A general criterion for molecular recognition: implications for chiral interactions

A general criterion is formulated for molecular recognition. The criterion for recognition is the inequality of the distance matrices of complexes of different compounds with a resolving agent under ambient experimental conditions. It is shown how this criterion provides for an objective, well-defined, and simple explanation for recognition of chiral compounds. This approach may be used to explain models (e.g., three-point of attachment) and relationships for chiral recognition. It is also shown how one-, two-, or three-point mechanisms are equivalent in this formalism and could result in chiral recognition. Examples are used to illustrate how the so called one- or two-point mechanisms may be operative in many experimental findings. Symmetry requirements of resolving agents may also be derived from considerations of distance matrices. Finally, the reciprocal relationship of chiral resolving agents is easily derived from the present method of analysis.     

Probability rule for chiral recognition

Molecular Chirality is of central interest in biological studies because enantiomeric compounds, while indistinguishable by most inanimate systems, show profoundly different properties in biochemical environments. Enantioselective separation methods, based on the differential recognition of two optical isomers by a chiral selector, have been amply documented. Also, great effort has been directed towards a theoretical understanding of the fundamental mechanisms underlying the chiral recognition process. Here we report a comprehensive data examination of enantio separation measurements for over 72000 chiral selector-select and pairs from the chiral selection compendium CHIRBASE. The distribution of alpha = k'(D)/k'(L) values was found to follow a power law, equivalent to an exponential decay for chiral differential free energies. This observation is experimentally relevant in terms of the number of different individual or combinatorial selectors that need to be screened in order to observe alpha values higher than a preset minimum. A string model for enantiorecognition (SMED) formalism is proposed to account for this observation on the basis of an extended Ogston three-point interaction model. Partially overlapping molecular interaction domains are analyzed in terms of a string complementarity model for ligand-receptor complementarity. The results suggest that chiral selection statistics may be interpreted in terms of more general concepts related to biomolecular recognition.     

The nature of chiral recognition: Is it a three-point interaction?

Evolution of the initial “three-point attachment model” resulted in the understanding that an interaction in at least three configuration-dependent points is needed for a chiral selector to recognize entantiomers. Thermodynamic enantioselectivity of this interaction can result in chiral discrimination of the enantiomers, with the exception of a temperature range where enthalpic and entropic contributions to the free energy of discrimination balance each other. Similarly, a three-point interaction is needed for a chiral inductor to modify enantiospecifically a prochiral molecule. The difference between a theoretical interaction point and real interaction sites in chemical molecules is emphasized. The role of conformational rigidity of chiral species is discussed in relation to the dependence of spatial arrangement of three active points on the configuration of the species. Chirality 9:99–102, 1997. © 1997 Wiley-Liss, Inc.     

A vivid model illustrating chiral recognition induced by achiral structures

If diastereomeric complexes are adsorbed on a surface or if they include a molecule of solvent, two points of attractive interaction between the chiral species of the complex can be sufficient for mutual chiral recognition of these species. In special cases even one single point of interaction is sufficient. This extension of the three-point contact rule of Dalgliesh, first observed in chiral ligand-exchange chromatography, can be demonstrated by using hands.     

Interactions of chiral molecules with an (r)-n-(3,5-dinitrobenzoyl) phenylglycine HPLC stationary phase

Forty different chiral molecules were studied by liquid chromatography with a Pirkle-type, (R)-N-(3,5-dinitrobenzoyl) phenylglycine (DNBPG), chiral stationary phase column. The dramatic effect of a small molecular change on chiral recognition was demonstrated using DL-amino acid derivatives. The inductive effect on chiral recognition was also studied using trifluoro-, trichloro-, dichloro-, monochloroacetyl, and acetyl derivatives of four different chiral amines. The study of the enantiomer separation of 11 different crown ethers of 2,2′-binaphthyldiyl showed that the rigidity of the chiral center can be an additional parameter in chiral recognition for the DNBPG phase but not for a β-cyclodextrin bonded chiral phase. It is apparent from this study that steric effects, inductive effects, and molecular rigidity play important roles in chiral recognition with DNBPG chiral stationary phases.     

A fluorescent chiral chemosensor for the recognition of the two enantiomers of chiral carboxylates

A new 7-nitrobenz-2-oxa-1,3-diazole (NBD)-based fluorescent chiral chemosensor (NBD-1) was prepared and applied to the recognition of the two enantiomers of the tetrabutylammonium salts of N-t-Boc-α-amino acids and chiral carboxylic acids including naproxen. In particular, the chiral recognition by the new fluorescent chiral chemosensor for the two enantiomers of N-t-Boc-threonine (tetrabutylammonium salt) was quite excellent, the Stern-Volmer constant ratio (K(D)/K(L)) for the two enantiomers being as high as 4.89.     

