΔδ, the experimental determination of E allows a more reliable interpretation of the results and opens up new possibilities for the study of enantiodifferentiation data derived from novel NMR experiments, setup improvements or new CAs. Finally, the different relationships between signal enantiodifferentiation, signal enantioresolution, and other main experimental issues of enantiodifferentiation experiments are addressed.