Highly Enantioselective Fluorescent Recognition of Both Unfunctionalized and Functionalized Chiral Amines by a Facile Amide Formation from a Perfluoroalkyl Ketone

The H₈BINOL‐based perfluoroalkyl ketone (S)‐ 2 is found to exhibit highly enantioselective fluorescent enhancements toward both unfunctionalized and functionalized chiral amines. It greatly expands the substrate scope of the corresponding BINOL‐based sensor. A dramatic solvent effect was observed for the reaction of the amines with compound (S)‐ 2 . In DMF, cleavage of the perfluoroalkyl group of compound (S)‐ 2 to form amides was observed but not in other solvents, such as methylene chloride, chloroform, THF, hexane, and perfluorohexane. Thus, the addition of another solvent, such as THF, can effectively quench the reaction of compound (S)‐ 2 with amines in DMF to allow stable fluorescent measurement. This is the first example that the formation of strong amide bonds under very mild conditions is used for the enantioselective recognition of chiral amines. The mechanism of the reaction of compound (S)‐ 2 with chiral amines is investigated by using various analytical methods including mass spectrometry as well as NMR and UV/Vis absorption spectroscopy.     

Stereoselective tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform: practical synthesis of α-tribromomethyl amines

The unprecedented nucleophilic tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform has been shown to be a highly stereoselective and practical method for the synthesis of enantiomerically pure α-tribromomethyl amines. THF has proven to be the best solvent in this addition reaction. By changing the reaction solvent from THF to DMF, 2,2-dibromoaziridines can also be synthesized directly from bromoform and N-(tert-butanesulfinyl)imines under similar reaction conditions.     

Enhancing the Orienting Properties of Poly(γ‐benzyl‐L‐glutamate) by means of Additives

Residual dipolar couplings (RDCs) have recently become increasingly important in organic structure determination due to their unique information content. One main limitation for the use of RDCs in organic compounds is the orientation that needs to be induced to be able to measure RDCs. So far, there are very few possibilities to modulate the orientational properties of organic solutes and even less when chiral media are considered. Based on our recent findings that the critical concentration of the liquid‐crystalline phase of homopolypeptides depends on their molecular weight, we sought for further ways to modulate the orienting properties. We were especially interested in seeing whether we could not only influence the induced degree of orientation, but whether we could also change the solute′s preferred orientation and even enhance enantiodifferentiation. We thus tried different aprotic and protic additives and were successful in all of the above‐mentioned aspects by using CCl₄ as the additive. Furthermore, we consider DMSO to be a very useful additive. The LC phase of low MW poly(γ‐benzyl‐L ‐glutamate) (PBLG) is usually unstable when DMSO is added. The high MW PBLG used in this study, however, remained stable up to a DMSO/CDCl₃ ratio of 1:2. By using this combination of solvents, the alignment of the two enantiomers of a compound, which is insoluble in CDCl₃, namely, the HCl salt of a tryptophane ester, was possible leading to high‐quality spectra. The two enantiomers of the tryptophane ester showed different couplings, thus indicating that enantiodifferentiation is taking place. Thus we were able to modulate the orienting properties (degree of orientation, preferred orientation and enantiodifferentiation) of PBLG by using additives and to increase the accessible solvent and solute range significantly.     

Copper-based reverse ATRP process of styrene in mixed solvents

Xylene/N,N-dimethylformamide (DMF) and xylene/ethanol were employed as mixed solvents, respectively, for the reverse atom transfer radical polymerization (R-ATRP) of styrene with the azobisisobutyronitrile (AIBN)/CuBr₂/N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA) initiating system. With a limited amount of DMF added in, CuBr₂/PMDETA complex could dissolve well in the reaction system, so the control of polymerization was enhanced compared with the one in which simplex xylene was used as solvent. But the polarity of DMF leaded kinetics to deviation from first order. Ethanol could also improve the solubility of catalyst and be scavenged quickly by argon at 110°, therefore the impact of polarity of solvent on kinetics was negligible. Induction periods were not observed here indicating rapidly establishment of equilibrium between Cu(I) and Cu(II). This method that adding a little amount of polar solvent with low boiling point into non-polar solvent gives a new way to solve the problem of poor solubility of the catalyst in R-ATRP.     

