Diastereoselective Research Articles

Separation of Amlodipine Enantiomers by Diastereomeric Salt Formation

Separation of Amlodipine Enantiomers by Diastereomeric Salt Formation

Diastereoselective formation of homochiral flexible perylene bisimide cyclophanes and their hybrids with fullerenes.

Cyclophanes of different ring sizes featuring perylene-3,4:9,10-tetracarboxylic acid bisimide (PBI) linked by flexible malonates were designed, synthesized, and investigated with respect to their structural, chemical and photo-physical properties. It is predominantly the number of PBIs and their geometric arrangement, which influence dramatically their properties. For example, two-PBI containing cyclophanes reveal physico-chemical characteristics that are governed by strong co-facial π–π interactions. This is in stark contrast to cyclophanes with either three or four PBIs. Key to co-facial π–π stackings are the flexible malonate linkers, which, in turn, set up the ways and means for diastereoselectivity of the homochiral PBIs at low temperatures, on one hand. In terms of selectivity, diastereomeric (M,M)/(P,P) : (M,P)/(P,M) pairs with a ratio of approximately 10 : 1 are discernible in the 1H NMR spectra in C2D2Cl4 and a complete diastereomeric excess is found in CD2Cl2. On the other hand, symmetry-breaking charge transfer as well as charge separation at room temperature are corroborated in steady-state and time-resolved photo-physical investigations. Less favourable are co-facial π–π stackings in the three-PBI containing cyclophanes. For statistical reasons, the diastereoisomers (M,M,M)/(P,P,P) and (M,M,P)/(P,P,M) occur here in a ratio of 1 : 3. In this case, symmetry-breaking charge transfer as well as charge separation are both slowed down. The work was rounded-off by integrating next to the PBIs, for the first time, hydrophobic or hydrophilic fullerenes into the resulting cyclophanes. Our novel fullerene–PBI cyclophanes reveal unprecedented diastereoselective formation of homochiral (M,M)/(P,P) pairs exceeding the traditional host–guest approach. Hybridization with fullerenes allows us to modulate the resulting solubility, stacking, cavity and chirality, which is of tremendous interest in the field.

Tersaphilones A-E, cytotoxic chlorinated azaphilones from the deep-sea-derived fungus Phomopsis tersa FS441

Abstract Five new chlorinated azaphilone derivatives, tersaphilones A-E along with three known analogues were isolated from the deep-sea-derived fungus Phomopsis tersa FS441. Structures of the new compounds with absolute configurations were determined by comprehensive chemical analyses including spectroscopic techniques, ECD calculation, and single crystal X-ray diffraction. Among them, tersaphilone B possessed the unique 6/6-6 carbon skeleton with a cleaved tetrahydrofuranyl ring. Besides, tersaphilones D and E were a pair of diastereomers featuring a characteristic epoxide ring, which were rarely-occurring in azaphilones. Moreover, all compounds were evaluated for their anticancer activity using a panel of four tumor cell lines, wherein the novel tersaphilones D and E showed significant cytotoxicity against MCF-7, SF-268, and A549 cell lines with the IC50 values ranging from 5.4 to 8.3 μM.

Effect of Substituent of Roof Shape Amines on the Molecular Recognition of Optically Active Acids by NMR Spectroscopy

AbstractOptically active roof shape derivatives of benzyl amines were synthesized and screened as chiral solvating agents for the study of molecular recognition of chiral compounds by NMR and UV spectroscopy. The effect of substituents on the aromatic ring of benzyl unit is investigated to assess the binding ability with the analyte and an experimental correlation is observed. Altering the substituents on the ring of benzyl amine and the acidic substrates, significantly influence the CSA interactions. The supramolecular interactions between acid and amine in the single crystal X‐ray analysis of the diastereomeric salts provide further insight of the mode of molecular recognition.

Entropic-Based Separation of Diastereomers: Size-Exclusion Chromatography with Online Viscometry and Refractometry Detection for Analysis of Blends of Mannose and Galactose Methyl-\u03b1-pyranosides at \u201cIdeal\u201d Size-Exclusion Conditions

