外消旋萘普生酯类在(S,S)-Whelk-O1与CDMPC手性柱上的对映体分离及手性识别机理的比较

在Pirkle型的(S,S)-Whelk-O 1与纤维素衍生物型的CDMPC两种手性柱上对六种 外消旋萘普生酯进行了对映体分离，通过研究烷氧基结构上的差异以及流动相中不 同的醇类添加剂对手性识别的影响，探讨和比较了外消旋萘普生酯在两种手性固定 相上手性识别的机理。对于 (S,S)-Whelk-O 1， 溶质与固定相之间的吸引作用于 手性识别的主要因素，而对于CDMPC，溶质在手性空腔中的空间适应性很可能是手 性识别的关键。     

Amplification of chirality: the "sergeants and soldiers" principle applied to dynamic hydrogen-bonded assemblies

The amplification of supramolecular chirality has been studied in dynamic chiral hydrogen-bonded assemblies 1(3).(CA)(6) using "Sergeants and Soldiers" experiments. Previously, we have shown that chiral centers present in either the dimelamine component 1 or the cyanurate component CA quantitatively induce one handedness (M or P) in the assembly. This offers the possibility to study the amplification of chirality under two different kinetic regimes. When chiral dimelamines 1 are used, the exchange of chiral components and (M/P)-interconversion, i.e., interconversion between the (M)- and (P)-isomers of assembly 1(3).(CA)(6), take place via identical pathways (condition A). When chiral cyanurates CA are used, the exchange of chiral components occurs much faster than (M/P)-interconversion (condition B). Experimentally, a much stronger chiral amplification is observed under condition B. For example, the observed chiral amplification for a mixture of chiral and achiral components (40:60) is 46% under condition B and 32% under condition A. Kinetic models were developed to fit the experimental data and to simulate chiral amplification in dynamic systems in general. These simulations show that it is theoretically possible that the diastereomeric excess in a dynamic system is more than 99% with less than 1% chiral component present!     

Recent progress in enantiomer separation by capillary electrochromatography

Enantiomer separation by electrochromatography (CEC) can be performed in three modes: (i) open-tubular capillary electrochromatography (o-CEC), in which the chiral selector is physically adsorbed coated, and thermally immobilized or covalently attached to the internal capillary wall; (ii) packed capillary electrochromatography (p-CEC), in which the capillary is either filled with chiral modified silica particles or with an achiral packing material, and a chiral selector is added to the mobile phase; and (iii) monolithic (rod)-capillary electrochromatography (rod-CEC) in which the chiral stationary phase (CSP) consists of a single piece of porous solid. We present an overview on methods and new trends in the field of electrochromatographic enantiomer separation such as CEC with either nonaqueous mobile phases or stationary phases with incorporated permanent charges, or with packing beds consisting of nonporous silica particles or particles with very small internal diameters.     

Control of helix sense in protein-mimicking backbone by the noncovalent chiral effect

We have reviewed our previous work regarding induction or control of a peptide helix sense through chiral stimulus to the peptide chain terminus. An optically inactive 3(10)-helix designed mainly with unusual alpha-amino acid residues was commonly employed. Such an N-terminal-free peptide generates a preferred helix sense by chiral acid molecule. A helix sense pre-directed in chiral sequence is also influenced or controlled by the chiral sign of such external molecule. Here free amide groups in the 3(10)-helical N-terminus participate in the formation of a multipoint coordinated complex. The terminal asymmetry produces the noncovalent chiral domino effect (NCDE) to influence the whole helix sense. The NCDE-mediated control of helicity provides the underlying chiral nature of protein-mimicking helical backbones: notably, chiral recognition at the terminus and modulation of helical propensity through chiral stimulus. The above items from our previous reports have been outlined and reviewed together with their significance in biopolymer science and chiral chemistry.     

