Chiral Derivatives Research Articles

NMR and X-ray studies of apetalic acid isolated from Calophyllum brasiliense and of its chiral amides

The tropical tree Calophyllum brasiliense Cambess. (Clusiaceae) grows in rain forests from Brazil to Mexico. Its leaves, as well as those of other Calophyllum species, are rich sources of chromanone acids, such as apetalic acid, isoapetalic acid, and their derivatives. Apetalic acid has shown significant antimycobacterial activity. The biological activity of apetalic acid has been related to the configuration of three asymmetric centers and the stereochemistry of the molecule; however, the C-19 configuration in the acidic side chain has not been fully resolved. For this reason, the unequivocal determination of the absolute configuration by means of X-ray crystallography in a sample of unique homogeneous apetalic acid stereoisomer was the most important point to start this study. Chiral amides were prepared using the carboxyl group. We determined the C-19 stereochemistry of apetalic acid and its specific chiral derivatives using NMR, X-ray diffraction, and molecular mechanics. Finally, we observed that steric hindrance in the side chain of apetalic acid leads to restriction of rotation around the pivotal linkage C-10–C-19, establishing chiral centers at C2(R), C3(S), and C19(R). We were able to separate the derivatives of these two high-rotatory-barrier conformers of apetalic acid by forming diastereoisomeric amides with phenylglycine methyl ester having a chiral center at C-2′. Our results confirmed the existence of atropisomerism in the apetalic acid molecule.

Stereospecific Epoxidation of Limonene Catalyzed by Peroxygenase from Oat Seeds.

Limonene is one of the most abundant naturally occurring cyclic monoterpenes and has recently emerged as a sustainable alternative to petroleum-based solvents as well as a chemical platform for the production of value-added compounds. The biocatalytic epoxidation of both enantiomers of limonene was carried out in the presence of a peroxygenase-containing preparation from oat (Avena sativa) flour. Different reaction profiles were observed depending on the starting enantiomer of limonene, but in both cases the 1,2-monoepoxide was obtained as the main product with excellent diastereoselectivity. Trans-1,2-monoepoxide and cis-1,2-monoepoxide were isolated from the reaction of (R)-limonene and (S)-limonene, respectively, and the reactions were scaled-up to 0.17 M substrate concentration. The process is valuable for operational simplicity, lack of toxic metal catalysts, and cost-effectiveness of the enzymatic source. Pure stereoisomers of 1,2-monoepoxides of limonene constitute a useful starting material for biorenewable polymers, but can be also converted into other chiral derivatives by epoxide ring opening with nucleophiles. As a proof of concept, a tandem protocol for the preparation of enantiopure (1S,2S,4R)-1,2-diol from (R)-limonene and (1R,2R,4S)-1,2-diol from (S)-limonene was developed.

Convenient Genetic Encoding of Phenylalanine Derivatives through Their α-Keto Acid Precursors.

The activity and function of proteins can be improved by incorporation of non-canonical amino acids (ncAAs). To avoid the tedious synthesis of a large number of chiral phenylalanine derivatives, we synthesized the corresponding phenylpyruvic acid precursors. Escherichia coli strain DH10B and strain C321.ΔA.expΔPBAD were selected as hosts for phenylpyruvic acid bioconversion and genetic code expansion using the MmPylRS/pyltRNACUA system. The concentrations of keto acids, PLP and amino donors were optimized in the process. Eight keto acids that can be biotransformed and their coupled genetic code expansions were identified. Finally, the genetic encoded ncAAs were tested for incorporation into fluorescent proteins with keto acids.