The separation of carbohydrate diastereomers by an ideal size-exclusion mechanism, i.e., in the absence of enthalpic contributions to the separation, can be considered one of the grand challenges in chromatography: Can a difference in the location of a single axial hydroxy group on a pyranose ring (e.g., the axial OH being located on carbon 2 versus on carbon 4 of the ring) sufficiently affect the solution conformational entropy of a monosaccharide in a manner which allows for members of a diastereomeric pair to be separated from each other by size-exclusion chromatography (SEC)? Previous attempts at answering this question, for aqueous solutions, have been thwarted by the mutarotation of sugars in water. Here, the matter is addressed by employing the non-mutarotating methyl-α-pyranosides of d-mannose and d-galactose. We show for the first time, using SEC columns, the entropically driven separation of members of this diastereomeric pair, at a resolution of 1.2–1.3 and with only a 0.4–1% change in solute distribution coefficient over a 25 °C range, thereby demonstrating the ideality of the separation. It is also shown how the newest generation of online viscometer allows for improved sensitivity, thereby extending the range of this so-called molar-mass-sensitive detector into the monomeric regime. Detector multidimensionality is showcased via the synergism of online viscometry and refractometry, which combine to measure the intrinsic viscosity and viscometric radius of the sugars continually across the elution profiles of each diastereomer, methyl-α-d-mannopyranoside and methyl-α-d-galactopyranoside.

NMR and Computational Studies as Analytical and High-Resolution Structural Tool for Complex Hydroperoxides and Diastereomeric Endo-Hydroperoxides of Fatty Acids in Solution-Exemplified by Methyl Linolenate.

A combination of selective 1D Total Correlation Spectroscopy (TOCSY) and 1H-13C Heteronuclear Multiple Bond Correlation (HMBC) NMR techniques has been employed for the identification of methyl linolenate primary oxidation products without the need for laborious isolation of the individual compounds. Complex hydroperoxides and diastereomeric endo-hydroperoxides were identified and quantified. Strongly deshielded C–O–O–H 1H-NMR resonances of diastereomeric endo-hydroperoxides in the region of 8.8 to 9.6 ppm were shown to be due to intramolecular hydrogen bonding interactions of the hydroperoxide proton with an oxygen atom of the five-member endo-peroxide ring. These strongly deshielded resonances were utilized as a new method to derive, for the first time, three-dimensional structures with an assignment of pairs of diastereomers in solution with the combined use of 1H-NMR chemical shifts, Density Functional Theory (DFT), and Our N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) calculations.

Novel oligomeric neolignans with PTP1B inhibitory activity from the bark of Magnolia officinalis var. biloba

The barks of Magnolia officinalis var. biloba, Magnoliae cortex, have been used as traditional Chinese medicines for several centuries. In this study, phytochemical investigation of M. officinalis var. biloba bark extract afforded five pairs of novel enantiomeric oligomeric neolignans, (±)-mooligomers A–E (1–5). (±)-1 and (±)-2 were two diastereomeric pairs of enantiomers with six C6-C3 subunits, and (±)-4 was a pair of previously unreported tetrameric neolignans bearing eight C6-C3 subunits. (±)-5 is the first example of a naturally occurring trilignan featuring an eight-membered ring with a magnolol moiety. The absolute configurations of (±)-1−(±)-5 were elucidated on the basis of HRESIMS, 1D and 2D NMR spectroscopy and electronic circular dichroism (ECD) calculations. Among the compounds tested for their PTP1B inhibitory activities, (±)-2, (±)-4 and (±)-5 displayed significant PTP1B inhibitory activities with IC50 values of 0.14–2.10 μM. Furthermore, a Molecular docking simulation of PTP1B and active compounds [(±)-2, (±)-4 and (±)-5] exhibited that these active compounds possess low binding affinities ranging from − 5.9 to − 7.7 kcal/mol.

Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.

Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 c) and (R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain-1, with 1 c (IC50 =78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.

Separating chiral isomers of amphetamine and methamphetamine using chemical derivatization and differential mobility spectrometry.

The separation and analysis of chiral compounds, especially enantiomers, presents a great challenge to modern analytical chemistry, particularly to mass spectrometry (MS). As a result, integrated orthogonal separations, such as chiral liquid chromatography (chiral LC), gas chromatography (GC), or capillary electrophoresis (CE), are often employed to separate enantiomers prior to MS analysis. Here, we combine chemical derivatization with differential mobility spectrometry (DMS) and MS to separate and quantitate the transformed enantiomeric pairs R- and S-amphetamine, as well as R- and S-methamphetamine. We also demonstrate separation of these drugs by using reverse-phase LC. However, while the LC method requires ∼5min to provide separation, we have developed a flow-injection analysis (FIA) method using DMS as the exclusive mode of separation (FIA-DMS), requiring only ∼1.5min with equivalent quantitative metrics (1-1000ng/mL range) to the LC method. The DMS-based separation of each diastereomeric pair is driven by differences in binding energies between the analyte ions and the chemical modifier molecules (acetonitrile) added to the DMS environment.

