Selector Screening for Enantioseparation of dl‐α‐Methyl Phenylglycine Amide by Liquid–Liquid Extraction

Enantioseparation through liquid extraction technology is an emerging field, e.g., enantioseparations of amino acids (and derivatives thereof), amino alcohols, amines, and carboxylic acids have been reported. Often, when a new selector is developed, the versatility of substrate scope is investigated. From an industrial point of view, the problem is typically approached the other way around, and for a target racemate, a selector needs to be found in order to accomplish the desired enantioseparation. This study presents such a screening approach for the separation of the enantiomers of dl ‐α‐methyl phenylglycine amide (dl ‐α‐MPGA), a model amide racemate with high industrial relevance. Chiral selectors that were reported for other classes of racemates were investigated, i.e., several macrocyclic selectors and Pd‐BINAP complexes. It appeared very challenging to obtain both high extraction yields and good enantioselectivity for most selectors, but Pd‐BINAP‐based selectors performed well, with enantioselectivities up to 7.4 with an extraction yield of the desired enantiomer of 95.8%. These high enantioselectivities were obtained using dichloromethane as solvent. Using less volatile chlorobenzene or 1‐chloropentane, reasonable selectivities of up to 1.7 were measured, making these the best alternative solvents for dichloromethane. Chirality 27:123–130, 2015. © 2014 Wiley Periodicals, Inc.     

Studies on Enantioselective Liquid–Liquid Extraction of Amino‐(4‐nitro‐phenyl)‐acetic Acid Enantiomers: Modeling and Optimization

BINAP‐metal complexes were prepared as extractant for enantioselective liquid–liquid extraction (ELLE) of amino‐(4‐nitro‐phenyl)‐acetic acid (NPA) enantiomers. The influence of process variables, including types of organic solvents and metal precursor, concentration of ligand, pH, and temperature on the efficiency of the extraction, were investigated experimentally. An interfacial reaction model was established for insightful understanding of the chiral extraction process. Important parameters required for the model were determined. The experimental data were compared with model predictions to verify the model prediction, It was found that the interfacial reaction model predicted the experimental results accurately. By modeling and experiment, an optimal extraction condition with pH of 7 and host (extractant) concentration of 1 mmol/L was obtained and high enantioselectivity (α_op) of 3.86 and performance factor (pf) of 0.1949 were achieved. Chirality 26:79–87, 2014. © 2013 Wiley Periodicals, Inc.     

Synthesis of CuPF6‐(S)‐BINAP loaded resin and its enantioselectivity toward phenylalanine enantiomers

A type of resin‐anchored CuPF₆‐(S )‐BINAP was synthesized and identified. The PS‐CuPF₆‐(S )‐BINAP resin was used to adsorb the phenylalanine enantiomers. The results showed that the adsorption capacity of PS‐CuPF₆‐(S )‐BINAP resin toward L‐phenylalanine was higher than that of resin toward D‐phenylalanine. PS‐CuPF₆‐(S )‐BINAP resin exhibited good enantioselectivity toward L‐phenylalanine and D‐phenylalanine. The influence of phenylalanine concentration, pH, adsorption time, and temperature on the enantioselectivity of the resin were investigated. The results showed that the enantioselectivity of the resin increased with increasing the phenylalanine concentration, pH, and adsorption time, while it decreased with an increase in temperature. The causes for these influences are discussed. The highest enantioselectivity (α = 2.81) was obtained when the condition of phenylalanine concentration was 0.05 mmol/mL, pH was 8, adsorption time was 12 h, and temperature 5°C. The desorption test for removing D/L‐phenylalanine on PS‐CuPF₆‐(S )‐BINAP resin was also investigated. The desorption ratios of D‐phenylalanine and L‐phenylalanine at pH of 1 were 95.7% and 94.3%, respectively. This result indicated that the PS‐CuPF₆‐(S )‐BINAP resin could be regenerated by shaking with an acidic solution. The reusability of the PS‐CuPF₆‐(S )‐BINAP resin was also assessed and the resin exhibited considerable reusability.     

Synthesis, characterization and application of Ru(BINAP) (Acac) (MNAA) (MeOH), a highly effective catalyst for the asymmetric hydrogenation of 2-(6′-methoxynaphth-2′-yl)acrylic acid

Ru(S-BINAP) (Acac) (MNAA) (MeOH) (1) (where MNAA (2) = 2-(6′-methoxynaphth-2′-yl)acrylate anion), a highly effective catalyst for the asymmetric hydrogenation of 2-(6′-methoxynaphth-2′-yl) acrylic acid (3), was isolated from a dichloromethane/methanol (vol./vol. = 1/4) solution of Ru(S-BINAP) (Acac)₂ and excess of 2-(6′-methoxynaphth-2′-yl)acrylic acid after the solution was exposed to visible light for 2 weeks. On side by side comparison studies, the rate of the hydrogenation of 3 catalyzed by 1 was found to be substantially faster than the same reaction catalyzed by Ru(S-BINAP) (OAc)₂. The molecular structure of 1 was unambiguously characterized by single crystal X-ray diffraction.     

