Diastereomeric Amides Research Articles

Application of methyl itaconate–anthracene adducts (MIAs) in configuration assignment of chiral primary amines by means of 1H NMR

Methyl itaconate–anthracene adducts (MIAs) were previously introduced as chiral derivatizing agents (CDAs) for the determination of chiral secondary alcohols. In this study, they were further employed with chiral primary amines to assign their absolute configuration. Each chiral amine compound was linked to the (R)- and (S)-MIAs through amidation to obtain diastereomeric amides in moderate yield. The modified Mosher's method was applied, where the difference in chemical shift (ΔδSR = δHS−MIA-amide – δHR−MIA-amide) values of each substituent of the chiral amine adducts was utilized to validate the capability of MIAs as CDAs. Finally, the proposed model was successfully achieved, and the MIAs were proven effective for the determination of the absolute configuration of chiral amines.

Enantiopurification of Mandelic Acid by Crystallization-Induced Diastereomer Transformation: An Experimental and Computational Study

Chiral purification is crucial in the pharmaceutical industry due to the dramatic differences in biological activity of the two enantiomers of most chiral drugs. In this work, we demonstrate a new enantiopurification route for an important drug precursor, mandelic acid, by forming a diastereomeric amide with enantiopure 1-phenylethylamine. We show that in the presence of a strong base, the resulting diastereomeric system not only undergoes a reversible epimerization reaction but also exhibits a surprising difference in crystallization behavior, i.e., at room temperature, one epimer forms a metastable gel phase, only converting to a more stable crystal over several days, while the other forms a stable crystalline phase. Exploiting these properties, a facile purification technique via crystallization-induced diastereomer transformation (CIDT) was achieved enabling good product yield (>70%) and excellent optical purity (>92%). Enantiopure mandelic acid (∼91% e.e.) can then be recovered via acid hydrolysis. This work highlights that for compounds that are neither conveniently racemizable nor conglomerate-forming such as mandelic acid, CIDT is a powerful alternative to the deracemization technique, capable of yields greater than the 50% in contrast to traditional resolution techniques.

Resolution via diastereomeric amides of enantiopure 1,4-benzoxathian-2- and 3-carboxylic acids and determination of their configuration.

1,4‐Benzoxathiane, 2‐ or 3‐substituted, is an important scaffold, and despite its presence in several therapeutic agents, it is chemically unexploited. Furthermore, only a few examples in literature report this moiety in its enantiopure form. Here, taking advantage to the formation of diastereomeric amides by using (S)‐phenylethylamine, which show significant differences in terms of 1H‐nuclear magnetic resonance (NMR) spectra and other physical chemical properties, we defined for the first time the absolute configuration of each amide, both 2‐ or 3‐substituted. Moreover, the diastereomeric amides were further hydrolyzed in acid conditions, letting to the achievement of the corresponding 1,4‐benzoxathian carboxylic acids.

The synthesis of cis- and trans-3-(4-hydroxyphenyl)cyclobutanecarboxylic acids and the study of their derivatives as GPR-40 receptor ligands

Aim. To synthesize cis- and trans-isomers of 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid and evaluate the biological activity of their derivatives against GPR-40.Results and discussion. Cis- and trans-isomers of 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid were synthesized. The derivatives of this compound were tested as GPR-40 agonists and exhibited the micromolar activity.Experimental part. The methyl ester of 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid was obtained as a mixture of cis/trans-isomers in 3 steps starting from a commercially available 3-oxocyclobutanecarboxylic acid. Further transformation of this compound into isomerically pure 3-(4-hydroxyphenyl)cyclobutanecarboxylic acids was achieved in five steps based on the chromatographic separation of diastereomeric amide derivatives. New GPR-40 ligands were obtained by O-alkylation of a phenolic oxygen atom of the corresponding carboxylic acid methyl ester. The biological activity of the agonists synthesized was studied using a fluorometric bioassay and the engineered Chinese hamster ovary (CHO) stable cell line expressing the human GPR-40.Conclusions. An effective synthetic approach to 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid allowing to isolate two single cis/trans-stereoisomers of this compound has been developed. In order to demonstrate the possibility for the bioisosteric replacement of the ethylene moiety in the structures of free fatty acid receptor (FFAR) agonists by the cyclobutane ring, four new GPR-40 ligands possessing the micromolar activity have been synthesized.Received: 22.08.2020 Revised: 11.10.2020 Accepted: 17.10.2020

Synthesis of enantiomerically pure inherently chiral calix[4]arenes using the meta-substitution strategy