Chiral capillary electrophoresis-mass spectrometry: modes and applications

A review is presented to highlight several approaches for coupling capillary electrophoresis (CE) and electrospray ionization-mass spectrometry (ESI-MS) for analysis of chiral compounds. A short discussion of commercially available CE-MS instruments and interface design is followed by a detail review on various modes of chiral CE-MS. In general, for each CE-MS mode, the capabilities, applications and limitations for chiral analysis have been pointed out. The first mode, chiral capillary zone electrophoresis-mass spectrometry (CZE-MS) in which neutral derivatized cyclodextrins (CDs) are used is possible using either column coupling with voltage switching or a partial-filling technique (PFT). However, some applications of direct coupling of CZE-MS mode are also reported. The second mode is a chiral electrokinetic chromatography-mass spectrometry (EKC-MS) in which a charged chiral selector such as a sulfated beta-CD or a vancomycin could be conveniently employed. This is because these chiral selectors have a significantly higher countercurrent electrophoretic mobility which prevents the entrance of these selectors into the mass spectrometer. The combination of counter-migration and PFT demonstrates that this synergism could be successfully applied to chiral analysis of a broader range of compounds. It is well-known that the on-line coupling of micellar electrokinetic chromatography to mass spectrometry (MEKC-MS) is problematic because the high surface activity and nonvolatile nature of conventional surfactant molecules lower the electrospray ionization efficiency. However, a recent report demonstrates that this hyphenation is now possible with the use of molecular micelles. Various MEKC-ESI-MS parameters that can be used to optimize both chiral resolution and ESI response are discussed. Finally, two recent examples that demonstrate the feasibility of using either open-tubular or packed chiral CEC with MS are reviewed. This survey will attempt to cover the state-of-the-art on various modes of CE-MS from 1998 up to 2002.     

Synthesis of Chiral beta 3-aminoxy peptides

A series of chiral beta(3)-aminoxy acids or amides with various side chains have been synthesized via two different approaches. One is the Arndt-Eistert homologation approach, using chiral alpha-aminoxy acids as starting materials. The other approach, utilizing the enantioselective reduction of beta-keto esters catalyzed by baker's yeast or chiral Ru(II) complexes, produces chiral beta(3)-aminoxy acids with nonproteinaceous side chains. The oligomers of beta(3)-aminoxy acids can be readily prepared using EDCI/HOAt as the coupling reagent.     

毛细管电泳新型手性分离体系研究进展

在现代分离科学中,手性化合物的分离分析一直是研究的重点和难点。相比于高效液相色谱（HPLC）、气相色谱（GC）等传统色谱分析方法,毛细管电泳（CE）技术凭借其高效率、低消耗、分离模式多样化等诸多优势,已经发展成为手性分离研究领域最有应用前景的分析方法之一。近年来,研究人员在CE手性分析方法的构建过程中,基于毛细管电动色谱（EKC）、配体交换毛细管电泳（LECE）、毛细管电色谱（CEC）等各种基础电泳模式,不断地对传统手性分离体系进行优化和改造,构建出了许多高性能的新型手性CE分离体系。如利用各类功能化离子液体以"手性离子液体协同拆分""手性离子液体配体交换""离子液体手性选择剂"等模式设计出多种基于离子液体的CE手性分离体系;利用纳米材料独特的尺寸效应、多样性、可设计性等特点,直接或与传统手性选择剂有机结合构建CE手性分离体系。此外,金属有机骨架材料修饰、低共熔溶剂修饰、非连续分段式部分填充等各式新颖的CE手性分离体系也都被研究人员成功开发,并表现出较大的发展潜力。该综述将对近年来（尤其是2015~2019年）此类新型CE手性分离体系的发展状况进行梳理,并结合相应的手性识别机理研究和手性CE方法实际应用情况,对该领域存在的问题及发展前景进行分析和展望。     

Enantiomer separation of drugs by micellar electrokinetic chromatography using chiral surfactants

A review surveying enantiomer separations by micellar electrokinetic chromatography (MEKC) using chiral surfactants is described. MEKC is one of the most popular techniques in capillary electrophoresis, where neutral compounds can be analyzed as well as charged ones, and the use of chiral micelles enable one to achieve the enantioseparation. The chiral MEKC systems are briefly reviewed according to the types of chiral surfactants along with typical applications. As chiral micelles or pseudostationary phases in MEKC, various natural and synthetic chiral surfactants are used, including several low-molecular-mass surfactants and polymerized surfactants or high-molecular-mass surfactants. Cyclodextrin modified MEKC using chiral micelles is also considered.     