Control of optically active structure of thioether-phthalocyanine aggregates by chiral Pd(II)-BINAP complexes in toluene and at the toluene/water interface

The Pd(II)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP)-mediated chiral assembly of thioether-derivatised phthalocyanatomagnesium(II) compounds (MgPc(SR)8, SR is benzylthio (SBz) or benzhydrylthio (Bh)) was formed in toluene and at the toluene/water interface, and investigated by means of UV-Vis absorption and circular dichroism (CD) spectroscopy combined with the centrifugal liquid-membrane (CLM) devise. Interfacial tension measurements indicated that, in the presence of PdSO4 in the aqueous phase, BINAP ligand adsorbed as a monolayer forming Pd(II)BINAP2+ complex at the toluene/water interface. UV-Vis absorption spectrum of MgPc(SR)8 in the Q-band region was blue-shifted in toluene upon addition of [Pd(II)BINAP]Cl2, but red-shifted at the toluene/water interface when Pd(II)BINAP2+ was formed at the interface. These results suggested that MgPc(SR)8-Pd(II)BINAP complex formed H-aggregate (face-to-face type) in toluene solution and J-aggregate (end-to-end type) at the toluene/water interface, respectively. Moreover, the specific bisignate CD spectral pattern in both systems indicated that the aggregates of MgPc(SR)8-Pd(II)BINAP complexes were chirally twisted, well controlled by the chirality of BINAP ligand. Very interestingly, the morphology of MgPc(SBz)8-Pd(II)BINAP and MgPc(SBh)8-Pd(II)BINAP aggregates formed at the toluene/water interface were significantly different as the rodlike and the ribbonlike crystalline structure, respectively, as observed by a scanning electron microscopy (SEM). On the basis of these experimental results, we proposed schematic molecular models of the chiral aggregates of MgPc(SR)8-Pd(II)BINAP complexes and demonstrated the specific role of the toluene/water interface.     

Synthesis and biological properties of aryl methyl sulfones

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC₅₀ COX-1?=?0.04 and COX-2?=?0.10?μM, and naproxen: IC₅₀ COX-1?=?11.3 and COX-2?=?3.36?μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies.The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.     

Enantioselective liquid‐liquid extraction of DL‐mandelic acid using chiral diphosphine ligands as extractants

In order to expand the application range of chiral diphosphine ligands, (S)‐BINAP, (S)‐SEGPHOS, and (S)‐MeO‐BIPHEP were employed as extractants to recognize DL‐mandelic acid. The results indicated that (S)‐SEGPHOS‐Cu exhibited considerable ability to recognize DL‐mandelic acid with operational enantioselectivity (α) of 2.677. The process of extraction of DL‐mandelic acid using (S)‐SEGPHOS‐Cu as extractant was systematically investigated. Performance factor (pf) was adopted to comprehensively evaluate the extraction. After optimization by response surface methodology (RSM), the optimal extraction condition is temperature of 5.5°C, (S)‐SEGPHOS‐Cu concentration of 3.0 mmol/L, and pH of 8.0. And the predicted and experimental maximum values of pf were 0.26374 and 0.26839, respectively.     

Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of 4′-methyl-6′-substituted aristeromycins

The need of long-term treatment for chronic HBV, emergence of drug-resistant viruses and inefficiency of currently approved therapies to eliminate covalently closed circular DNA (cccDNA), mandates identification of potent and selective inhibitors of HBV replication with novel mechanisms of action. Entecavir, a carbocyclic guanosine nucleoside analog, is the most potent inhibitor of HBV replication on the market. Moreover, the naturally occurring carbocyclic nucleosides aristeromycin are known for their wide range of antiviral activities.

In this research, we have utilized BINAP directed rhodium catalyzed reductive carbocyclization of 1,6-enynes (8a–b) through asymmetric hydrogenation which is an approach, not yet explored in carbocyclic sugar synthesis. Interestingly, we obtained exclusive anti-(9a) and Z-anti (9b) carbocyclic sugars. The new aristeromycin analogs (10a–b) with scaffold combination of entecavir and aristeromycin were then synthesized using the Mitsunobu reaction followed by deprotection.