A meta-substituted aminocalix[4]arene 4 immobilized in the cone conformation was prepared via mercuration of the starting tetra-propoxy derivative, followed by nitrosation and reduction reactions. Acylation of the amino group by chiral amino acid residues ((S)-N-trifluoroacetyl-Ala or (S)-N-trifluoroacetyl-Phe) allowed for the preparation of diastereomeric amides that were separated by preparative TLC on silica gel. Subsequent cyclization under Bischler-Napieralski reaction conditions yielded calixarenes 7b and 7c bearing an oxazole moiety in the meta position instead of the expected upper rim-bridged compounds. The reaction sequence represents a straightforward approach towards enantiomerically pure inherently chiral calix[4]arene derivatives (without HPLC separation steps). The absolute configuration of the enantiomers were confirmed by single crystal structure determination (X-ray).

Enantioseparation of (RS)-fexofenadine and enhanced detection as the diastereomeric amide and anhydride derivatives using liquid chromatography-mass spectrometry.

Enantioselective analysis of (RS)-fexofenadine was carried out by achiral HPLC via a derivatization approach using N-hydroxy-benzotriazolyl-(S)-naproxen ester (synthesized for this purpose) and three chirally pure amines as chiral derivatizing reagents. There occurred formation of amide and anhydride types of diastereomeric derivatives. These were separated and isolated by HPLC (analytical and preparative). The structures and configurations were verified via recording full-scan product ion mass spectra using LC-MS, 1 HNMR spectra, Chem3D Pro 12.0 software and the software Gaussian 09 Rev.A.02 program and hybrid density functional B3LYP with 6-31G basis set supplemented with polarimetry. Experimental conditions for synthesis and separations were optimized and the elution order was established. Analytical separation was performed on a C18 analytical column with different ratios of MeCN-TEAP buffer and MeOH-TEAP buffer (v/v) adjusted to pH 7.5 as mobile phase at a flow rate of 0.7 mL min-1 . Detection was performed via UV absorbance at 225 nm. The method was validated in accordance with International Conference on Harmonization guidelines. The detection limits were 6.25 and 7.87 ng mL-1 for first and second eluting diastereomeric derivatives, respectively.

Liquid chromatographic enantioseparation of racemic beta-blockers via synthesis of diastereomeric amides and (S)-levofloxacin esters as chiral derivatizing agents

Liquid chromatographic enantioseparation of racemic beta-blockers via synthesis of diastereomeric amides and (S)-levofloxacin esters as chiral derivatizing agents

Synthesis of optically pure ant pheromones with high enantiomeric purity.

Chemical ecology studies with insects have founded that pheromonal communications often includes several components which can be linear, cyclic or heterocyclic compounds, in the case of chiral pheromones, insect often show the ability to characterize between and respond differently to stereoisomer. Among the most notable are those cases in which differential interspecific responses to enantiomer serve as a species isolating mechanism, the relationship between stereoisomers and pheromone activity are highly specific, meaningful assays and evaluation of the responses of insect to chiral pheromones must be carried out using substances of the highest possible chiral purity, we prepare ant pheromones using poly methyl methacrylate as chiral auxiliaries with high enantiomeric purity and the prepared compounds were characterized with spectroscopic data and the diastereomeric amides were separated using high performance liquid chromatography and give high enantiomeric excess, also we study the biological applications of our products and give agood results.

Improved Synthesis of Racemate and Enantiomers of Taniguchi Lactone and Conversion of Their C–C Double Bonds into Triple Bonds

cis-2-Butene-1,4-diol was heated with triethyl orthoacetate and p-hydroquinone as catalyst at 170 °C to give racemic Taniguchi lactone. It was converted into diastereomeric amides with (S)-1-phenylethylamine for stereoisomer resolution. The double bonds of (±)-, (R)- and (S)-Taniguchi lactones were brominated and dehydrobrominated in two steps, using at first DBU and then LDA, to deliver the triple bonds.

Synthesis and Desymmetrization of meso‐2,3‐Diphenylpiperazine for Application in Asymmetric Transformations

AbstractThe meso‐2,3‐diphenylpiperazine was prepared in 86 % yield with 99:1 dr from the readily accessible 5,6‐diphenyl‐2,3‐dihydropyrazine by NaBH4/MeOH reduction. The corresponding diastereomeric amides prepared using (R)‐(‐)‐menthyl chloroformate, after separation, benzylation and hydrolysis gave both isomers of optically active N‐benzyl‐2,3‐diphenylpiperazine samples in up to 94 % ee which after further enrichment using the simple achiral oxalic acid afforded samples of both enatiomers in 99 % ee. Reaction of the chiral optically active N‐benzyl‐2,3‐diphenylpiperazine with terminal alkynes and aldehydes in the presence of ZnCl2 gave the corresponding propargylamines with very high diasterioselectivities (up to 99:1 dr) from which both enantiomers of chiral allenes were obtained in up to 82–86 % ee by reaction with ZnBr2 in toluene at 120 °C.