Enantioseparation of mandelic acid enantiomers in ionic liquid aqueous two-phase extraction systems

In the past decade, ionic liquids have received great attention owing to their potential as green solvent alternatives to conventional organic solvents. In this work, hydrophobic achiral ionic liquids (1-butyl-3-methylimidazolium-hexafluorophosphate([bmim][PF₆]), 1-octyl-3-methylimidazolium tetrafluoroborate([omim][BF₄])) were used as solvents in chiral liquid-liquid extraction separation of mandelic acid (MA) enantiomers with β-cyclodextrin (β-CD) derivatives as hydrophilic chiral selectors preferentially forming complexes with (R)-enantiomers. Factors affecting the separation efficiency were optimised, namely the type of the extraction solvents and β-CD derivatives, concentrations of the β-CD derivatives and MA enantiomers, pH, and temperature. Excellent enantioseparation of MA enantiomers was achieved in the ionic liquid aqueous two-phase extraction systems under the optimal conditions of pH 2.5 and temperature of 5°C with the maximum enantioselectivity (α) of 1.74. The experimental results demonstrated that the ionic liquid aqueous two-phase extraction systems with a β-CD derivative as the chiral selector have a strong chiral recognition ability, which might extend the application of ionic liquids in chiral separation.     

Two chiral cadmium carboxylate framework isomers generated by spontaneous resolution: synthesis,structures and properties

Two three-dimensional (3-D) chiral coordination polymers, [Cd(NDC)(DMF)]_n (1_L and 1_D: H₂NDC = 1,4-naphthalenedicarboxylic acid and DMF = N,N′-dimethylformamide), have been synthesized by introducing the rigid achiral dicarboxylic acid ligand under solvo-thermal conditions, without chiral template or additives. Both chiral Cd-CPs were characterized by single crystal X-ray crystallography, and structural analysis indicates that 1_L and 1_D are enantiomers based on the zigzag [Cd(COO)₂(DMF)]_n rod secondary building units, featuring the left- or right-hand 2₁ Cd-O-C-O-Cd helix chains and left- or right-hand 4₁ screw [Cd(NDC)]_n columns, respectively. The FT-IR, TGA, powder X-ray diffraction and solid-state luminescence of 1 have been investigated. It is intriguing that the evidence from the circular dichroism spectroscopies confirms enantiomeric excess in the whole spontaneous resolution crystallization.     

Poly(γ‐benzyl‐L‐glutamate)‐functionalized single‐walled carbon nanotubes from surface‐initiated ring‐opening polymerizations of N‐carboxylanhydride

Single‐walled carbon nanotubes (SWCNTs) have been functionalized with poly(γ‐benzyl‐L ‐glutamate) (PBLG) by ring‐opening polymerizations of γ‐benzyl‐L ‐glutamic acid‐based N‐carboxylanhydrides (NCA‐BLG) using amino‐functionalized SWCNTs (SWCNT‐NH₂) as initiators. The SWCNT functionalization has been verified by FTIR spectroscopy and transmission electron microscopy. The FTIR study reveals that surface‐attached PBLGs adopt random‐coil conformations in contrast to the physically absorbed or bulk PBLGs, which exhibit α‐helical conformations. Raman spectroscopic analysis reveals a significant alteration of the electronic structure of SWCNTs as a result of PBLG functionalization. The PBLG‐functionalized SWCNTs (SWCNT‐PBLG) exhibit enhanced solubility in DMF. Stable DMF solutions of SWCNT‐PBLG/PBLG with a maximum SWCNTs concentration of 259 mg L^?1 can be readily obtained. SWCNT‐PBLG/PBLG solid composites have been characterized by differential scanning calorimetry, thermogravimetric analysis, wide/small‐angle X‐ray scattering (W/SAXS), scanning electron microscopy, and polarized optical microscopy for their thermal or morphological properties. Microfibers containing SWCNT‐PBLG and PBLG can also be prepared via electrospinning. WAXS characterization reveals that SWCNTs are evenly distributed among PBLG rods in solution and in the solid state where PBLGs form a short‐range nematic phase interspersed with amorphous domains. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2340–2350, 2010     