Differentiation and Quantification of Diastereomeric Pairs of Glycosphingolipids Using Gas-Phase Ion Chemistry.

Glycosphingolipids (GSLs), including lyso-glycosphingolipids (lyso-GSLs) and cerebrosides (HexCer), constitute a sphingolipid subclass. The diastereomerism between their monosaccharide head groups, glucose and galactose in mammalian cells, gives rise to an analytical challenge in the differentiation of their biological roles in healthy and disease states. Shotgun tandem mass spectrometry has been demonstrated to be a powerful tool in lipidomics analysis in which the differentiation of the diastereomeric pairs of GSLs could be achieved with offline chemical modifications. However, the limited number of standards, as well as the lack of the comprehensive coverage of the GSLs, complicates the qualitative and quantitative analysis of GSLs. In this work, we describe a novel strategy that couples shotgun tandem mass spectrometry with gas-phase ion chemistry to achieve both differentiation and quantification of the diastereomeric pairs of GSLs. In brief, deprotonated GSL anions, [GSL-H]-, and terpyridine-magnesium complex dications, [Mg(Terpy)2]2+, are sequentially injected and mutually stored in a linear ion trap to form charge-inverted complex cations, [GSL-H + MgTerpy]+. The collision-induced dissociation of the charge-inverted complex cations leads to significant spectral differences between the diastereomeric pairs of GSLs, which permits their distinction. Moreover, we describe a relative quantification strategy with the normalized %Area extracted from selected diagnostic ions in binary mixtures. Analytical performance with the selected pure-component pairs, lyso-GSLs and HexCer(d18:1/18:0), was also evaluated in terms of accuracy, repeatability, and interday precision. The pure components could be extended to different fatty acyl chains on cerebrosides with a limited error, which allows for the relative quantitation of the diastereomeric pairs without all standards. We successfully applied the presented method to identify and quantify, on a relative basis, the GSLs in commercially available total cerebroside extracts from the porcine brain.

Divergent and Multi-Stage Photoisomerization of Four-Coordinated Boron Compounds with a Naphthyl-Pyridyl/Thiazolyl Backbone.

Examination of the photoreactivity of a new class of N,C-chelate organoboron compounds, including a series of unsymmetrically substituted boron molecules, B(naph-pyridyl)(Ar1 )(Ar2 ) and B(naph-thiazolyl)(Ar1 )(Ar2 ), led to the discovery of new and divergent photothermal isomerization phenomena. These include the clean and regioselective photoisomerization by unsymmetrical boron, forming borepin isomers, some of which further isomerize to the corresponding boratanorcaradiene diastereomer pairs as a result of the generation of two chiral centers. Significantly, the boratanorcaradienes involving a 3-thienyl substituent on boron were found to thermally convert to BN-fluoranthene annulated borapentalene via an unprecedented reversible boratacyclopropane-boratacyclopentene rearrangement. Changing the pyridyl donor to a thiazolyl donor on the boron was found to provide the B(naph-thiazolyl)(Mes)2 compounds with a distinct new photoisomerization pathway-instead of borepin, forming new blue fluorescent polycyclic azaborinine species. This work illustrates the richness and complexity of boron photochemistry.

Eco-friendly and Enantiospecific Biginelli Synthesis Using (+)-Myrtenal as the Substrate - An Impeccable and Unequivocal Analysis of the Product.

We found in the literature, an excellent review of the Biginelli reaction that addresses the methodologies for obtaining enantiopure dihydropyrimidinones (DHPMs). In 1992, optically pure DHPMs were obtained by fractional crystallization of the diastereomeric ammonium salt derivative with (S)-(-) and (R)- (+)-α-methyl benzylamine and by other chiral resolution techniques, such as chiral high-performance liquid chromatography (HPLC). Asymmetric syntheses of these compounds are also explained in the literature. The main strategy is to use acid catalysts such as organophosphates, organometallic complexes, amines and diamines, nanocomposites, and chiral ionic liquids, e.g., L-prolinium sulfate (Pro2SO4). The objective was to study the Biginelli reaction with a chiral aldehyde. A mixture of ethyl acetoacetate (0.26 g, 3 mmol), urea (0.18 g, 3 mmol) and ethyl lactate (EL) (1 mL) was left under heating at 70°C and stirring for 1 h. Next, (-)-(1R)-myrtenal (0.45 g, 3 mmol) was added, and the medium was heated for 5 h more until the formation of a white solid. Ten millilitres of distilled water was added, and the product was extracted with CH2Cl2 (3 x 4 mL). The solvent was evaporated, and the product was recrystallized from ethanol-water. (+)-Myrtenal was used as a chiral substrate for a study that led to ethyl (R)-4-((1R,5S)- 6,6-dimethylbicyclo [3.1.1]hept-2-en-2-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate by the Biginelli synthesis using EL as a green solvent. The result is the first example of the enantiospecific Biginelli reaction. The product was exhaustively characterized by several physical analysis methods, i.e., 1H, 13C and 2D nuclear magnetic resonance (NMR) spectroscopies, infrared (IR) spectroscopy, mass spectrometry (MS), and high-resolution MS (HRMS), and its structure was unequivocally elucidated by X-ray crystallography. Compound (4R)-4-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-6-methyl-2-oxo-1,2,3,4- tetrahydropyrimidine- 5-ethyl carboxylate is the first example of the enantiospecific Biginelli reaction. In addition, the process has the advantage of using EL as a green solvent. The product was characterized by 1H, 13C, and 2D NMR and IR spectroscopy, MS, HRMS, and X-ray crystallography.

