Diastereomeric Derivatives Research Articles

ChemInform Abstract: Synthesis of Chiral Tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones.

Abstract In our investigations of potential hypoglycemic agents,2 it was desired to evaluate optically pure tetrahydropyrrolo[2,1-β]thiazol-5-ones. A novel, practical synthesis of each enantiomer of 1 via formation, separation, and hydrolysis of diastereomeric amidine derivatives is described.

ChemInform Abstract: Synthesis of (23R)- and (23S)-23H-Isocalysterols, Marine Sterols with a Cyclopropene Moiety in the Side Chain.

A synthesis of (23R)- and (23S)-23H-calysterols 2a and 2b from pregnanoic ester 10 is reported. Alkylation of 10 with dibromide 19b, followed by reduction of the carboethyloxy group to a methyl group, afforded (Z)-vinylic bromide 22. Dibromocyclopropanation of 22 yielded the diastereomeric tribromocyclopropane derivatives 15c and 15d. The corresponding 3-hydroxy-5-ene 17c was transformed into 2a via 25 and a cyclopropenyllithium intermediate. An alternative synthetic route involving vinylsilane 13 and (E)-vinylic bromide 14 has also been examined.

Resolution approaches to enantiomers of 4-formyl[2.2]paracyclophane

Three techniques for the resolution of 4-formyl[2.2]paracyclophane were examined with the separation of the diastereomeric derivatives with ( R)- and ( S)-2-hydrazino-2-oxo- N-(1-phenylethyl)acetamide followed by their hydrolysis being found to be the most efficient, allowing ( Rp)- and ( Sp)-4-formyl[2.2]paracyclophanes to be obtained with 99.5% and 98.7% ee, respectively.

Application of (S)-N-(4-Nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as a chiral derivatizing reagent for reversed-phase high-performance liquid chromatographic separation of diastereomers of amino alcohols, non-protein amino acids, and PenA

Indirect enantioresolution of 15 primary and secondary amino group containing compounds (amino alcohols, non-protein amino acids, PenA) was done using the reagent (S)-N-(4-Nitrophenoxycarbonyl) phenylalanine methoxyethyl ester [(S)-NIFE] by reversed-phase high-performance liquid chromatography. The diastereomeric derivatives were analyzed under reversed-phase conditions using linear gradient. The detection was at 205 nm and sharp peaks were obtained. The reagent used is comparatively economic than the other derivatizing reagents. Method validation was also done.

Halogenated Fatty Acid Amides and Cyclic Depsipeptides from an Eastern Caribbean Collection of the Cyanobacterium Lyngbya majuscula

A lipophilic extract of an eastern Caribbean collection of Lyngbya majuscula yielded two new halogenated fatty acid amides, grenadamides B (1) and C (2), and two new depsipeptides, itralamides A (3) and B (4), along with the known compounds hectochlorin and deacetylhectochlorin. The recently reported depsipeptide carriebowmide (5) was also present in the extract and isolated as its sulfone artifact (6). Compounds 1-4 were identified by spectroscopic methods. The configurations of the amino acid residues of 3, 4, and 6 were determined by LC-MS analyses of diastereomeric derivatives of the acid hydrolysates (advanced Marfey's method). Based on the configurational analysis of 6, in direct comparison with authentic carriebowmide (5), a minor structural revision of 5 is proposed. Compounds 1 and 2 displayed marginal activity against the beet armyworm (Spodoptera exigua). Compounds 1-4 and 6 were assessed for general cell toxicity in human embryonic kidney (HEK293) cells. Only itralamide B (4) displayed significant cytotoxicity, showing an IC(50) value of 6 +/- 1 muM.

Resolution/Deracemization of Chiral α-Amino Acids Using Resolving Reagents with Flexible Stereogenic Centers

This work has demonstrated that a previously unexplored approach to separation of enantiomers via formation of diastereomeric derivatives with three stereogenic centers has obvious practical potential and deserves further systematic study. The design reported here is based on the unusual application of a configurationally unstable stereogenic nitrogen, which plays a key role in setting up the stereochemical match between the three stereogenic centers in the corresponding products.

Proximal heteroalkylation of monoalkoxycalix[4]arenes in synthesis of inherently chiral molecules

Proximal heteroalkylation of monoalkyl ethers of calix[4]arenes or p- tert-butylcalix[4]arenes in NaH/CH 3CN or NaOH/DMSO, respectively, was applied for synthesis of inherently chiral calixarenes with ABHH substitution pattern. The introduction by the method of ( R)- or ( S)- N-(α-phenylethyl)acetamide chiral auxiliary group gives mixtures of diastereomeric derivatives of inherently chiral calixarenes, which were separated by column chromatography. The chiral calixarenes were thoroughly characterized by 1H, 13C NMR, and X-ray diffraction methods.

