Diastereoselective Research Articles

How To Control Recognition: From Brucinium Double Salts to Racemic Resolution

Studying the mechanisms of racemic resolution of the model compound N-(3-nitrobenzoyl)aspartic acid by formation and fractional crystallization of brucinium diastereomeric salts, we found that depending on the environment (solvents) the recognition leads to effective or ineffective racemic resolution. During successful racemic resolution, bis(brucinium)-N-(3-nitrobenzoyl)-l-aspartate hydrate methanol solvate precipitates as the first fraction. In turn, double salts and solid solution are formed in the fruitless racemic resolution. Formation of the double salt results from recognition of centrosymmetric anionic dimers on the common brucinium corrugated layer. The common brucinium corrugated layer together with its solvation sphere participates in recognition of the anions, leading to formation of the solid solution. Changing the solvent system according to its dielectric constant, more dispersive or more directional interactions gain importance. The racemic resolution and formation of bis(brucinium)-N-(3-n...

Enantioselective retention mechanisms of dipeptides on antibiotic-based chiral stationary phases: Leucyl-leucine, glycyl-leucine, and leucyl-glycine as case studies

Chromatographic behaviors of dipeptides consisting of leucine and glycine were studied on two antibiotic-based chiral stationary phases (CSPs) with teicoplanin (Chirobiotic T) or ristocetin A (Chirobiotic R) as chiral selectors under reversed-phase conditions. The effect of mobile phase pH on the retention of stereoisomers of dipeptides was investigated and thermodynamic characteristic of adsorption were measured at different pH values. It was shown that the retention of dipeptides depends on the ionization of their molecules in the mobile phase, as different ionic forms have different affinity towards antibiotic selectors. Enantioselectivity of the bound antibiotics with respect to Leu-Leu stereoisomers was achieved via steric modulation of ion-ion interactions between the solute and the selector, while in the case of Gly-Leu enantiomers non-ionic interactions such as hydrogen bonding might play the key role. In both cases, the dipeptides terminating in D-Leu were retained stronger than their optical antipodes, whereas the enantiomers of Leu-Gly were hardly separated. The regression analysis of the retention data applying the Horvath-Melander-Molnar model revealed that different types of enantioselectivity resides in particular ionic forms of the compounds: cations are responsible for the separation of diastereomeric pairs and the anionic and zwitterionic forms have a universal enantioselectivity on the Chirobiotic T CSP, and the anions and zwitterions are the enantioselective forms for the Chirobiotic R CSP.

Structural Analysis ofd-Phenylglycinamide Salts Uncovers Potential Pitfalls in Chiral Resolution via Diastereomeric Salt Formation

d-Phenyglycinamide (d-PGA) was shown to form diastereomeric salts with a series of dicarboxylic acids (malic, methylsuccinic, camphoric) and the drug naproxen. Structural analysis of the 21 newly d...

Selective Synthesis of Interlocked Molecules with Topological Chirality

Mechanically interlocked molecules can be chiral if each of the rings has no bilateral symmetry. Although chiral catenanes have been isolated from racemic mixtures via chromatographic techniques, these optically active molecules have not been directly synthesized until now. In this issue of Chem, Goldup and co-workers describe an auxiliary approach for the stereoselective synthesis of the topological enantiomers of chiral [2]catenanes. This methodology enables exploration of the potential applications of these chiral molecules in areas such as medicine and materials science.

New homochiral and heterochiral Mo(VI) complex from racemic ligand: Synthesis, X-ray structure, diastereomers separation and biological activities

A diastereomeric pair (homochiral and heterochiral) of Schiff base dioxo molybdenum complex was synthesized using chiral ligand (HL: R/S-1-((naphtalen-3-yl)methylenamino)propan-2-ol) in racemic form. Then, to separation of this diastereomeric pair, crystallization method was proposed which was successful with acetonitrile. 1H NMR technique was used to confirm the results. The complexes thoroughly characterized using FT-IR, elemental analysis, 1H NMR and 13C NMR techniques, and MoO2L(LH2)1 has been structurally characterized using single-crystal X-ray diffraction. The cytotoxic activity of the new compounds has been evaluated using MCF-7 (human breast adenocarcinoma) and HeLa (human cervix adenocarcinoma), in addition to normal human fibroblast cells using the MTT cytotoxicity assay. Compounds MoO2L(LH2)1 and MoO2L(LH2)2 revealed IC50 values 18 µM and 37 µM on MCF-7 and 58 µM and 17 µM on HeLa, respectively. MoO2L(LH2)2 showed high selectivity (3–13 folds) for cancerous cells over normal cells, as the maximum cell mortality of 8.77%. Furthermore, The HSA- and DNA-binding of the Mo(VI) complexes were investigated by absorption, emission spectroscopy, viscosity measurements and molecular docking. Their binding constant are calculated as: HSA-binding of MoO2L(LH2)1 is 6.7 × 104 M−1 and of MoO2L(LH2)2 is 5.8 × 104 M−1, while their DNA-binding are 5.6 × 104 M−1 and 2.2 × 105 M−1, respectively. Their thermodynamic parameters were also determined at different temperatures.