Estimation of Enantiomeric Excess Based on Rapid Host–Guest Exchange

Chiral molecules possess enantiomers that have non-superimposable chemical structures but exhibit identical nuclear magnetic resonance (NMR) spectra. This feature prevents the use of NMR spectroscopic methods for the determination of enantiomeric excesses (ee) of chiral molecules, using simple mixtures of their enantiomers. Recently, however, it was reported that the addition of a symmetrical prochiral molecule (a reporter or host) into a solution of chiral analyte can lead to estimation of ee through interactions involving rapid exchange of the chiral analyte (guest) in the formed host–guest complex. This is due to the ee-dependent splitting of NMR resonances of the prochiral host molecule based on averaging the chemical shift non-equivalency caused by the presence of a chiral guest. The mechanism is not dependent on diastereomer formation, and 1:1 host–guest complexes can also show ee-dependent NMR peak splitting. Prochiral molecules capable of ee sensing using the NMR technique are now referred to as so-called prochiral solvating agents (pro-CSAs). pro-CSAs represent a family of reagents distinct from the commonly used NMR chiral derivatizing reagents (where chiral auxiliaries are used to derivatize enantiomers to diastereomers) or chiral solvating agents (where chiral auxiliaries interact in an asymmetric manner with analyte enantiomers). pro-CSA methods are unique since neither pro-CSA nor NMR contains chiral factors, making the technique neutral with respect to chirality. Here, we review our recent work on this matter involving several different nominally achiral receptor molecules whose unique guest binding properties and solution characteristics (especially with regard to NMR spectroscopy) allow for the estimation of ee in the corresponding chiral guests.

Intrinsic anisotropy parameters of a series of lanthanoid complexes deliver new insights into the structure-magnetism relationship

Intrinsic anisotropy parameters of a series of lanthanoid complexes deliver new insights into the structure-magnetism relationship

Reversed-phase-HPLC enantioseparation and control of enantiomeric purity of duloxetine using a new chiral reagent and recovery of enantiomers.

This study reports a rapid and low-cost LC method for control of enantiomeric purity of duloxetine. Though duloxetine, as marketed and administered, is expected to be a single (S)-enantiomer, the analysis of a few commercial branded samples by the method developed and presented here showed that they contain a relatively high percentage of (R)-enantiomer (e.g., 2.71-5.42%, which is undesirable in drug formulations). A new chiral derivatizing reagent [isatinyl-(S)-naproxen amide] was synthesized on (S)-naproxen platform. Diastereomeric derivatives were synthesized under microwave irradiation and were separated using reversed-phase-HPLC on a C18 column. A combination of acetonitrile and triethylammonium phosphate buffer (9 mM, pH 4) as the mobile phase and detection at 273 nm were found successful. The diastereomeric derivatives at preparative scale were separated using open column chromatography, and the native enantiomers were obtained and characterized. The HPLC separation method was validated for detection limit, linearity, accuracy, and precision. The limits of detection of (S,R)-diastereomer and (S,S)-diastereomer were found to be 12 and 16 pg/mL, respectively, for the 20-μL injected volume. The method so developed has a practical significance and greater societal impact in establishing the control of enantiomeric purity and in ensuring the enantiomeric purity of the drug meant for human consumption.

Development of chiral bisphosphoric acid/boronic acid co-catalyst system for enantioselective SN2’ reaction

An enantioselective intramolecular SN2’ reaction of geometrically defined allylic substrates was developed by introducing a co-catalyst system composed of chiral bisphosphoric acid and phenylboronic acid. In the enantioselective nucleophilic substitution reaction using chiral phosphoric acids and derivatives (CPAs) as the catalyst, the formation of the corresponding CPA ester, which is afforded through the SN2 reaction of the substrate with the nucleophilic phosphate anion generated during the activation of a leaving group, has been a serious problem because of the catalyst deactivation. The developed co-catalyst system surmounted this fundamental problem by efficiently suppressing the catalyst deactivation process to afford enantioenriched vinyl epoxides in good yields with moderate to high enantioselectivities. Mechanistic elucidation of the present enantioselective intramolecular SN2’ reaction using the co-catalyst system revealed that the leaving group is involved in the enantio-determining transition states, and the anti-SN2’ pathway is considered to be the rational mechanism of the present allylic substitution reaction. In addition, the stereospecific Meinwald rearrangement of the thus-formed enantioenriched vinyl epoxide was aided by an equimolar amount of a Lewis acid, affording the corresponding all-carbon quaternary α-vinyl cyclohexanone without marked loss of enantiomeric purity.

Seven-Step Total Synthesis of Sporothriolide.

An enantioselective total synthesis of sporothriolide, a bioactive furofurandione-type fungal metabolite, has been achieved in a 21% overall yield from a commercially available β,γ-unsaturated carboxylic acid via seven steps. The key steps of this synthesis include a highly diastereoselective Michael addition of a chiral oxazolidinone derivative to a nitro olefin, the exploitation of an aromatic ring as a masked carboxylic acid functionality, and the base-promoted elimination of nitrous acid to install the α-methylene lactone unit of sporothriolide in the final step.

Synthesis and structures of three new pyridine-containing oxazoline ligands of complexes for asymmetric catalysis.