流动相组成对有机硒手性化合物拆分的影响

 在自制的涂敷型纤维素 三 (3,5 二甲基苯基氨基甲酸酯 ) (CDMPC)手性固定相上拆分了一些结构相似的有机硒手性化合物 ,详细考察了三元流动相对手性拆分的影响 ,并探讨了溶质分子与手性固定相相互作用的模式。实验结果表明 :在二元流动相中加入极少量的质子性改性剂 (醇 )或非质子性改性剂 (乙腈 ) ,可使溶质的保留和手性拆分发生较大的变化。     

Chiral ionic liquids for enantioseparation of pharmaceutical products by capillary electrophoresis

A chiral ionic liquid (IL), S-[3-(chloro-2-hydroxypropyl)trimethylammonium] [bis((trifluoromethyl)sulfonyl)amide] (S-[CHTA](+)[Tf(2)N](-)), which can be easily and readily synthesized in a one-step process from commercially available reagents, can be successfully used both as co-electrolyte and as a chiral selector for CE. A variety of pharmaceutical products including atenolol, propranolol, warfarin, indoprofen, ketoprofen, ibuprofen and flurbiprofen, can be successfully and baseline separated with the use of this IL as electrolyte. Interestingly, while S-[CHTA](+)[Tf(2)N](-) can also serve as a chiral selector, enantioseparation cannot be successfully achieved with S-[CHTA](+)[Tf(2)N](-) as the only chiral selector. In the case of ibuprofen, a second chiral selector, namely a chiral anion (sodium cholate), is needed for the chiral separation. For furbiprofen, in addition to S-[CHTA](+)[Tf(2)N](-) and sodium cholate, a third and neutral chiral selector, 1-S-octyl-beta-d-thioglucopyranoside (OTG), is also needed. Due to the fact that the chirality of this chiral IL resides on the cation (i.e., -[CHTA](+)), and that needed additional chiral selector(s) are either chiral anion (i.e., cholate) or chiral neutral compound (OTG), the results obtained seem to suggest that additional chiral selector(s) are needed to provide the three-point interactions needed for chiral separations.     

Quantitative 1H NMR method for the routine spectroscopic determination of enantiomeric purity of active pharmaceutical ingredients fenfluramine, sertraline, and paroxetine

Determining the enantiomeric purity of chiral therapeutic agents is important in the development of active pharmaceutical ingredients (API). A strategy for determining the enantiomeric purity of three APIs was developed using nuclear magnetic resonance (NMR) and the chiral solvating agent (CSA) 1,1-bi-2-naphthyl (1). While chiral chromatography is widely used to evaluate enantiomeric purity, it can sometimes suffer from tedious sample preparation obviating rapid measurements that are sometimes needed during the manufacture of such agents. The techniques described herein provide comparable enantiomeric purity results with those obtained with traditional chiral HPLC and other published methods for these compounds. Chiral analysis of standard samples of methylbenzylamine enantiomeric mixtures using 1 were found to be quantitative to approximately 1% minor enantiomer. Enantiomeric purity determination by NMR utilizing chiral solvating agents do not require special instrumental techniques, chemical derivatization or standards and is therefore ideally suited for rapid routine analysis. As a result, the technique demonstrated is commonly used in our laboratory as a complementary or alternative method to chiral HPLC or optical rotation measurements for routine determination of enantiomeric purity.     

Convenient Syntheses of Some C4 Chiral Building Blocks Starting From (S)-Malic Acid

In the field of chiral technology, the synthesis of chiral intermediates and chiral building blocks occupies an important position. Chiral building blocks bearing double and / or multiple functionalities is particularly useful for the synthesis of chiral pharmaceuticals and chiral agrochemicals. In the recent years, we have been engaged in the development of synthetic methodology based on (S)-malic acid1-s. In these studies, malimide 2, easily accessible from (S)-malic acid, was shown to be a useful multifunctional building block in the asymmetric synthesis of natural products and chiral drugs (Scheme 1).     