A Triskelion-Shaped Saddle-Helix Hybrid Nanographene.

A unique rippled nanographene consisting of 52 fused rings is presented in which six out-of-plane motifs are fully fused into a triangular aromatic surface with a size of approximately 2.5 nm. Three units of an unprecedented fully lateral π-extended octabenzo[5]helicene together with three units of saddle-shaped heptagonal rings are combined in a single structure, leading to a well-soluble warped nanographene. The two diastereomeric pairs of possible enantiomers were isolated, and their linear, non-linear, and chiroptical properties were evaluated, revealing outstanding quantum yield and brightness values at low energy, together with good chiroptical responses in both absorption and emission.

A Triskelion‐Shaped Saddle–Helix Hybrid Nanographene

AbstractA unique rippled nanographene consisting of 52 fused rings is presented in which six out‐of‐plane motifs are fully fused into a triangular aromatic surface with a size of approximately 2.5 nm. Three units of an unprecedented fully lateral π‐extended octabenzo[5]helicene together with three units of saddle‐shaped heptagonal rings are combined in a single structure, leading to a well‐soluble warped nanographene. The two diastereomeric pairs of possible enantiomers were isolated, and their linear, non‐linear, and chiroptical properties were evaluated, revealing outstanding quantum yield and brightness values at low energy, together with good chiroptical responses in both absorption and emission.

New Discoveries in Enantiomeric Separation of Racemic Tofisopam

Resolution process of tofisopam has been re-evaluated now based on our new investigations. Originally, it was carried out in the water-chloroform system, where the intermediate salt of high diastereomeric excess was described as (R)-TOF·(R,R)-DBTA·(H2O)3. Opposed to previous assumptions, we have actually found that a different solvate composition, (R)-TOF‐(R,R)-DBTA-CHCl3, forms with chloroform, in which molecules of CHCl3 are captured and held with different strengths. Moreover, resolution of TOF with (R,R)-DBTA is possible (and favourable) in water-free solvent and solvent mixture. However, presence of chloroform is essential, and thus, chloroform is also a suitable solvent alone. Among the tested solvents, toluene-chloroform mixture results in the highest resolution efficiency, while the highest enantiomeric purity was achieved when acetonitrile was in the system too. Resolution efficiency can be also increased by using the quasi-racemic resolving agent and thermodynamic control. Purification of enantiomeric mixtures was examined, and recrystallization of the diastereomeric salt was found to be the most efficient solution. Instructive behaviour of the complex enantiomer-conformer system of tofisopam is emphasized.

All-Fullerene Electron Donor-Acceptor Conjugates.

The synthesis and characterization of a covalent all-fullerene C60 -Lu3 N@Ih -C80 electron donor-acceptor conjugate has been realized by sequential 1,3-dipolar cycloaddition reactions of azomethine ylides on Lu3 N@Ih -C80 and C60 . To the best of our knowledge, this is the first time that two fullerenes behaving as both electron donor (Lu3 N@Ih -C80 ) and acceptor (C60 ) are forming an electroactive dumbbell. DFT calculations reveal up to 16 diastereomeric pairs, that is, 8 with syn and 8 with anti orientation, with the anti-RSSS isomer being the most stable. Spectroelectrochemical absorption and femtosecond transient absorption experiments support the notion that a C60 ⋅- -Lu3 N@Ih -C80 ⋅+ charge-separated state is formed. Spin conversion from the charge-separated singlet state C60 ⋅- -Lu3 N@Ih -C80 ⋅+ into the corresponding triplet state is facilitated by the heavy-atom effect stemming from the Lu3 N-cluster, which, in turn, slows down the charge recombination by one order of magnitude.

All‐Fullerene Electron Donor–Acceptor Conjugates

AbstractThe synthesis and characterization of a covalent all‐fullerene C60‐Lu3N@Ih‐C80 electron donor–acceptor conjugate has been realized by sequential 1,3‐dipolar cycloaddition reactions of azomethine ylides on Lu3N@Ih‐C80 and C60. To the best of our knowledge, this is the first time that two fullerenes behaving as both electron donor (Lu3N@Ih‐C80) and acceptor (C60) are forming an electroactive dumbbell. DFT calculations reveal up to 16 diastereomeric pairs, that is, 8 with syn and 8 with anti orientation, with the anti‐RSSS isomer being the most stable. Spectroelectrochemical absorption and femtosecond transient absorption experiments support the notion that a C60⋅−‐Lu3N@Ih‐C80⋅+ charge‐separated state is formed. Spin conversion from the charge‐separated singlet state C60⋅−‐Lu3N@Ih‐C80⋅+ into the corresponding triplet state is facilitated by the heavy‐atom effect stemming from the Lu3N‐cluster, which, in turn, slows down the charge recombination by one order of magnitude.