Three new chiral pyridine-containing oxazoline derivatives with fluorine and perfluoromethyl groups, namely, 2-({2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C21H16F3N3O, 2-({5-fluoro-2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C18H17F4N3O, and 2-({2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C22H16F3N3O, as chiral ligands in metal-catalysed asymmetric reactions, were synthesized and characterized by spectral and X-ray diffraction methods. The conformation of the molecules is influenced by strong N-H...N hydrogen bonding and weak C-H...X (X= O and N) interactions. There are no intermolecular hydrogen bonds in the crystal structures of the analysed compounds. Hirshfeld surface analysis showed that the H...H contacts constitute a high percentage of the intermolecular interactions. The conformational analysis was performed by theoretical calculations using the density functional theory (DFT) method. The mechanism of complex formation in terms of the electron-withdrawing effect of the substituents on the oxazoline ring and the ligand conformation is discussed.

Efficient Asymmetric Simmons-Smith Cyclopropanation and Diethylzinc Addition to Aldehydes Promoted by Enantiomeric Aziridine-Phosphines

During an implementation of current research, a set of optically pure chiral aziridines and aziridine imines bearing a phosphine moiety was prepared with high values of chemical yield. The above chiral heteroorganic derivatives were tested for catalytic utility as chiral ligands in asymmetric Simmons-Smith cyclopropanation and asymmetric diethylzinc addition to various aldehydes. Most of the desired products were formed in high chemical yields, with satisfactory values of enantiomeric excess (sometimes more than 90%) and diastereomeric ratios (in case of cyclopropanation reaction).

Mechano‐Optical Response of Novel Polymer Composites Based on Elastic Polyurethane Matrix Filled with Low‐Molar‐Mass Cholesteric Droplets

AbstractAmong the various types of liquid crystalline (LC) structures, the cholesteric mesophase attracts special attention in view of helical supramolecular structure determining their specific optical properties. The helix pitch of cholesteric liquid crystals is very sensitive to mechanical stress, resulting in change of their optical properties and position of selective light reflection peak. Here, films of polymer‐dispersed cholesteric liquid crystals based on polyurethane elastomer are prepared and studied. Liquid crystal mixtures based on chiral cholesterol derivatives are uniformly dispersed in the form of micrometer‐sized droplets in an elastomeric matrix. A significant mechano‐optical response of the composites under the action of deformation is demonstrated, and the change in the position of the selective light reflection band during mechanical stress is studied in detail. A shift in the selective light reflection peak by 100 nm or more is found. This process is accompanied by color transformations of brightly colored films. Such materials can be promising for creating stress and deformation sensors, ripple and bending sensors, and other technical devices.

Gas Chromatography Multiresidue Method for Enantiomeric Fraction Determination of Psychoactive Substances in Effluents and River Surface Waters

Determination of psychoactive substances (PAS) and/or their metabolites in surface waters is crucial for environmental risk assessment, and disclosure of their enantiomeric fractions (EF) allows discrimination between consumption, direct disposal, and synthesis pathways. The aim of this study was to develop and validate an indirect method by gas chromatography coupled to mass spectrometry (GC–MS) based on derivatization using (R)-(−)-α-methoxy-α-(trifluoromethyl) phenylacetyl chloride as chiral derivatization reagent, for enantiomeric quantification of amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxymethamphetamine (MDMA), norketamine, buphedrone (BPD), butylone, 3,4-dimethylmethcathinone (3,4-DMMC), 3-methylmethcathinone, and quantification of 1-benzylpiperazine and 1-(4-metoxyphenyl)-piperazine. The method allowed to evaluate the occurrence, spatial distribution, and the EF of the target chiral PAS in Portuguese surface waters and in effluents from 2 wastewater treatment plants (WWTP). For that, water samples were pre-concentrated by solid phase extraction using OASIS® MCX cartridges, derivatized and further analyzed by GC–MS. Both enantiomers of AMP, (R)-MDMA, (S)-MAMP, and the first eluted enantiomer of BPD (configuration not assigned) were found in surface waters, while effluent samples showed both enantiomers of MDMA, (S)-MAMP, (R)-AMP, and the first eluted enantiomer of BPD and 3,4-DMMC. According to our knowledge, this is the first multiresidue analytical method by CG–MS enrolling cathinones, amphetamines, and piperazines. The presence of illicit synthetic cathinones in Douro River estuary is here reported for the first time, along with other amphetamine derivatives. The potential of the method to monitor consumption of the target PAS was demonstrated.