Immobilization and chromatographic evaluation of novel regioselectively substituted amylose‐based chiral packing materials for HPLC

The regioselectively substituted amylose derivatives bearing a 4‐tert‐butylbenzoate or 4‐chlorobenzoate group at 2‐position, and 3,5‐dichlorophenylcarbamate and a small amount of 3‐(triethoxysilyl)propylcarbamate groups at 3‐ and 6‐positions were synthesized by a two‐step process based on the esterification of 2‐position of a glucose unit. The obtained derivatives were effectively immobilized onto macroporous silica gel by intermolecular polycondensation of triethoxysilyl groups. Their chiral recognition abilities were evaluated as chiral packing materials (CPMs) for high‐performance liquid chromatography. These CPMs showed high chiral recognition as well as the conventional coated‐type CPM, and can be used with the eluents‐containing chloroform and tetrahydrofuran. With the extended use of these eluents, improvement of chiral recognition and reversed elution orders were realized. For some racemates, the immobilized CPM exhibited ability comparable or better to the commercial immobilized amylose‐ or cellulose‐based columns, Chiralpak IA, IB, and IC. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Chiral interaction in Gly-capped N-terminal motif of 3(10)-helix and domino-type induction in helix sense

Chiral interaction of helical peptide with chiral molecule, and concomitant induction in its helix sense have been demonstrated in optically inactive nonapeptide (1) possessing Gly at its N-terminus: H-Gly-(Delta(Z)Phe-Aib)(4)-OCH(3) (1: Delta(Z)Phe = Z-dehydrophenylalanine; Aib = alpha-aminoisobutyric acid). Spectroscopic measurements [mainly nuclear magnetic resonance (NMR) and circular diochroism (CD)] as well as theoretical simulation have been carried out for that purpose. Peptide 1 in the 3(10)-helix tends to adopt preferentially a right-handed screw sense by chiral Boc-L-amino acid (Boc: t-butoxycarbonyl). Induction in the helix sense through the noncovalent chiral domino effect should be derived primarily from the complex supported by the three-point coordination on the N-terminal sequence. Thus the 3(10)-helical terminus consisting of only alpha-amino acid residues enables chiral recognition of the Boc-amino acid molecule, leading to modulation of the original chain asymmetry. Dynamics in the helix-sense induction also have been discussed on the basis of a low-temperature NMR study. Furthermore, the inversion of induced helix sense has been achieved through solvent effects.     

Synthesis and evaluation of two novel “mixed” chiral stationary phases deriving from tyrosine: Csps designed for the resolution of either π-acid or π-basic racemates

The synthesis and chromatographic evaluation of two novel chiral stationary phases (CSPs) deriving from (S)-tyrosine are reported. The chiral graft has been designed in order to bear both π-acid and π-basic sites, each one being connected to a distinct asymmetric centre. An intramolecular π-π interaction may take place within these CSPs, leading to an energetically favoured conformation of the chiral selector (CS). The enantiorecognition ability of these CSPs was investigated for various classes of either π-acid or π-basic racemates. It is shown that these CSPs are able to separate simultaneously π-acid and π-basic racemates. Finally, chiral recognition mechanisms and mobile phase optimization are discussed.     

The development of biphasic chiral recognition in chiral separation

In chiral separation, enantioseparation factor is an important parameter which influences the resolution of enantiomers. In this current overview, a biphasic chiral recognition method is introduced to the readers. This method can significantly improve the enantioseparation factor in two‐phase solvent through adding lipophilic and hydrophilic chiral selectors which have opposite chiral recognition ability to organic and aqueous phases, respectively. This overview presents the development and applications of biphasic chiral recognition in liquid‐liquid extraction and counter current chromatography. It mainly focuses on the topics of mechanism, advantages and limitations, applications, and key factors of biphasic chiral recognition. In addition, the future outlook on development of biphasic chiral recognition also has been discussed in this overview.     

Chiral symmetry conservation principle

We show a chiral symmetry conservation principle based on chemical kinetics using stochastic results. Suppose the chiral symmetry conservation is evoked, and our universe can be considered globally asymmetric. In that case, there are at least two mirrored asymmetric universes if all the chiral properties are strongly correlated. However, if the chiral correlations are weak or nonexistent, there are possibly Many-(Chiral-Symmetry)-Worlds. Alternatively, if our universe is only locally asymmetric, there could be a single universe with segregated chiral regions. The possible mechanisms of the primordial chiral symmetry breaking can only be found if the chiral symmetry is not truly conserved by assuming the initial racemic conditions. In that case, our universe is asymmetric and could be alone. On the other hand, if the chiral symmetry is conserved, there is no chance of finding the primordial chiral symmetry breaking. Based on this conservation (or not), it is possible to infer two opposite hypotheses, where two general scenarios about the chiral universes are possible.     