Specific and Selective Quantitation of Antiviral Drugs in the Presence of Impurities by Liquid Chromatography

A stability indicating reversed phase high performance liquid chromatography method was developed and validated for the determination of the antiviral drugs of nevirapine, lamivudine and zidovudine in combination drug product. The chromatographic separation of nevirapine, lamivudine, zidovudine and eight specified impurities of thymine, thymidine, zidovudine related compound B, nevirapine related compound A, nevirapine related compound B, salicylic acid, cytosine, lamivudine diastereomer impurity were achieved with Waters symmetry C18 (250 mm x 4.6 mm i.d., 5 μm) column. The method was validated according to the ICH guidelines with respect to system suitability, linearity, precision, accuracy, robustness, LOQ, LOQ, selectivity and specificity. Forced degradation study was also performed in tablet to demonstrate the stability indicating power of the optimized HPLC method. The samples were degraded in hydrogen peroxide condition indicating that the drug product is susceptible to oxidation. Statistical analysis proves that the method can be repeated and selective for the estimation of said drugs. The method could effectively separate the drug from its degradation product hence it can be used as a stability indicating method. This developed procedure is also applicable for the determination of instability of the drug and dissolution behavior of the said products in commercial products.

Stereochemistry of the Kabachnik‐Fields Condensation of Terpenic Amino Oximes with Aldehydes and Dimethyl Phosphite

AbstractThree‐component condensation of aldehydes and dimethyl phosphite with α‐amino oximes derived from (−)‐α‐pinene and (+)‐3‐carene (Kabachnik‐Fields reaction) resulted in amino phosphonates as pairs of diastereomers. Diastereomeric ratio depends on the catalyst used (SnCl2×2H2O, SiO2, Al2O3‐H+) and the heating type (conventional or microwave). The best results were achieved by MW irradiation with simultaneous cooling. Stereochemical assignment of the key derivatives was made by X‐ray diffractometry. According to quantum chemical calculations (DFT PBE0/def2‐TZVPP) and spectroscopic data, the terpenic α‐amino phosphonates should be conformationally inhomogeneous, exhibiting a tendency to form H‐bonded dimers (DFT M06/def2‐SVP, IR). One‐bond spin‐spin coupling 1JP–C was found to be diagnostic for the configuration assignment since the value 1JP–C depends on the dihedral angle between bond C−P and axis of the electron lone pair at the neighboring nitrogen (NMR, DFT PBE0/aug‐cc‐pVTZ−J).

Photoredox-Catalyzed Diastereoselective C–H Arylation/Epimerization of Piperidines

Key words iridium catalysis - photoredox catalysis - diastereoselectivity - C–H arylation - piperidines

Female-Produced Sex Pheromone of Tetrastichus planipennisi, a Parasitoid Introduced for Biological Control of the Invasive Emerald Ash Borer, Agrilus planipennis.