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines using chiral cationic Ru(diamine) complexes as catalysts: the counteranion and solvent effects,and substrate scope

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines catalyzed by chiral cationic η⁶-arene-(N-monosulfonylated diamine) Ru(II) complexes has been investigated. Strong counteranion and solvent effects on the enantioselectivity were observed. The ruthenium catalyst bearing non-coordinating BArF^? anion was found to be particularly effective for the hydrogenation of acyclic and exocyclic N-alkyl ketimines in the presence of (Boc)₂O in dichloromethane or even under solvent-free conditions, providing chiral amines with up to >99% ee and full conversions. Alternatively, the ruthenium catalyst bearing achiral phosphate anion together with corresponding phosphoric acid as the additive was also efficient for the hydrogenation of N-alkyl ketimines in the absence of (Boc)₂O with excellent enantioselectivities and full conversions. For N-aryl ketimines lower enantiomeric excesses were observed by using the ruthenium catalyst bearing BArF^? anion. This catalytic protocol thus provides a facile and practical access to optically active amines and has been successfully employed in the gram-scale synthesis of enantiomerically pure (+)-sertraline.     

Effects of Ionic Liquid [Me3NC2H4OH]+[ZnCl3]− on γ‐Radiation Polymerization of Methyl Methacrylate in Ethanol and N,N‐Dimethylformamide

Summary: Radiation‐induced polymerization of methyl methacrylate (MMA) in ethanol (EtOH) and N,N‐dimethylformamide (DMF) in the presence of ionic liquid [Me₃NC₂H₄OH]⁺[ZnCl₃]⁻ is reported. A substantial increase in monomer conversion and molecular weight is observed at room‐temperature ionic liquid (RTIL) >60 vol.‐%, and the resulting PMMA has a broad multimodal MWD. A clear difference in the MWD pattern is noted between EtOH/RTIL and DMF/RTIL systems, probably due to the complicated interactions between the solvent and ionic liquid.

Gel permeation chromatography traces of poly(methyl methacrylate) obtained by radiation polymerization in EtOH/RTIL and DMF/RTIL mixed solvent. Organic/RTIL (v/v): 1) 100:0; 2) 80:20; 3) 60:40; 4); 40:60; 5) 0:100.     

Enantiomeric recognition of chiral invertomers through NMR in chiral oriented phases: a study of cis-decalin

We describe a deuterium 1D and 2D NMR study of cis-decalin in various chiral and achiral polypeptide oriented solvent systems and the effect of the acquisition temperature. Organic solutions of poly-γ-benzyl-l-glutamate (PBLG) or poly-ε-carbobenzyloxy-l-lysine (PCBLL) in dichloromethane or chloroform allow the chiral invertomers of cis-decalin to be differentiated at low temperature. At high temperature, it is possible to distinguish between deuterium nuclei of the molecule which become enantiotopic under rapid kinetic averaging. The results obtained illustrate the capability of such polypeptide liquid-crystalline solvents to enantioselectively interact with unfunctionalised chiral cycloalkanes and highlight the analytical potential of NMR analysis in chiral liquid crystal based solvents in the investigation of interconverting chiral conformers.     

Retention of fluorinated chiral selectors in biphasic fluorinated solvent systems and its application to the separation of enantiomers by countercurrent chromatography

Ethoxynonafluorobutane (ENFB) has been used as a component of new biphasic solvent mixtures. The suitability of several mixtures as solvent systems in countercurrent chromatography was tested. The applicability of the ENFB/2-PrOH/H₂O mixture to the separation of enantiomers, in combination with a fluorinated chiral selector (CS), was evaluated. N-Perfluoroundecanoyl-l-proline-3,5-dimethylanilide (2), analogous to the previously used N-dodecyl-l-proline-3,5-dimethylanilide (1), was synthesized for this purpose. The capacity of the new solvent system to retain the fluorinated CS in the fluorinated phase used as stationary was examined. Chiral selector 1 was applied in analogous conditions for comparative purposes. Additionally, MTBE/phosphate buffer solvent system was also used with the two CSs. The ENFB/2-PrOH/H₂O (25:35:40) mixture was found to be adequate in the enantioseparation of DNB-Leu and DNB-Leu-tBu. Enantioselectivity was maintained in the fluorinated solvent system without compromising eluting time. The complete separation of DNB-Leu-tBu was achieved and no leaks of CS to the mobile phase were detected.     