Model Building on Selectivity of Gas Antisolvent Fractionation Method Using the Solubility Parameter

Solubility parameters are widely used in the polymer industry and are often applied in the high pressure field as well as they give the possibility of combining the effects of all operational parameters on solubility in a single term. We demonstrate a statistical methodology to apply solubility parameters in constructing a model to describe antisolvent fractionation based chiral resolution, which is a complex process including a chemical equilibrium, precipitation and extraction as well. The solubility parameter used in this article, is the Hansen parameter. The evaluation of experimental results of resolution and crystallization of ibuprofen with (R)-phenylethylamine based on diastereomeric salt formation by gas antisolvent fractionation method was carried out. Two sets of experiments were performed, one with methanol as organic solvent in an undesigned experiment and one with ethanol in a designed experiment. The utilization of D-optimal design in order to decrease the necessary number of experiments and to overcome the problem of constrained design space was demonstrated. Linear models including dependence of pressure, temperature and the solubility parameter were appropriate to describe the selectivity of the GASF optical resolution method in both sets of experiments.

Resolution of ibuprofen with primary amine carbamates in supercritical carbon dioxide

Three new, successful resolving agents, namely (S)-2-phenylglycinol, (R)-1-phenylethanaminium (R)-(1-phenylethyl) carbamate and (S)-2-hydroxy-1-phenylethanaminium (S)-(2-hydroxy-1-phenylethyl) carbamate of ibuprofen are presented. The carbamate salts are stable white crystals, they can be easily stored and handled. All salt forming resolution were performed in supercritical carbon dioxide as the only solvent. The enantioseparations were efficient (approx. 50 % enantiomeric purities, > 90 % yields in the crystalline phase) and robust. Unlike previous experiences with primary amine resolving agents, the diastereomeric salt formations and resolutions were competed in short times, even within one hour suggesting that the carbamates are intermediates of the salt formation reaction.

Solid acid catalyzed aldol dimerization of levulinic acid for the preparation of C10 renewable fuel and chemical feedstocks

The acid catalyzed condensation of levulinic acid was studied using a series of solid acid catalysts: Amberlyst-15, SiO2-SO3H, Dowex50WX8, Carbon-SO3H, TiO2-SO3H, Al2O3-SO3H, H3PW12O40, and Nb2O5.H2O under neat conditions at 110–130 °C. The major dimerization product was identified as tetrahydro-2-methyl-5,γ-dioxo-2-furanpentanoic acid. In addition, four minor products were identified as diastereomeric pairs of 3-(2-methyl-5-oxo-tetrahydrofuran-2-yl)-4-oxopentanoic acid and 3-acetyl-2-methyl-tetrahydro-5-oxo-2-furanpropanoic acid by spectroscopic and computational methods. A mechanism is proposed to explain the formation of five dimerization products where the major product is formed via the aldol condensation of C5 enol form of levulinic acid and four minor products are arising from the aldol condensations C3 enol form of levulinic acid. The highest total yield 56% was obtained with the use SiO2-SO3H as the solid acid catalyst and the reminder of the mass balance was unreacted levulinic acid. The SiO2-SO3H catalyst could be recycled four times with some loss in catalytic activity.

The relative toxicity of brodifacoum enantiomers

Brodifacoum (BDF) is a potent, long-acting anticoagulant rodenticide that can cause fatal poisoning in humans. The chemical structure of BDF includes 2 chiral carbons, resulting in 2 pairs of diastereomers, BDF-cis (R/S and S/R) and BDF-trans (R/R and S/S). However, the relative potency of these molecules is not known. The purpose of this study was to compare the in vitro and in vivo toxic effects of the 2 BDF diastereomer pairs. In adult Sprague-Dawley rats BDF-cis was significantly more toxic than BDF-trans (LD50 values of 219 versus 316 μg/kg, respectively) while racemic BDF had intermediate potency (266 μg/kg). In adult New Zealand white rabbits, BDF-cis had a longer half-life than BDF-trans which could contribute to its observed increased toxicity. Lastly, BDF-cis (10 μM), but not BDF-trans, damaged cultured SH-SY5Y human neuroblastoma cells by attenuating mitochondrial reductive capacity. Taken together, these data suggest that different toxic manifestations of BDF poisoning in mammals could be attributed, in part, to differences in relative enantiomer concentrations present in racemic formulations of this commercially-available toxicant.