Scalemic and racemic imprinting with a chiral crosslinker

The development of molecularly imprinted chiral stationary phases has traditionally been limited by the need for a chiral pure template. Paradoxically, availability of a chiral pure template largely defeats the purpose of developing a chiral stationary phase. To solve this paradox, imprinting of scalemic and racemic template mixtures was investigated using both chiral (N-α-bismethacryloyl-l-alanine) and achiral (N,O-bisacrylamide ethanolamine) crosslinkers. Imprinting of scalemic mixtures provided polymers capable of partial separation of Boc-tyrosine enantiomers with virtually the same results when using either the chiral or achiral crosslinker. However, the chiral crosslinker was required for chiral differentiation by the racemic imprinted polymers which were evaluated in both batch rebinding and chromatographic modes. Batch rebinding analysis revealed intersecting binding isotherms for the L- and D-Boc-tyrosine, indicating bias for the D or L enantiomer is concentration dependent. Partial chromatographic separation was achieved by the racemic imprinted polymers providing variable D or L bias in equal probability over multiple replicates of polymer synthesis. Correlation of enantiomer bias with the batch rebinding results and optimization of HPLC parameters are discussed.     

16种手性化合物在不同自制手性固定相上的拆分比较

采用高效液相色谱法,在自制的纤维素-三(3,5-二甲基苯基氨基甲酸酯)(ATEO-OD)、纤维素-三(4-甲基苯基氨基甲酸酯)(ATEO-OG)和纤维素-三(4-甲基苯基甲酸酯)(ATEO-OJ)3种手性柱上对16种不同结构的手性化合物进行了拆分和比较.试验结果表明:16个手性样品在这3种手性固定相上分别获得了不同程度的拆分,A TEO-OD对所分析样品具有更好的手性识别能力,ATEO-OG和ATEO-OJ的手性识别能力相当.     

Azithromycin as a new chiral selector in capillary electrophoresis

In capillary electrophoresis (CE), separation of enantiomers of a chiral compound can be achieved through the chiral interactions and/or complex formation between the chiral selector and the enantiomeric analytes on leaving their diastereomeric forms with different stability constants and hence different mobilities. A great number of chiral selectors have been employed in CE and among them macrocyclic antibiotics exhibited excellent enantioselective properties towards a wide number of racemic compounds. The use of azithromycin (AZM) as a chiral selector has not been reported previously. This work reports the use of AZM as a chiral selector for the enantiomeric separations of five chiral drugs and one amino acid (tryptophan) in CE. The enantioseparation is carried out using polar organic mixtures of acetonitrile (ACN), methanol (MeOH), acetic acid and triethylamine as run buffer. The influences of the chiral selector concentration, ACN/MeOH ratio, applied voltage and capillary temperature on enantioseparation are investigated. The results show that AZM is a viable chiral selector in CE for the enantioseparation of the type of chiral drugs investigated.     

Synthesis and structural chemistry of alkali metal tris(HMDS) magnesiates containing chiral diamine donor ligands

Six alkali metal tris(HMDS) magnesiate complexes (HMDS, 1,1,1,3,3,3,-hexamethyldisilazide) containing chiral diamine ligands have been prepared and characterised in both the solid- and solution-state. Four of the complexes have a solvent-separated ion pair composition of the form [{M·(chiral diamine)(2)}(+){Mg(HMDS)(3)}(-)] [M = Li for 1 and 3, Na for 2 and 4; chiral diamine = (-)-sparteine for 1 and 2, (R,R)-TMCDA for 3 and 4, (where (R,R)-TMCDA is N,N,N',N'-(1R,2R)-tetramethylcyclohexane-1,2-diamine)] and two have a contacted ion pair composition of the form [{K·chiral diamine}(+){Mg(HMDS)(3)}(-)](n) [chiral diamine = (-)-sparteine for 5 and (R,R)-TMCDA for 6]. In the solid-state, complexes 1-4 are essentially isostructural, with the lithium or sodium cation sequestered by the respective chiral diamine and the previously reported anion consisting of three HMDS ligands coordinated to a magnesium centre. As such, complexes 1-4 are the first structurally characterised complexes in which the alkali metal is sequestered by two molecules of either of the chiral diamines (-)-sparteine (1 and 2) or (R,R)-TMCDA (3 and 4). In addition, complex 4 is a rare (R,R)-TMCDA adduct of sodium. In the solid state, complexes 5 and 6 exist as polymeric arrays of dimeric [{K·chiral diamine}(+){Mg(HMDS)(3)}(-)](2) subunits, with 5 adopting a two-dimensional net arrangement and 6 a linear arrangement. As such, complexes 5 and 6 appear to be the only structurally characterised complexes in which the chiral diamines (-)-sparteine (5) or (R,R)-TMCDA (6) have been incorporated within a polymeric framework. In addition, prior to this work, no (-)-sparteine or (R,R)-TMCDA adducts of potassium had been reported.     