Highly enantioselective asymmetric direct aldol reaction promoted by aziridine amides constructed on chiral terpene scaffold.

Optically pure, diastereomeric aziridine amides built on the chiral skeletons of camphor, fenchone, and menthone have proven to be highly efficient ligands for enantioselective asymmetric direct aldol reaction in the presence of water and zinc triflate. Desired products were formed in moderate to high chemical yields (up to 95%) and with enantiomeric excess up to 99%. The influence of the stereogenic centers located at the aziridine subunit on the stereochemical course of the reaction is discussed.

Stereochemical Aspects of T3P Amidations

Propanephosphonic acid anhydride (T3P) is a process-friendly commercial reagent that is useful for direct carboxamide formation from the carboxylic acid and amine components. For amidation reactions of certain tetrahydroisoquinolonic carboxylic acids and electron-poor anilines, the phosphonate carboxylate mixed anhydride intermediate evidently eliminates under basic conditions to give a ketene, whose addition reaction in turn leads to a mixture of diastereomeric amide products. For example, 1,4-diazabicyclo[2,2,2]octane, used as the base, provides mostly the 3,4-cis product, whereas N-methylimidazole leads efficiently to the 3,4-trans product. A mechanistic rationale, along with compelling evidence for the intermediate ketene, is provided, as are several examples of the efficient T3P-mediated preparation of carboxamides that are of interest as active antimalarials.

Thin-layer chromatographic enantioseparation of (RS)-etodolac using indirect approach

Enantioseparation of (RS)-etodolac was achieved by an indirect approach. Extraction of the drug (RS)-etodolac (Etd) was done from commercially available tablets, as its racemic mixture; it was purified, characterized, and was used for enantioseparation studies. Diastereomeric amides of (RS)-Etd were synthesized using a commercial sample of enantiomerically pure (R)-(−)-1-cyclohexylethylamine. Derivatization reactions were carried out under conditions of stirring at room temperature (30°C for 2 h) for (RS)-Etd and under microwave irradiation (MWI). The derivatives (as diastereomeric amides) were separated by thin-layer chromatography (TLC). The successful solvent system for separating the diastereomeric amides of (RS)-Etd was acetonitrile—methanol—dichloromethane—water (6:1:1:0.5, v/v). Spots were located by use of iodine vapor. The diastereomeric amides were recovered by preparative method; these were purified and characterized by recording their m.p., λmax (ultraviolet [UV]), infrared (IR) spectra, speci...

Design of Selenium-Based Chiral Chemical Probes for Simultaneous Enantio- and Chemosensing of Chiral Carboxylic Acids with Remote Stereogenic Centers by NMR Spectroscopy.

Selenium-based enantiopure chiral chemical probes have been designed in a modular way starting from available amino alcohols. The probes developed were found to be efficient in chemoselective interaction with carboxylic functions of chiral substrates leading to diastereomeric amide formation and in sensing α-, β-, and remote (up to seven bonds away from the carboxylic group) chiral centers by using 77 Se NMR spectroscopy. As a result, it was possible to determine the enantiomeric ratio of structurally diverse individual chiral acids including polyfunctional compounds and drugs with high accuracy. An approach to analyzing the crude reaction mixtures has been successfully developed by using bifunctional selenium- and fluorine-containing chiral probes. More importantly, it was revealed that, based on the 77 Se NMR data obtained, it is possible to obtain primary information about the location and nature of the substituents at the chiral center (chemo- and enantiosensing), which can simplify the structural elucidation of complex compounds. The derivatization procedure takes as little as 5 min and can be performed directly in an NMR tube followed by NMR measurements without any isolation and purification steps.

Synthesis and asymmetric resolution of a dopaminergic compound: 2-amino-5-methoxyindane

The racemic synthesis and subsequent resolution of 2-amino-5-methoxyindane enantiomers were achieved starting from 5-bromoindan-2-ol in six steps with 38% total yield. The first step involved the substitution of the Br atom by using NaOMe in the presence of CuI to afford 5-methoxyindan-2-ol. The OH group of 5-methoxyindan-2-ol was converted into its mesylate ester, which was converted into the corresponding azide by reaction with sodium azide. The Pd–C-catalyzed hydrogenation of the azide functional group in the presence of CHCl3, followed by neutralization of the amine hydrochloride salt with NaOH, furnished the rac-2-amino-5-methoxyindane. Next, rac-2-amino-5-methoxyindane was converted into its diastereomeric amide derivatives by reaction with (R)-mandeloyl chloride. The diastereomeric amide mixture was separated by recrystallization to give the (R,S)- and (R,R)-diastereomers. The absolute configuration of the (R,S)-isomer was determined by X-ray crystallography. The hydrolysis of these diastereomers gave (R)- and (S)-2-amino-5-methoxyindane with high enantiopurity.