The rotameric (R*,S*)- and (R*,R*)-biaryl-3,3′-diphthalides of polyphenylene series

A wide range of diastereomeric pairs of biaryl-3,3′-diphthalides with aromatic (heteroaromatic) substituents of polyphenylene series (including halogen substituted) was synthesized. All of them were separated and characterized by the methods of X-ray analysis, HPLC, IR-, 1H and 13C NMR spectroscopy. It was determined that solubility, tendency to adsorption and related to it retention times, chemical shifts of equivalent hydrogen and carbon atoms of biaryl-3,3′-diphthalides diastereoisomers are determined firstly by the stereo-electronic effects of two adjacent strongly polar phthalide groups. It was shown that both in crystalline phase and in solution all the diphthalides, regardless of the chemical structure of their substituents, are existing as stable rotamers with cis or synperiplanar (chiral forms) and trans or antiperiplanar (meso-forms) conformation.

Biotransformed Metabolites of the Hop Prenylflavanone Isoxanthohumol.

A metabolic conversion study on microbes is known as one of the most useful tools to predict the xenobiotic metabolism of organic compounds in mammalian systems. The microbial biotransformation of isoxanthohumol (1), a major hop prenylflavanone in beer, has resulted in the production of three diastereomeric pairs of oxygenated metabolites (2–7). The microbial metabolites of 1 were formed by epoxidation or hydroxylation of the prenyl group, and HPLC, NMR, and CD analyses revealed that all of the products were diastereomeric pairs composed of (2S)- and (2R)- isomers. The structures of these metabolic compounds were elucidated to be (2S,2″S)- and (2R,2″S)-4′-hydroxy-5-methoxy-7,8-(2,2-dimethyl-3-hydroxy-2,3-dihydro-4H-pyrano)-flavanones (2 and 3), (2S)- and (2R)-7,4′-dihydroxy-5-methoxy-8-(2,3-dihydroxy-3-methylbutyl)-flavanones (4 and 5) which were new oxygenated derivatives, along with (2R)- and (2S)-4′-hydroxy-5-methoxy-2″-(1-hydroxy-1-methylethyl)dihydrofuro[2,3-h]flavanones (6 and 7) on the basis of spectroscopic data. These results could contribute to understanding the metabolic fates of the major beer prenylflavanone isoxanthohumol that occur in mammalian system.

Brønsted Acid Catalyzed Diastereoselective [4+3] Cycloaddition

Brønsted Acid Catalyzed Diastereoselective [4+3] Cycloaddition

Chiral Tetraaryl‐ and Tetraalkynylborates as Chiral Solvating Agents for Tetraalkylammonium Salts

The application of tetracarbon‐substituted chiral borate sodium salts (NaBR*4) as NMR chiral solvating agents for various tetraalkylammonium salts (R4NX) has been successfully demonstrated. Ion exchange between R4NX and NaBR*4 proceeded in excellent yields and provided the corresponding diastereomeric salts (R4NBR*4). The ee values of the R4NX salts were determined by 1H NMR analysis of R4NBR*4. Two types of chiral borates, tetraaryl‐ and tetraalkynylborates with optically active 1,1′‐binaphthyl components were used. At the beginning of this research, we investigated the efficacy of a known chiral tetraarylborate developed by Pommerening et al. for R4NX. To expand the possibility of further structural design of the chiral borate, we designed chiral tetraalkynylborates as a new structure. Their synthesis and application are also described.

Selectivity evaluation of phenyl based stationary phases for the analysis of amino acid diastereomers by liquid chromatography coupled with mass spectrometry

D-amino acids (AA) analysis is becoming more and more relevant for metabolomics, therefore new analytical tools need to be developed. A common approach to achieve AA enantioseparation is chiral derivatization. Among the chiral derivatization reagents, (+) or (-)-1-(9-fluorenyl) ethyl chloroformate ((+) or (-)-FLEC) has proved to be one of the most versatile. Suitable chiral selectivity for FLEC derivatives of amino acids could be obtained in reversed-phase HPLC using nonpolar stationary phases (C4, C8 and C18) and tetrahydrofuran (THF) based mobile phases. This study is meant to provide alternatives to the use of THF as organic modifier by evaluating the selectivity obtained on two phenyl based stationary phases for 19 FLEC-DL-AA pairs of diastereomers using UHPLC-MS. Several mobile phases consisting of ammonium acetate and different common organic solvents (acetonitrile (ACN), methanol (MeOH), 2-propanol (IPA)) were tested using gradient elution. Experimental design was employed for the optimization of the separation conditions. In the optimized conditions, complete chiral separation can be achieved for 18 out of 19 FLEC-DL-AAs in less than 30 min.

Investigating the isolation and interconversion of two diastereoisomers in an octahedral system

Two diastereoisomers of bis(2-benozylpyridine-O,N)dichloridonickel(ii) have been prepared, and experimentally and theoretically studied.