Conversion of a racemate into a single enantiomer in one step by chiral liquid chromatography: Studies with rac-2,2′-diiodobiphenyl

The enantiomers of rac-2,2′-diiodobiphenyl were separated by liquid chromatography on microcrystalline triacetylcellulose. The conformational lability, a large separation factor α, and a suitable capacity factor k′(+) of this biphenyl allowed us to convert the racemate into 90% of enantiomerically pure (-)-2,2′-diiodobiphenyl and 10% of pure (+)-2,2′-diiodobiphenyl, respectively, by a series of in situ racemization-elution cycles. The much better retained (+)-enantiomer was racemized on the chromatographic column at 50°C after the less retained (-)-enantiomer has already been eluted at 8°C. © 1995 Wiley-Liss, Inc.     

Molecular tweezers for enantiodiscrimination in NMR: Di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl benzenedicarboxylates

A series of new chiral molecular tweezers, di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Axially chiral N‐(o‐aryl)‐4‐hydroxy‐2‐oxazolidinone derivatives from diastereoselective reduction of N‐(o‐aryl)‐2,4‐oxazolidinediones: Thermally interconvertible atropisomers via ring‐chain‐ring tautomerization

The reduction of the axially chiral N‐(o‐aryl)‐5,5‐dimethyl‐2,4‐oxazolidinediones by NaBH₄ yielded axially chiral N‐(o‐aryl)‐4‐hydroxy‐5,5‐dimethyl‐2‐oxazolidinone enantiomers having a chiral center at C‐4, with 100% diastereoselectivity as has been shown by their ¹H and ¹³C NMR spectra and by enantioselective HPLC analysis. The resolved enantiomeric isomers were found to interconvert thermally through an aldehyde intermediate formed upon ring cleavage via a latent ring‐chain‐ring tautomerization. It was found that the rate of enantiomerization depended on the size and the electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen of the heterocycle. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Chiral Resolution and Absolute Configuration of the Enantiomers of the Psychoactive “Designer Drug” 3,4‐Methylenedioxypyrovalerone

Illicit rac‐MDPV (3,4‐methylenedioxypyrovalerone), manufactured in clandestine labs, has become widely abused for its cocaine‐like stimulant properties. It has recently been found as one of the toxic materials in the so‐called “bath salts,” producing, among other effects, psychosis and tachycardia in humans when introduced by any of the several routes of administration (e.g., intravenous, oral, etc.). The considerable toxicity of this “designer drug” probably resides in one of the enantiomers of the racemate. In order to obtain a sufficient amount of the enantiomers of rac‐MDPV to determine their activity, we improved the known synthesis of rac‐MDPV and found chemical resolving agents, (+)‐ and (–)‐2’‐bromotetranilic acid, that gave the MDPV enantiomers in >96% enantiomeric excess as determined by ¹H nuclear magnetic resonance and chiral high‐performance liquid chromatography. The absolute stereochemistry of these enantiomers was determined by single‐crystal X‐ray diffraction studies. Chirality 27:287‐293, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

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.     

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.     

Use of S-Mosher acid as a chiral solvating agent for enantiomeric analysis of some trans-4-(4-fluorophenyl)-3-substituted-1-methylpiperidines by means of NMR spectroscopy.

S-Mosher acid 1 induced chemical-shift differences (Delta delta) in NMR spectra of chiral trans-4-fluorophenyl-3-substituted-1-methylpiperidines. The magnitude of Delta delta in (1)H and (19)F NMR spectra varied with the substituent at position 3 of the piperidine ring. The magnitudes of Delta delta observed for certain protons and for the fluorine in the 4-fluorophenyl group were sufficiently large to allow determination of enantiomeric composition.     