Synthesis of conformationally restricted glutamic acid analogs based on the spiro[3.3]heptane scaffold

A library of isomeric glutamic acid analogs based on the spiro[3.3]heptane skeleton is designed. Two members of the library, ( R)- and ( S)-2-amino-spiro[3.3]heptane-2,6-dicarboxylic acid hydrochlorides, were synthesized. The stereochemistry of the synthesized amino acids was determined using 1H– 1H-NOESY of their diastereomeric derivatives. The aminocarboxylate moiety and the carboxylic group in the synthesized glutamic acid analogs are ‘fixed’ in space relative to each other due to the rigid spirocyclic scaffold and therefore, they can be used to probe topologies of different glutamate receptors.

Synthesis and application of new chiral variants of Marfey's reagent for liquid chromatographic separation of the enantiomers ofα-amino acids

Summary Two new structural variants of Marfey's reagent (1-fluoro-2,4-dinitrophenyl-5-l-alaninamide, FDNP-l-Ala-NH2) were synthesized by nucleophilic substitution of one fluorine atom in 1,5-difluoro-2,4-dinitrobenzene (DFDNB) by l-methioninamide or d-phenylglycinamide. The new variants FDNP-l-Met-NH2 and FDNP-d-Phg-NH2 were characterized and used for derivatization of twenty-six α-amino acids. The resulting diastereomeric derivatives were separated on a reversed-phase C18 HPLC column using a linear gradient of acetonitrile and aqueous trifluoroacetic acid (TFA) and the results were compared with those obtained by use of Marfey's reagent. To determine and establish the efficiency of both the new variants, separation results were compared for diastereomers of five representative amino acids (Ala, Phe, Ser, Asp, and Asn) prepared with MR, FDNP-l-Phe-NH2, FDNP-l-Val-NH2, FDNP-l-Leu-NH2, and FDNP-l-Pro-NH2, experiments being performed under identical conditions. Both the new chiral reagents enabled better sep...

Synthesis of 2-aryloxypropanoic acids analogues of clofibric acid and assignment of the absolute configuration by 1H NMR spectroscopy and DFT calculations

A new set of optically active 2-aryloxypropanoic acids has been synthesized through a simple strategy, in good yields and excellent enantiomeric excesses. Their absolute configuration was assigned by means of a NMR-based approach consisting of the derivatization of the carboxylic acids with ethyl mandelate and the comparison of the chemical shifts of the obtained diastereomers. The effectiveness of such an approach has been tested against a larger set of chiral α-substituted-carboxylic acids and by performing high level density functional theory (DFT) calculations on a set of low energy conformations for each diastereomeric derivative. The employed computational procedure has enabled us to find a semiquantitative relationship between the experimental NMR data and the theoretically calculated energy gaps which confirms the theoretical foundations of the NMR strategy and allows to understand when and why it is most likely to fail.

Fluorescent high-performance liquid chromatographic analysis of vigabatrin enantiomers after derivatizing with naproxen acyl chloride

Vigabatrin is widely used as an anticonvulsant in the treatment of seizures. Vigabatrin is usually supplied as racemate in formulation, but only the (S)-(+)-enantiomer of vigabatrin is pharmacologically active. A simple and sensitive liquid chromatographic method is described for the separation and quantification of vigabatrin enantiomers. The method is based on derivatizing racemic vigabatrin with a fluorescent chiral reagent (naproxen acyl chloride). The resulting diastereomeric derivatives are highly responsive to a fluorimetric detector ( λ ex = 230 nm, λ em = 350 nm). The lower quantitation limit of the method is attainable at 25 nM for (S)-(+)-vigabatrin or (R)-(−)-vigabatrin with a detection limit of about 2.5 nM (S/N = 3 with 10 μl injected). Application of the method to the analysis of vigabatrin in serum of dosed patients proved feasible.

Chiral discrimination of primary amines by HPLC after labeling with a chiral derivatization reagent, trans‐2‐(2,3‐anthracenedicarboximido)‐cyclohexanecarbonyl chloride

Enantiomeric discrimination of chiral primary amines was performed by both reversed-phase HPLC and normal-phase HPLC after labeling with a chiral fluorescent derivatization reagent, (1R,2R)- and (1S,2S)-trans-2-(2,3-anthracenedicarboximido)cyclohexanecarbonyl chloride. Use of HPLC permits separation of diastereomeric derivatives of amines up to C30 which have a primary amino group at the middle of the alkyl chain. The derivatives of primary amines having an anteiso alkyl chain, which has a chiral branched-methyl at the n-3 position of the alkyl chain, were also separated by HPLC, and it was also possible to separate niphatesine D by reversed-phase HPLC after derivatization.