New chiral stationary phases for liquid chromatography based on small molecules: Development,enantioresolution evaluation and chiral recognition mechanisms

Recently, we reported the development of new chiral stationary phases (CSPs) for liquid chromatography (LC) based on chiral derivatives of xanthones (CDXs). Based on the most promising CDX selectors, 12 new CSPs were successfully prepared starting from suitable functionalized small molecules including xanthone and benzophenone derivatives. The chiral selectors comprising one, two, three, or four chiral moieties were covalently bonded to a chromatographic support and further packed into LC stainless-steel columns (150 × 2.1 mm I.D.). The enantioselective performance of the new CSPs was evaluated by LC using different classes of chiral compounds. Specificity for enantioseparation of some CDXs was observed in the evaluation of the new CSPs. Besides, assessment of chiral recognition mechanisms was performed by computational studies using molecular docking approach, which are in accordance with the chromatographic parameters. X-Ray analysis was used to establish a chiral selector 3D structure.     

NMR chiral discrimination of chalcogen containing secondary alcohols

Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatizing agents. The BINOL/DMAP ternary complex demonstrated a simple and fast protocol for determining enantiopurity. The drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral derivatizing agent (CDA) for NMR chiral discrimination of chalcogen containing secondary alcohols. The chiral recognition by CDA and chiral solvating agent (CSA) was assessed using ¹H, ⁷⁷Se‐{1H}, and ¹²⁵Te‐{1H} NMR spectroscopy. A simple model for the assignment of the absolute configuration from NMR data is presented.     

Chiral separation based on immobilized intact and fragmented cellobiohydrolase II (CBH II): A comparison with cellobiohydrolase I (CBH I)

Intact and fragmented cellobiohydrolase II (CBH II) were immobilized to silica and used as chiral stationary phases (CSPs) for liquid chromatographic separations of enantiomers. Both acidic and basic chiral compounds could be resolved into their enantiomers on these phases. The enantioselectivities obtained on intact CBH II and its core were almost equivalent. Comparisons were also made with CBH I silica. It was found that the new materials show quite different chiral and chromatographic properties. The enzymatic activity of the CBH II in free solution was influenced by alprenolol and mexiletine, both separated on the corresponding CSP. It indicates that the sites for catalysis and for chiral recognition overlap. © 1995 Wiley-Liss, Inc.     

Chromatographic optical resolution on trans-1,2-diaminocyclohexane derivatives: Theory and applications

An overall view on some new chiral stationary phases based on (trans)-1,2-diaminocyclohexane is illustrated. The selected chiral moiety, derivatized with different aroyl groups, has been linked to a silica matrix in order to give chiral stationary phases (CSPs) enabling them to be used efficiently in the normal and reverse phase, both for analytical and preparative purposes. In addition new polymeric CSPs have been prepared by using the same selector, suitably modified, as monomer. The new chiral stationary phases have been characterised by physicochemical methods and used for the resolution of various racemic compounds classes such as α-aryloxyacetic acids, alcohols, sulfoxides, selenoxides, phosphinates, tertiaryphosphine oxides, benzodiazepines etc. without prederivatization or as amines, amino acids, amino alcohols, nonsteroidal antiinflammatory agents in a derivatized form. The separated solutes structural variety suggests that multiple interaction sites are involved in the recognition process: some thermodynamic data relative to the CSPs—selectands interactions are also illustrated. © 1992 Wiley-Liss, Inc.     

Liquid chromatographic separation of chiral diarylcarbinols

The direct HPLC separation of three chiral carbinols of general formula Mesityl-CH(OH)-Aryl has been achieved using Pirkle (R)-DNBPG ionic or covalent columns and, for Aryl = o-tolyl, on a Chiralpak OP(+) phase. It is apparent that steric hindrance and hydrogen bonding play important roles in chiral recognition. Two compounds structurally very similar but lacking the hydroxyl group were not resolved in their enantiomeric pairs. © 1992 Wiley-Liss, Inc.     