Enantioselective σ1 receptor binding and biotransformation of the spirocyclic PET tracer 1′‐benzyl‐3‐(3‐fluoropropyl)‐3H‐spiro[[2]benzofuran‐1,4′‐piperidine]

It was shown that racemic (±)‐ 2 [1′‐benzyl‐3‐(3‐fluoropropyl)‐3H‐spiro[[2]benzofuran‐1,4′‐piperidine], WMS‐1813 ] represents a promising positron emission tomography (PET) tracer for the investigation of centrally located σ₁ receptors. To study the pharmacological activity of the enantiomers of 2 , a preparative HPLC separation of (R)‐2 and (S)‐2 was performed. The absolute configuration of the enantiomers was determined by CD‐spectroscopy together with theoretical calculations of the CD‐spectrum of a model compound. In receptor binding studies with the radioligand [³H]‐(+)‐pentazocine, (S)‐2 was thrice more potent than its (R)‐configured enantiomer (R)‐2 . The metabolic degradation of the more potent (S)‐enantiomer was considerably slower than the metabolism of (R)‐2 . The structures of the main metabolites of both enantiomers were elucidated by determination of the exact mass using an Orbitrap‐LC‐MS system. These experiments showed a stereoselective biotransformation of the enantiomers of 2 . Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

High‐performance liquid chromatography separation of enantiomers of mandelic acid and its analogs on a chiral stationary phase

The enantiomers of mandelic acid and its analogs have been chromatographically separated on a chiral stationary phase (CSP) derived from 4‐(3,5‐dinitrobenzamido) tetrahydrophenanthrene. The rationale of separations of these compounds is discussed with respect to the method development for determining enantiomeric purity and possibility of obtaining enantiomerically pure materials by high‐pressure liquid chromatography. The relationship of analyte structure to the extent of enantiomeric separation has been examined and separation factors (α) are presented for various groups of structurally related compounds. Chiral recognition models have been suggested to account for the observed separations. These models provide mechanistic insights into the chiral recognition process. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Chiral enamines derived from 2-(2′-pyrido)acetophenone and 2-(2′-quinolino)acetophenone as ligands in copper(I) catalyzed enantioselective cyclopropanations

Optically active enamines of 2-(2′-pyrido)acetophenone or 2-(2′-quinolino)acetophenone with (R)-1-phenylethylamine, (R)-1-(1-naphthyl)ethylamine, (R)-cyclohexylethylamine, and (R)-phenylglycinol were prepared and their copper(I) complexes used in the enantioselective cyclopropanation of styrene with ethyl- and menthyldiazoacetate. Enantioselectivities of up to 42% enantiomeric excess were obtained for cis/trans 2-phenylcyclopropan-1-carboxylic acid ethyl esters, as determined by gas-liquid chromatography (GLC) on chiral chromatographic columns. © 1995 Wiley-Liss, Inc.     

Enantiomeric Discrimination of Isoxazoline Fused β‐amino Acid Derivatives using (18‐Crown‐6)‐2,3,11,12‐tetracarboxylic Acid as a Chiral NMR Solvating Agent

(18‐Crown‐6)‐2,3,11,12‐tetracarboxylic acid is a useful chiral NMR solvating agent for isoxazoline‐fused β‐amino acid derivatives. Isoxazoline substrates are analyzed as their hydrochloride salts in methanol‐d₄. The crown ether and substrate associate through the formation of three hydrogen bonds between the protonated amine and crown ether oxygen atoms. Enantiomeric discrimination is observed for two or more resonances of every substrate. At least one of these resonances is free of overlap with other resonances in the spectrum and has large enough enantiomeric discrimination to enable the determination of enantiomeric purity. 2D COSY methods can be used to identify additional resonances that exhibit enantiomeric discrimination in the NMR spectrum. Chirality, 25:48‐53, 2013.© 2012 Wiley Periodicals, Inc.     

Synthesis,HPLC Enantioresolution,and X‐ray Analysis of a New Series of C5‐methyl Pyridazines as N‐Formyl Peptide Receptor (FPR) Agonists

The synthesis of three racemates and the corresponding non‐chiral analogues of a C5‐methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC‐UV were investigated using four chiral stationary phases (CSPs: Lux Amylose‐2, Lux Cellulose‐1, Lux Cellulose‐2 and Lux Cellulose‐3). The best resolution was achieved using amylose tris(5‐chloro‐2‐methylphenylcarbamate) (Lux Amylose‐2), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X‐ray crystallographic analysis and comparative chiral HPLC‐UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC₅₀ values in the micromolar range. Chirality 25:400–408, 2013. © 2013 Wiley Periodicals, Inc.     