Asymmetric activation of chiral alkoxyzinc catalysts by chiral nitrogen activators for dialkylzinc addition to aldehydes: super high-throughput screening of combinatorial libraries of chiral ligands and activators by HPLC-CD/UV and HPLC-OR/RIU systems

Asymmetric catalysts, prepared by chiral ligand exchange or chiral modification, can evolve further into highly activated catalysts through engineering with chiral activators. Two new methodologies for "super high-throughput screening" (SHTS) of chiral ligands and activators have been developed as a combination of HPLC-CD/UV (CD/ UV = circular dichroism/ultraviolet spectroscopy) or -OR/RIU (OR/RIU = optical rotation/refractive index unit) with a combinatorial chemistry (CC) factory. With these techniques, the % ee of the product is determined within minutes without separation of the enantiomeric products by using a nonchiral stationary phase. Therefore, those SHTS techniques combined with our 'asymmetric activation' concept can provide a powerful strategy for finding the best activated chiral catalyst.     

Design of chiral organocatalysts for practical asymmetric synthesis of amino acid derivatives

A series of structurally rigid, chiral quaternary ammonium salts and several chiral sec-amine catalysts derived from commercially available (R)- or (S)-binaphthol have been designed as new C(2)-symmetric chiral phase-transfer catalysts and chiral bifunctional amino-catalysts. These chiral organocatalysts have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives.     

Enantiomer separation of chiral pharmaceuticals by capillary electrochromatography

Enantiomer separation of chiral pharmaceuticals by capillary electrochromatography (CEC) is achieved with open-tubular capillaries (o-CEC), with packed capillaries (p-CEC) or with monolithic capillaries. In o-CEC, capillaries are coated with a thin film containing cyclodextrin derivatives, cellulose, proteins, poly-terguride or molecularly imprinted polymers as chiral selectors. In p-CEC, typical chiral HPLC stationary phases such as silica-bonded cyclodextrin or cellulose derivatives, proteins, glycoproteins, macrocyclic antibiotics, quinine-derived and 'Pirkle' selectors, polyacrylamides and molecularly imprinted polymers are used as chiral selectors. Chiral monolithic stationary phases prepared by in situ polymerization into the capillary were also developed for electrochromatographic enantiomer separation.     

Chiral Amplification in Nature: Studying Cell‐Extracted Chiral Carotenoid Microcrystals via the Resonance Raman Optical Activity of Model Systems

Carotenoid microcrystals, extracted from cells of carrot roots and consisting of 95 % of achiral β‐carotene, exhibit a very intense chiroptical (ECD and ROA) signal. The preferential chirality of crystalline aggregates that consist mostly of achiral building blocks is a newly observed phenomenon in nature, and may be related to asymmetric information transfer from the chiral seeds (small amount of α‐carotene or lutein) present in carrot cells. To confirm this hypothesis, we synthesized several model aggregates from various achiral and chiral carotenoids. Because of the sergeant‐and‐soldier behavior, a small number of chiral sergeants (α‐carotene or astaxanthin) force the achiral soldier molecules (β‐ or 11,11′‐[D₂]‐β‐carotene) to jointly form supramolecular assemblies of induced chirality. The chiral amplification observed in these model systems confirmed that chiral microcrystals appearing in nature might consist predominantly of achiral building blocks and their supramolecular chirality might result from the co‐crystallization of chiral and achiral analogues.