Precolumn diastereomerization and micellar electrokinetic chromatography on a plastic microchip: Rapid chiral analysis of amino acids

Precolumn derivatization and chiral separation of DL-amino acids based on diastereomerization have been performed on an integrated poly(dimethylsiloxane) microchip. Diastereomeric derivatives were formed in a microfabricated precolumn reactor by the reaction of amino acid enantiomers with o-phthaldialdehyde/2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranose (OPA/TATG), and separated by MEKC in an achiral environment without chiral selectors in the running buffer. Optimized precolumn reactions and chiral separations of amino acids were achieved within 2.5 min. Resolutions of diastereomers of OPA/TATG-amino acids were in the range of 2.5-6.1 at optimized separation conditions. Simultaneous separation of a mixture of five chiral amino acids was successfully performed in a single run in less than 100 s.

Conversion of linoleic acid into novel oxylipins by the mushroom Agaricus bisporus

Oxylipins are associated with important processes of the fungal life cycle, such as spore formation. Here, we report the formation of FA metabolites in Agaricus bisporus. Incubation of a crude extract of lamellae with linoleic acid (18:2) led to the extensive formation of two oxylipins. They were identified as 8(R)-hydroxy-9Z,12Z-octadecadienoic acid (8-HOD) and 8(R),11 (S)-dihydroxy-9Z,12Z-octadecadienoic acid (8,11-diHOD) by using RP-HPLC, GC-MS, IR, GC-MS analysis of diastereomeric derivatives, and 1H NMR and 13C NMR spectroscopy. Neither compound has been reported before in A. bisporus. Oleic (18:1), alpha-linolenic (18:3n-3), and gamma-linolenic (18:3n-6) acids were converted into their 8-hydroxy derivatives as well, and 18:3n-3 was further metabolized to its 8,11-diol derivative. Reactions with [U-13C]18:2 demonstrated that the compounds 8-HOD and 8,11-diHOD were formed from exogenously supplied 18:2. When [U-13C]8-HOD was supplied, it was not converted into 8,11-diHOD, indicating that it was not an intermediate in the formation of 8,11-diHOD. When a crude extract of A. bisporus was incubated under an atmosphere of 16O2/18O2, the two hydroxyl groups of 8,11-diHOD contained either two 180 atoms or two 60 atoms. Species that contained one of each isotope could not be detected. We propose that the formation of the 8,11-dihydroxy compounds occurs through either an 8,11-endoperoxy, an 8-peroxo free radical, or an 8-hydroperoxy intermediate. In the latter case, the reaction should be catalyzed by dioxygenase with novel specificity.

Capillary Electrophoresis for Diastereomers of (R,S)-Tetrahydroisoquinoline-3-Carboxylic Acid Derivatized with (R)-4-Nitro-7-(3-Aminopyrrolidin-1-yl)-2,1,3-Benzoxadiazole: Effect of Molecular Geometries

Diastereomers derived from (R,S)-tetrahydroisoquinoline-3-carboxylic acid (Tic), a potential neurotoxin with a chiral fluorescence tagging reagent, (R)-4-nitro-7-(3-aminopyrrolidin-1-yl)-2,1,3-benzoxadiazole (NBD-APy), are well resolved by capillary electrophoresis (CE). For a better understanding of the separation mechanism, a semiempirical computational method (i.e., AM1 method) is used to study the molecular geometry, relative energy, and size of the derivatives. The molecular sizes are estimated to be 216.3 and 240.6 cm3/mol for (R)-NBD-APy-(R)-Tic and (R)-NBD-APy-(S)-Tic, respectively. The CE elution order of the diastereomeric derivatives confirms the AM1 computational results: (R)-NBD-APy-(R)-Tic elutes before (R)-NBD-APy-(S)-Tic. The effects of running buffer pH and the addition of a chiral selector, beta-cyclodextrin (beta-CD), on the separation are studied. In the presence of beta-CD, the migration behavior of the diastereomers is changed because of the formation of CD inclusion complexes. Study of the space-filling models for optimized conformations of the diastereomeric derivatives and beta-CD suggests that the geometries of the diastereomers decides that the diastereomers are incorporated into the CD cavity to form CD inclusion complexes with different volumes. Experimental results from CE separations conclude the same.

Gas-chromatographic determination of the enantiomeric composition of optically active alcohols and amines using achiral bifunctional reagents

A technique for determining the enantiomeric composition of 2-octanol and α-phenylethylamine with the use of gas chromatography on optically inactive stationary phases is proposed. The technique is based on the formation of symmetrical diastereomeric derivatives upon the interaction of enantiomers with bifunctional achiral reagents: dimethyldichlorosilane, bromochloromethane, and dibromoethane. The reagents were chosen from the viewpoint of the synthesis of diastereomers with a minimum distance between the chiral centers. This minimum distance is responsible for a difference in the energies of interaction of the derivatives with the stationary liquid phase, which is sufficient for the separation of these derivatives.