An NMR method towards the routine chiral determination of natural products

State-of-the-art structure elucidation and dereplication of natural products is incomplete without the determination of enantiomeric purity, especially when compounds are to be biologically evaluated. An NMR procedure is presented in order to distinguish and determine enantiomers in natural product samples. The method is also of value in the structure elucidation process by providing information, which is otherwise of a non-routine nature. Using enantiomeric 1-acetoxychavicol acetates and carvones as model compounds, this study presents a chiral NMR procedure that allows distinction and determination of chiral antipodes of natural products in a routine set-up.     

Enantioselective synthesis and teratogenicity of propylisopropyl acetamide,a CNS‐active chiral amide analogue of valproic acid

Propylisopropyl acetamide (PID), an amide analogue of the major antiepileptic drug valproic acid (VPA), possesses favorable anticonvulsant and CNS properties. PID contains one chiral carbon atom and therefore exists in two enantiomeric forms. The purpose of this work was to synthesize the two PID enantiomers and evaluate their enantiospecific teratogenicity. Enantioselective synthesis of PID enantiomers was achieved by coupling valeroyl chloride with optically pure (4S)‐ and (4R)‐benzyl‐2‐oxazolidinone chiral auxiliaries. The two oxazolidinone enolates were alkylated with isopropyl triflate, hydrolyzed, and amidated to yield (2R)‐ and (2S)‐PID. These two PID enantiomers were obtained with excellent enantiomeric purity, exceeding 99.4%. Unlike VPA, both (2R)‐ and (2S)‐PID failed to exert teratogenic effects in NMRI mice following a single 3 mmol/kg subcutaneous injection. From this study we can conclude that individual PID enantiomers do not demonstrate stereoselective teratogenicity in NMRI mice. Due to its better anticonvulsant activity than VPA and lack of teratogenicity, PID (in a stereospecific or racemic form) has the potential to become a new antiepileptic and CNS drug. Chirality 11:645–650, 1999. © 1999 Wiley‐Liss, Inc.     

Study on the stereoselective excretion of tetrahydropalmatine enantiomers in rats and identification of in vivo metabolites by liquid chromatography‐tandem mass spectrometry

The objective of this work was to study the stereoselectivity in excretion of tetrahydropalmatine (THP) enantiomers by rats and identify the metabolites of racemic THP (rac‐THP) in rat urine. Urine and bile samples were collected at various time intervals after a single oral dose of rac‐THP. The concentrations of THP enantiomers in rat urine and bile were determined using a modification of an achiral–chiral high‐performance liquid chromatographic (HPLC) method that had been previously published. The cumulative urinary excretion over 96 h of (?)‐THP and (+)‐THP was found to be 55.49 ± 36.9 μg and 18.33 ± 9.7 μg, respectively. The cumulative biliary excretion over 24 h of (?)‐THP and (+)‐THP was 19.19 ± 14.6 μg and 12.53 ± 10.4 μg, respectively. The enantiomeric (?/+) concentration ratios of THP changed from 2.80 to 5.15 in urine, and from 1.36 to 1.80 in bile. The mean cumulative amount of (?)‐THP was significantly higher than that of (+)‐THP both in urine and bile samples. However, the enantiomeric (?/+) concentration ratios in rat urine and bile were significantly lower than those ratios in rat plasma. These findings suggested the excretion of THP enantiomers was stereoselective rather than a reflection of chiral pharmacokinetic aspects in plasma and (?)‐THP was preferentially excreted in rat urine and bile. Three O‐demethylation metabolites and the parent drug rac‐THP were detected by liquid chromatography‐tandem mass spectrometry in rat urine. One metabolite was obtained by preparative HPLC and identified as 10‐O‐demethyl‐THP. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Simultaneous LC/ESI‐MS Separation Method for the Enantioseparation of Some New Anticonvulsant Drugs