Synthesis of Polyanionic Cellulose Carbamates by Homogeneous Aminolysis in an Ionic Liquid/DMF Medium

Polyanionic cellulose carbamates were synthesized by rapid and efficient homogeneous aminolysis of cellulose carbonate half-esters in an ionic liquid/DMF medium. Cellulose bis-2,3-O-(3,5-dimethylphenyl carbamate), as a model compound, reacted with different chloroformates to cellulose carbonates. These intermediates were subjected to aminolysis, for which both the reactivity of different chloroformates towards C6-OH and the reactivity/suitability of the respective carbonate half-ester in the aminolysis were comprehensively studied. Phenyl chloroformate and 4-chlorophenyl chloroformate readily reacted with C6-OH of the model cellulose derivative, while 4-nitrophenyl chloroformate did not. The intermediate 4-chlorophenyl carbonate derivative with the highest DS (1.05) was then used to evaluate different aminolysis pathways, applying three different amines (propargyl amine, β-alanine, and taurine) as reactants. The latter two zwitterionic compounds are only sparingly soluble in pure DMF as the typical reaction medium for aminolysis; therefore, several alternative procedures were suggested, carefully evaluated, and critically compared. Solubility problems with β-alanine and taurine were overcome by the binary solvent system DMF/[EMIM]OAc (1:1, v/v), which was shown to be a promising medium for rapid and efficient homogeneous aminolysis and for the preparation of the corresponding cellulose carbamate derivatives or other compounds that are not accessible by conventional isocyanate chemistry. The zwitterionic cellulose carbamate derivatives presented in this work could be promising chiral cation exchangers for HPLC enantiomer separations.     

Electric field effects on nuclear spin�Cspin coupling tensors and chiral discrimination via NMR spectroscopy

Nuclear magnetic resonance spectrometers presently available are unable to recognize the two mirror-image forms of a chiral molecule, because in the absence of a chiral solvent, the NMR spectral parameters (chemical shifts and spin?Cspin coupling constants) are identical for the two enantiomers. This paper discusses how chirality may nevertheless, at least in theory, be recognized in liquid-state NMR spectroscopy by applying strong d.c. electric fields and measuring a pseudoscalar contribution to nuclear spin?Cspin coupling polarizability. Calculations are reported for medium-size chiral molecules, (2R)-N-methyloxaziridine, (R _a )-1,3-dimethylallene, and (2R)-2-methyloxirane. The very small contributions provided by the pseudoscalar of nuclear spin?Cspin coupling polarizability seem rather difficult to detect via NMR experiments in disordered phase.     

Development of a column-switching high-performance liquid chromatography for kynurenine enantiomers and its application to a pharmacokinetic study in rat plasma

Kynurenine (KYN), a tryptophan metabolite, is a precursor of kynurenic acid, which is an antagonist of N-methyl-d-aspartate receptor. In this study, an enantiomeric separation of d,l-KYN derivatized with the benzofurazan fluorescence reagent 4-N,N-dimethylaminosulfonyl-7-fluoro-2,1,3-benzoxadiazole (DBD-F) (DBD-d,l-KYN) was first investigated by using a high-performance liquid chromatography (HPLC) with several chiral columns. As a consequence, DBD-d,l-KYN was enantiomerically separated on a cellulose-type chiral column (CHIRALCEL OJ-RH) with a mobile phase of H₂O/CH₃CN/MeOH (40/50/10) containing 0.1% acetic acid. Under this condition, the separation factor and resolution were 1.48 and 1.28, respectively. Next, a column-switching HPLC consisting of both octadecylsilica and chiral columns was developed and used to determine both d- and l-KYN enantiomers in 10 μL of rat plasma following the intraperitoneal administration of d,l-KYN to rats (10 mg kg⁻¹). The result revealed that the concentration of l-KYN was higher than that of d-KYN, suggesting that d-KYN was eliminated faster than l-KYN.     