Stereoselective Self-Aggregation of 31 -Epimerically Pure Amino Analogs of Zinc Bacteriochlorophyll-d in an Aqueous Micelle Solution.

Zinc bacteriochlorophyll-d analogs possessing an amino group instead of the original hydroxy group at the C31 position were prepared by chemical modification of naturally occurring chlorophyll-a. The synthetic 31 -epimers were successfully separated by reverse phase HPLC to give diastereomerically pure samples. The stereochemistry of the chiral C31 -center in the separated amines was determined by NMR analysis of their diastereomeric amides as well as by their asymmetric synthesis from authentic stereoisomers. Both the epimers were monomeric in tetrahydrofuran to give sharp electronic absorption bands, while they self-aggregated to form chlorosomal oligomers with the redshifted bands in an aqueous Triton X-100 micelle solution (pH = 6.9). The resulting oligomers deaggregated by addition of p-toluenesulfonic acid to give monomeric N-protonated ammonium species. The aggregation and deaggregation were dependent on the 31 -stereochemistry, indicating that each epimer produced supramolecularly different self-aggregates.

Evaluation of the metabolic chiral inversion of d-selenomethionine in rats by stable isotope dilution gas chromatography–mass spectrometry

The stereoselective pharmacokinetics of selenomethionine enantiomers in rats has been studied to evaluate the chiral inversion of d-selenomethionine to the l-enantiomer. After bolus intravenous administration of d- or l-selenomethionine to rats, the plasma concentrations of these two enantiomers were determined by stereoselective gas chromatography–mass spectrometry with selected ion monitoring. This method involved derivatization of selenomethionine enantiomers with HCl in methanol to form methyl ester followed by N-acylation with (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form the diastereomeric amide, and separation of the diastereomer on GC with an achiral column. Plasma concentrations of administered d- and l-selenomethionine declined with terminal half-lives of 96±17min and 91±6min, respectively. l-Selenomethionine appeared rapidly in plasma after administration of d-selenomethionine, whereas d-selenomethionine was not detected in plasma after administration of l-selenomethionine. The fraction of conversion of d-selenomethionine to l-selenomethionine was estimated to be 61.3±14.5%. The present method evaluates the stereoselective pharmacokinetics of selenomethionine enantiomers, including the estimation of the metabolic chiral inversion.

A novel and simple method for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids: phosphonic acid analogues of proline

A simple and convenient method has been developed for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids. The thermal reaction of proline with diethyl phosphite in the presence of benzaldehyde gave an N-benzyl derivative of diethyl pyrrolidine-2-phosphonate, which was transformed into two diastereomeric amides by sequential debenzylation and acylation with (+)-dibenzoyl-l-tartaric anhydride. The two diastereomeric amides were separated by column chromatography and the structure of one of them was determined by X-ray crystallographic analysis. Hydrolysis of the amides in the usual manner afforded (R)- and (S)-pyrrolidine-2-phosphonic acids. The advantages of the present method are that it is easy, rapid, and prepares both enantiomers of pyrrolidine-2-phosphonic acids.

ChemInform Abstract: Chiral Blocks for the Synthesis of Cyclopentanoids from [2 + 2]‐Cycloadduct (I) of Dichloroketene and Dimethylfulvene.

AbstractThe opening of the cyclobutanone ring in compound (I) proceeds readily under the action of chiral amine (II) to afford inseparable diastereomeric amides (III) and (IV), which are converted into separable lactams (V) and (VI).

A simple and efficient synthesis of enantiomeric (3aRS,4RS,6aSR)-4-hydroxy-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-ones

Diastereomeric amides produced via the cleavage of easily available (±)-7,7-dichloro-4-exo-trimethylsilylbicyclo[3.2.0]hept-2-en-6-one by treatment with (+)-α-methylbenzylamine were transformed into bicyclic lactam-aminals, which can easily be separated by column chromatography on SiO2. The latter products lead to enantiomeric (3a,6a)-4-hydroxy-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-ones after the removal of the chiral auxiliary and epoxidation.