A sensitive and specific method for the simultaneous determination of the enantiomeric purity of 2,6‐dimethylphenoxyacetyl derivatives as trans or cis racemic and enantiomeric forms with 2‐ or 4‐aminocyclohexanol moiety ( 1 , 2 , 3 , 6 ) and their amine analogs ( 8 , 9 ) was developed. The compounds studied are known for their anticonvulsant activity and the most interesting pharmacological results were those for (±)‐trans‐2‐(2,6‐dimethylphenoxy)‐N‐(2‐hydroxycyclohexyl)acetamide ( 1 ) as well as (±)‐trans‐2‐[(2,6‐dimethylphenoxy)ethyl]aminocyclohexanol ( 8 ). The analytical method for determining the enantiomeric purity of the compounds studied is based on direct separation of the analytes using a chiral stationary phase (Chiralpak AS column). The mass spectrometric analysis was done on a coupled liquid chromatograph–mass spectrometer system with an electrospray ionization source (LC/ESI‐MS). For the compounds 1 , 8 , and 9 , the method allows an excellent separation of enantiomers, with a resolution higher than 3.2, and a tailing factor of less than 1.67 with a final enantiomer purity better than 97.5%. Chirality 26:144–149, 2014. © 2014 Wiley Periodicals, Inc.     

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 and enantiomeric analysis of cyclotriphosphazene derivatives with one centre of chirality

A series of chiral cyclotriphosphazene compounds 2-9 in which the spiro 3-amino-1-propanoxy moiety provides the one centre of chirality have been synthesised and characterised by elemental analysis, MS, ¹H and ³¹P NMR spectroscopies. The enantiomers of newly synthesised compounds have been analysed by the changes in the ³¹P NMR spectra on addition of a Chiral Solvating Agent (CSA), (S)-(+)-2,2,2-trifluoro-1-(9′-anthryl)ethanol. HPLC methods have been developed for the enantiomeric separations of chiral cyclotriphosphazenes containing one centre of chirality. It is found that chiral HPLC gave a good resolution of enantiomers of the racemic compounds 2-9 with resolution factors between 2.49 and 7.50 making them good candidates for enantiomeric separations and determination of absolute configuration.     

The absolute configuration of the enantiomers of 6-chloro-9-(4′-diethylamino-1′-methylbutyl)-amino-2-methoxyacridine (quinacrine)

Absolute configurations have been assigned to the enantiomers of the antimalarial drug quinacrine dihydrochloride. Condensation of (?)-(R)-4-amino-1-diethylaminopentane (from L -glutamic acid) with 6,9-dichloro-2-methoxyacridine gave (?)-(R)-6-chloro-9-(4′-diethylamino-1′-methylbutyl) amino-2-methoxyacridine [(?)-(R)-quinacrine] while (+)?(S)-quinacrine was obtained from the enantiomeric diamine.     

Enzymatic resolution of rac-1,1-dimethyl-1-sila-cyclohexan-2-ol by ester hydrolysis or transesterification using a crude lipase preparation of Candida cylindracea

Summary rac-2-Acetoxy-1,1-dimethyl-1-sila-cyclohexane (rac-2) was synthesized by esterification of rac-1,1-dimethyl-1-sila-cyclohexan-2-ol (rac-1) with acetic anhydride. Enantioselective hydrolysis of rac-2 in aqueous solution, catalysed by a crude lipase preparation of Candida cylindracea (EC 3.1.1.3), led to the formation of (S)-1 (95% ee). Enantioselective transesterification of rac-1 with triacetin in isooctane, catalysed by the same enzyme preparation, yielded (S)-2 (95% ee), which was separated by chromatography from non-reacted (R)-1 (96% ee). Recrystallization led to an improvement of the enantiomeric purity of (R)-1 and (S)-1 up to >98% ee. Thus the enantiomers of rac-1 were prepared (100 mg scale) with high enantiomeric purities by the use of two different types of enzyme-catalysed reaction.