The Asian eulophid wasp Tetrastichus planipennisi is being released in North America as a biocontrol agent for the emerald ash borer (Agrilus planipennis), a very destructive invasive buprestid beetle that is devastating ash trees (Fraxinus spp.). We identified, synthesized, and tested a female-produced sex pheromone for the wasp. The key component eliciting behavioral responses from male wasps in flight tunnel bioassays was identified as (6S,10S)-(2E,4E,8E)-4,6,8,10-tetramethyltrideca-2,4,8-triene. Female specificity was demonstrated by gas chromatographic (GC) comparison of male and female volatile emissions and whole body extracts. The identification was aided by coupled gas chromatography/mass spectrometry analysis, microchemical reactions, NMR, GC analyses with a chiral stationary phase column, and matching GC retention times and mass spectra with those of synthetic standards. The tetramethyl-triene hydrocarbon was synthesized as a mixture of two enantiomeric pairs of diastereomers, and as the pure insect-produced stereoisomer. In flight-tunnel bioassays, males responded to both the natural pheromone and the chiral synthetic material by upwind flight and landing on the source. In contrast, the mixture of four stereoisomers was not attractive, indicating that one or more of the "unnatural" stereoisomers antagonized attraction. Field trials, using yellow pan traps baited with natural pheromone, captured significantly more male wasps than control traps over a four week trial. The identified pheromone could increase the efficiency and specificity of the current detection methods for Tetrastichus planipennisi and aid in the determination of parasitoid establishment at release sites.

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Anti-adipogenic 18,19-seco-ursane stereoisomers and oleane-type saponins from Ilex cornuta leaves

Three undescribed seco-ursane stereoisomers, ilexcornutosides A–C, two undescribed triterpenoid saponins, ilexcornutosides D–E, and 11 known triterpenoids were isolated from the leaves of Ilex cornuta Lindl. & Paxton. Ilexcornutosides A–C and F with the same planar structures are unique 13(18)-ene-18,19-seco-ursane skeleton triterpenoids, identified as (3S,12R)-3-O-[β-d-glucopyranosyl-(1 → 2)-α-l-arabinopyranosyl]-12-hydroxyl-19-oxo-18,19-secours-13(18)-en-28,21-lactone. Among them, ilexcornutosides A and F (or ilexcornutosides B and C) are a pair of diastereomers at the C-20 position; ilexcornutosides A and C (or ilexcornutosides B and F) are a pair of diastereomers with epimerization at the C-21. Their structures were established by extensive spectroscopic (IR, 1D and 2D NMR, and HR-ESI-MS) and chemical analyses. The absolute configurations of ilexcornutosides A, B, D and F were determined by a single crystal X-ray diffraction analysis with a Cu Kα radiation. The inhibitory effect of ilexcornutosides A–F on the PPARγ expression was assessed in the 3T3-L1-Lenti-PPARγ-Luc cells using a single luciferase reporter assay. Ilexcornutosides A and C showed a comparable activity in decrease of the PPARγ expression to the positive control (T0070907) at 5 μM.

Tricyclic Sulfoxide–Alkene Hybrid Ligands for Chiral Rh(I) Complexes: The “Matched” Diastereomer Catalyzes Asymmetric C–C Bond Formations

Deprotonation of phenyldibenzo[b,f]tropylidene (8) with LDA/t-BuOK followed by quenching with either diastereomer of inexpensive glucose-based t-Bu-sulfinate (R)- or (S)-11 affords a sulfoxide–alkene hybrid ligand as the diastereomeric pairs (SS,SC)-9/(SS,RC)-10 and (RS,RC)-9/(RS,SC)-10, respectively, which via chromatographic/recrystallization may be separated into the four isomers. The optically pure diastereomeric ligands (SS,SC)-9 and (SS,RC)-10 react with [RhCl(coe)2]2 to form the dinuclear complexes (RS,SC)-11 and (RS,RC)-12, respectively, in which the bidentate ligands coordinate the metal centers through the sulfur and alkene donor functions. These complexes catalyze the conjugate addition of arylboronic acids to cyclic Michael acceptors with enantioselectivities of up to 99% ee. DFT calculations show the preponderant influence of planar chirality of the ligand alkene function. The enantioselectivity switch observed between (RS,SC)-11 and (RS,RC)-12 is explained by the inverted cis–trans coordinations of the substrate molecules in catalytic steps.

Diastereoselective thermal [3+2] cycloaddition reactions of nitrone possessing an amide functional group as hydrogen bond donor/acceptor

High diastereoselectivity in the [3+2] cycloaddition reactions of a series of maleimides with a nitrone capable of hydrogen bonding have been carried out. The cycloaddition reaction proceeded in highly diastereoselective manner leading to novel pyrrolo[3,4- d ]isoxazolidines with good yields. NMR studies revealed that in the performed cycloaddition reactions, a pair of diastereomers are formed in all cases and the cis -diastereomeric product is the favorite cycloadduct with de values up to 90%. It would appear that the presence of amide functionality at the phenyl moiety of nitrone can influence the diastereomeric ratio in the cycloaddition reactions and cis stereoselectivity is most likely dependent on the presence of this group. The nature of the cycloadddition process was interpreted in the framework of theMolecular Electron Density Theory.