Fluorinated phenylcyclopropylamines. Part 4: Effects of aryl substituents and stereochemistry on the inhibition of monoamine oxidases by 1-aryl-2-fluoro-cyclopropylamines

A series of para-ring-substituted ( E)- and ( Z)-1-aryl-2-fluorocyclopropylamines were examined as inhibitors of recombinant human liver monoamine oxidase A (MAO A) and B (MAO B). Unlike the parent 1-phenylcyclopropylamine, which is a selective inhibitor of MAO B, both ( E)- and ( Z)-diastereomers of derivatives having fluorine at the 2-position of the cyclopropane ring were potent and selective irreversible inhibitors of MAO A. Both electron releasing groups (Me, OMe) and electron attracting groups (Cl, F) substituted in the para-position caused a modest increase in activity. Geminal difluoro-substitution caused a loss of potency of 100-fold compared to either ( E)- or ( Z)-monofluorinated analogue. Surprisingly, (1 S,2 R)-2-fluoro-1-phenylcyclopropylamine and the (1 R,2 S)-enantiomer were essential equally potent as inhibitors of MAO A and MAO B. None of the tested 1-aryl-2-fluorocyclopropylamines exhibited significant inhibition of tyramine oxidase.

Preparation of enantiopure inherently chiral calix[5]arenes

Enantiopure inherently chiral calix[5]arenes were successfully prepared by separation of their ( R)-BINOL diastereomeric derivatives of the corresponding racemates by column chromatography instead of HPLC. A new type of inherently chiral calix[5]arene was obtained.

Simultaneous determination of amphetamine and methamphetamine enantiomers in urine by simultaneous liquid–liquid extraction and diastereomeric derivatization followed by gas chromatographic–isotope dilution mass spectrometry

A simple, rapid, reliable, and economic analytical scheme starting with in situ liquid–liquid extraction and asymmetric (or diastereomeric) chemical derivatization (ChD) followed by gas chromatography (GC)-isotope dilution mass spectrometry (MS) is described for the simultaneous determination of d- and l-amphetamine (AP) and methamphetamine (MA) in urine which could have resulted from the administration of various forms of questioned amphetamines or amphetamines-generating drugs. By using l- N-trifluoroacetyl-1-prolyl chloride ( l-TPC) as chiral derivatizing agent, resolutions of 2.2 and 2.0 were achieved for the separation of AP and MA enantiomeric pairs, respectively, on an ordinary HP-5MS capillary column. The GC–MS quantitation was carried out in the selected ion monitoring (SIM) mode using m/ z 237 and 251 as the quantifier ions for the respective diastereomeric pairs of AP- l-TPC and MA- l-TPC. The calibration curves plotted for the two pairs of analytes stretch with good linearity down to 45 ng/mL, and the limits of detection and quantitation determined were as low as 40 and 45 ng/mL, respectively. Also, a comparative study using 10 real-case urine specimens previously screened as positive for MA administration showed mostly tolerable biases between the two sums (of concentration) of d- and l-MA obtained via an asymmetric l-TPC-ChD approach and via an ordinary pentafluoropropionylation (PFPA-ChD) approach, respectively, as well as between the two sums of d- and l-AP obtained thereupon, thus validating the proposed analytical scheme as a promising forensic protocol for the detailed analysis of enantiomeric amphetamines in urine.

Synthesis and Stereostructure of Saturated Isoindolone-Fused Hetero Tri-, Tetra-, and Pentacyclic Compounds

t-2-Benzoyl-t-4-phenylcyclohexane-r-1-carboxylic acid reacts with hydrazine to give the saturated 1,7-diphenyl-trans-phthalazin-4(3H)-one. The reaction of the acid with ethylenediamine yields diastereomeric trans-imidazo[2,3-a]isoindoles, which differ in their C-1 configuration. The cyclizations of the acid with cis-2-aminocyclohexane- or 4-cyclohexenemethanol result in trans-isoindolo[2,1-a][3,1]benzoxazines, while in its reactions with the analogous di-endo- and di-exo-norbornane- and -norborneneamino alcohols, the acid gives methylene-bridged isomeric di-endo-norbornanes or a norbornene derivative; the corresponding diastereomeric di-exo derivatives have also been prepared. After isolation, the structures were established by means of 1H and 13C NMR spectroscopy, with application of DIFFNOE, DEPT, HMQC, HMBC, and 2D-COSY techniques.