Enantioselective Synthesis of SpirothiazolonesviaCooperative Catalysis

AbstractCooperative amino‐ and palladium catalysis utilizing heterocyclic systems containing strongly coordinating and adsorptive sulfur atom remains an underdeveloped area. Herein, we describe an enantioselective cyclization of enals with thiazole derivatives catalyzed with the combination of achiral Pd(0) complexes and chiral secondary amines. Chiral spirocyclic thiazolones were produced in yields ranging from 41% to 98% with stereoselectivities (from 5:1 to 12:1 dr, and 95–99% ee). Moreover, the developed strategy allows access to highly substituted chiral cyclopentane derivatives by additional transformations of spirocyclic thiazolones.magnified image

Atroposelective Synthesis of Conjugated Diene-Based Axially Chiral Styrenes via Pd(II)-Catalyzed Thioether-Directed Alkenyl C-H Olefination.

The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd(II)-catalyzed thioether-directed alkenyl C-H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.

Directed evolution of formate dehydrogenase and its application in the biosynthesis of L-phenylglycine from phenylglyoxylic acid

Formate dehydrogenase (FDH) is a d-2‑hydroxy acid dehydrogenase, and catalyzes the oxidation of formate to carbon dioxide, coupled with reduction of NAD+ to NADH that plays a key role in the process of NADH regeneration. In order to obtain high activity formate dehydrogenase mutants, the formate dehydrogenase CbFDHC23S was used as the parent to conduct two rounds of directed evolution, and a mutant M2 was obtained which specific activity was about 4 times more than the parent and was more suitable for coenzyme regeneration under physiological conditions. Then, the molecular mechanism of temperature characteristic and catalytic efficiency change was preliminarily elucidated by computer-aided method. Finally, an engineered E. coli strain was established to co-express formate dehydrogenase and l-leucine dehydrogenase and enantioselectively transform phenylglyoxylic acid to give l- phenylglycine (e.e. >99%), the yield and space-time yield of l- phenylglycine can reach 90.46% and 82.07 g·L−1·d−1. This study laid a theoretical foundation for the green biosynthesis of food additives such as chiral alcohols and amino acid derivatives catalyzed by FDH coupling to enhance the regeneration capacity of NADH, reduce the regeneration cost of NADH, and achieve high efficiency and low cost.

Rapid chiral discrimination of oncometabolite dl-2-hydroxyglutaric acid using derivatization and field asymmetric waveform ion mobility spectrometry/mass spectrometry.

2-Hydroxyglutaric acid is a chiral metabolite whose enantiomers specifically accumulate in different diseases. An enantiomeric excess of the d-form in biological specimens reflects the existence of various pathogenic mutations in cancer patients, however, conventional methods using gas or liquid chromatography and capillary electrophoresis had not been used for large clinical studies because they require multiple analytical instruments and a long run time to separate the enantiomers. Here, we present a rapid separation method for dl-2-hydroxyglutaric acid using a chiral derivatizing reagent and field asymmetric waveform ion mobility spectrometry/mass spectrometry, which requires a single analytical instrument and <1 s for the separation. We compared three derivatization methods and found that a method using (S)-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrrolidin-3-amine enables the separation. In addition, we were able to detect dl-2-hydroxyglutaric acid in standard solution at lower concentrations than that previously reported for the serum. These results show the potential of the method to be used in clinical analysis.

A β-cyclodextrin covalent organic framework used as a chiral stationary phase for chiral separation in gas chromatography

Chiral covalent organic frameworks (CCOFs) featuring chirality, stability, and good porosity have attracted a considerable amount of attention due to their important applications, such as asymmetric catalysis, chiral separation, and chiral recognition. In this study, a β-cyclodextrin (β-CD) covalent organic framework (β-CD-COF) diluted with polysiloxane OV-1701 was explored as a novel chiral stationary phase (CSP) for gas chromatography (GC) separation of racemates. The β-CD-COF coated capillary column had excellent selectivity, not only for the separation of linear alkanes, linear alcohols, fatty acid methyl esters mixture, the Grob mixture and positional isomers, but also for the resolution of chiral compounds, including chiral alcohols, aldehydes, ethers, and amino acid derivatives. In addition, the β-CD-COF-coated capillary column presented good repeatability and reproducibility. This work indicated the great potential of the CCOFs coated capillary column for the chromatographic separation of enantiomers.