Efficient route for the synthesis of 3,4-cycloalkoxy-2,5-diethoxycarbonyl-thiophenes obtained with bulky alkyl dibromides using trialkylamines as base-solvent

New reaction conditions were investigated for dialkylizing diethyl 3,4-dihydroxy-2,5-thiophenedicarboxylate with sterically hindered alkyl-dibromides, using as reaction system DMF-trialkylamine or only the trialkylamine as base-solvent. This methodology produced the corresponding 3,4-cycloalkoxy-2,5-diethoxycarbonyl-thiophene derivatives faster and with better yields than those reported previously for K₂CO₃-DMF. Experiments were performed with triethylamine, tripropylamine, and tributylamine. Tributylamine produced the best results in a general reaction with alkyl-bromides. Aromatic amines like N,N-dimethylaniline, N-methyldiphenylamine, and triphenylamine failed to react at all. Reactions using only the tributylamine as base-solvent demonstrated that DMF is not necessary as a solvent to obtain good yields.     

Nucleophilic fluoroalkylation of iminium salts

Iminium cations generated by the coupling of aldehydes, N-trimethylsilylamines and TMSOTf or by the methylation of imines with MeOTf smoothly react with silanes of a general formula Me₃SiR_f (R_f = CF₃, CCl₂F, C₆F₅) to afford the corresponding tertiary amines having a fluorinated substituent. The key step, involving C-C bond formation, is promoted by NaOAc or KF in DMF as a solvent.     

Synthesis of chiral vicinal C2 symmetric and unsymmetric bis(sulfonamide) ligands based on trans-1,2-cyclohexanediamine by aminolysis of N-tosylaziridines

The ring opening of N-tosylaziridines with aliphatic amines can be efficiently catalyzed by lithium perchlorate to provide derivatives of the trans-1,2-diamine in high yields. The reaction was used in desymmetrization of several cyclic N-tosylaziridines using chiral amines. Using this strategy, an efficient synthesis of chiral vicinal C₂ symmetric bis(sulfonamide) and unsymmetrical bis(sulfonamide) ligands based on trans-1,2-cyclohexanediamine was developed.     

Novel nitrogen ligands based on imidazole derivatives and their application in asymmetric catalysis

Recently prepared chiral amines have been used in the preparation of novel tridentate ligands based on an imidazole ring with an additional (hetero)ring. The synthesis was carried out by the reaction of chiral amines with suitable aldehydes (2-phenylimidazole-4-carbaldehyde, 2-hydroxybenzaldehyde or pyridine-2-carbaldehyde) under reductive conditions (H₂/Pd or NaBH₄). All ligands prepared showed strong hydrogen bonds in d₆-DMSO solution, which resulted in hindered imidazole tautomerism. The observed hindered tautomerism was studied by ¹H NMR spectroscopy. The structures of the prepared ligands were also confirmed by APCI mass spectroscopy. Both chiral amines and tridentate compounds have been applied as ligands in copper (II)-catalyzed nitroaldol reactions (Henry reaction). Various reaction conditions for the Henry reaction have been studied (influence of temperature, molar ratio, solvent or copper (II) precursors). The compounds prepared with the two imidazole rings showed fast reaction times and a reversal in enantioselectivity compared to other chiral amines.     

NH4I-promoted N-acylation of amines via the transamidation of DMF and DMA under metal-free conditions

An unprecedented NH₄I-promoted N-formylation and N-acetylization of various amines with dimethylformamide (DMF) and dimethylacetamide (DMA) has been developed. This protocol shows broad substrate scope for aromatic, aliphatic, and heterocyclic amines, which provides a metal-free strategy for N-acylation featuring mild reaction conditions, as well as inexpensive and readily available starting materials.