Preparation and evaluation of regioselectively substituted amylose derivatives for chiral separations

Six novel regioselectively substituted amylose derivatives with a benzoate at 2‐position and two different phenylcarbamates at 3‐ and 6‐positions were synthesized and their structures were characterized by ¹H nuclear magnetic resonance (NMR) spectroscopy. Their enantioseparation abilities were then examined as chiral stationary phases (CSPs) for high‐performance liquid chromatography (HPLC) after they were coated on 3‐aminopropyl silica gels. Investigations indicated that the substituents at the 3‐ and 6‐positions played an important role in chiral recognition of these amylose 2‐benzoate serial derivatives. The derivatives demonstrated characteristic enantioseparation and some racemates were better resolved on these derivatives than on Chiralpak AD, which is one of the most efficient CSPs, utilizing coated amylose tris(3,5‐dimethylphenylcarbamate) as the chiral selector. Among the derivatives prepared, amylose 2‐benzoate‐3‐(phenylcarbamate/4‐methylphenylcarbamate)‐6‐(3,5‐dimethylphenylcarbamate) exhibited chiral recognition abilities comparable to that of Chiralpak AD and may be useful CSPs in the future. The effect of mobile phase on chiral recognition was also studied. In general, with the decreased concentration of 2‐propanol, better resolutions were obtained with longer retention times. Moreover, when ethanol was used instead of 2‐propanol, poorer resolutions were often achieved. However, in some cases, improved enantioselectivity was achieved with ethanol rather than 2‐propanol as the mobile phase modifier.     

Enantioseparation on 4-halogen-substituted phenylcarbamates of amylose as chiral stationary phases for high-performance liquid chromatography

Four 4-halogen-substituted phenylcarbamate derivatives of amylose were prepared and their chiral recognition abilities as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) were evaluated and compared with those of the corresponding cellulose derivatives. The amylose derivatives with fluoro, chloro, bromo, or iodo group at the four-position on the phenyl group were found to show higher chiral resolving ability than the corresponding cellulose derivatives. Among four amylose derivatives 4-fluoro- and 4-chlorophenylcarbamates showed an excellent chiral recognition ability. Especially, amylose tris(4-chlorophenylcarbamate) resolved (±)-1,2,2,2-tetraphenylethanol with a very high α value (α = 8.29). In order to obtain useful information concerning the chiral recognition mechanism of this resolution, we also performed enantioseparation of a variety of analogous racemic alcohols, and found that both the hydroxy and bulky triphenylmethyl groups of the racemate are essential for the effective chiral recognition. Chirality 9:63–68, 1997. © 1997 Wiley-Liss, Inc.     

Determination of enantiomeric composition by negative-ion electrospray ionization-mass spectrometry using deprotonated N-(3,5-dinitrobenzoyl)amino acids as chiral selectors

The ability to use mixtures of deprotonated N-(3,5-dinitrobenzoyl)amino acids as chiral selectors for the determination of enantiomeric composition by electrospray ionization-mass spectrometry is demonstrated. For each experiment, two N-(3,5-dinitrobenzoyl)amino acids were chosen such that each would have opposite selectivity for the enantiomers of the analyte. Electrospray ionization-mass spectrometry, monitored in the negative ion mode, of solutions containing the two N-(3,5-dinitrobenzoyl)amino acids, sodium hydroxide, and the analyte, in a one-to-one mixture of methanol and water, afford peaks in the mass spectrum that correspond to the deprotonated 1:1 analyte-selector complexes. The ratio of the intensities of the complexes in the mass spectrum can be related to the enantiomeric composition of the analyte. Additionally, the sense and extent of chiral recognition is consistent with chromatographic observations, using chiral stationary phases derived from N-(3,5-dinitrobenzoyl)amino acids. Each analysis of enantiomeric composition requires less than 10 s to complete, indicating that this method has great potential for the development of fast-/high-throughput chiral analyses.     

HPLC enantioseparation on cellulose tris(3,5-dimethylphenylcarbamate) as a chiral stationary phase: Influences of pore size of silica gel,coating amount,coating solvent,and column temperature on chiral discrimination

Cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC) was coated on large-pore silica gels and used as a chiral stationary phase (CSP) for high-performance liquid chromatographic separation of enantiomers. The influences of pore size of silica gel, coating amount of CDMPC, coating solvent, and column temperature on chiral discrimination were investigated. CSPs prepared with a large-pore silica gel having a small surface area showed higher chiral recognition. The amount of CDMPC adsorbed on the silica gel influenced the chiral recognition of some racemates. Loading capacity of racemates increased with an increase of the amount of CDMPC supported on the silica gel, and a CSP coated with 45% CDMPC by weight can be used for both analytical and semi-preparative scale separations. The CDMPC, coated using acetone as the coating solvent, exhibited, in many cases, higher enantioselectivity than that obtained with tetrahydrofuran F as the coating solvent. © 1996 Wiley-Liss, Inc.