Isocyanate derivatization coupled with phospholipid removal microelution-solid phase extraction for the simultaneous quantification of (S)-metoprolol and (S)-α-hydroxymetoprolol in human plasma with LC–MS/MS

A sensitive liquid chromatography-tandem mass spectrometry (LC–MS/MS) assay was developed and validated for the quantification of (S)-metoprolol (MET) and its main metabolite, (S)-α-hydroxymetoprolol (OH-MET). Human plasma samples (50 μL) were spiked with both analytes and their deuterated internal standards (IS) (S)-MET-(d7) and α-OH-MET-(d5). Phospholipid removal microelution-solid phase extraction (PRM-SPE) was performed using a 4-step protocol with Oasis PRiME MCX μElution 96-well cartridges. The eluates were reconstituted in 100 μL of acetonitrile with 50 μg/mL (S)-α-methylbenzyl isocyanate (MBIC) for chiral derivatization. After 60 min at room temperature, the reaction was quenched using 100 μL of water 2 % formic acid. Chromatographic separation of the derivatized analytes was performed on a Kinetex phenyl-hexyl core-shell stationary phase with an elution gradient. Mobile phases were composed of a mixture of water and methanol, with ammonium formate and formic acid as buffers. Total runtime was 15 min. Analyte detection was performed by an AB/SCIEX 4000 QTRAP mass spectrometer with multiple reaction monitoring. Chromatograms showed MBIC successfully reacted with racemic MET, α-OH-MET, and their respective IS. Detection by positive electrospray ionization did not reveal derivatized by-products. Quantification ranges were validated for (S)-MET and (S)-α-OH-MET between 0.5–500 and 1.25−500 ng/mL, respectively, with correlation coefficients (r2) >0.9906. The PRM-SPE assay showed low matrix effects (86.9–104.0 %) and reproducible recoveries (69.4–78.7 %) at low, medium, and high quality control (QC) levels. Precision and accuracy were all comprised between 85–115 % for all three QCs, and between 80–120 % for the lower limit of quantification, for intra- and inter-day values (n = 6, 3 consecutive days). Non-derivatized analytes were stable at room temperature, after 3 freeze-thaw cycles, and stored for 30 days at −80 °C (n = 4). Reinjection reproducibility of a previously validated batch was achieved after 8 days under auto-sampler conditions, indicating the stability of (S)-MET and (S)-α-OH-MET derivatives. Its clinical use was established in a cohort of 50 patients and could be used to further investigate the clinical impact of (S)-MET concentrations.

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Nicotinamide-based supergelator self-assembling via asymmetric hydrogen bonding NH⋯OC and H⋯Br− pattern for reusable, moldable and self-healable nontoxic fuel gels

HypothesisDevelopment of highly efficient low-molecular weight gelators (LMWGs) for safe energy storage materials is of great demand. Energy storage materials as fuel gels are often achieved by construction of hybrid organic frameworks capable of multiple noncovalent interactions in self-assembly, which allow tuning required properties at the molecular level by altering individual building blocks of the LMWG. However, LMWGs have limited rechargeable capability due to their chemical instability. ExperimentsWe designed, synthesized and characterized a novel, bio-inspired chiral gemini amphiphile derivative 1 containing N-hexadecyl aliphatic tails from quaternized nicotinamide-based segment and bromide anion showing supergelation ability in water, alcohols, aprotic polar and aromatic solvents, with critical gel concentrations as low as 0.1 and 0.035 wt% in isopropanol and water, respectively. FindingsNanostructural architecture of the network depended on the solvent used and showed variations in size and shape of 1D nanofibers. Supergelation is attributed to a unique asymmetric NH⋯OC, H⋯Br− hydrogen bonding pattern between H-2 hydrogens from nicotinamide-based segment, amide functional groups from chiral trans-cyclohexane-1,2-diamide-based segment and bromide ions, supporting the intermolecular amide–amide interactions appearing across one strand of the self-assembly. Gels formed from 1 exhibit high stiffness, self-healing, moldable and colorable properties. In addition, isopropanol gels of 1 are attractive as reusable, shape-persistent non-toxic fuels maintaining the chemical structure with gelation efficiency for at least five consecutive burning cycles.