Molecular mechanics chiral recognition studies

An understanding of the recognition of chirality at a molecular level has become of interest in many fields of chemistry and biology. In the past decade, many attempts to clarify the mechanism of chiral recognition on CSPs for liquid chromatography have been made by means of chromatography, NMR spectroscopy,199 202 X-ray analysis, and computational methods.203 - 206 The successful studies have been mostly carried out for the small-molecule CSPs, especially cyclodextrin-based CSPs and Pirkle-type (brush-type) CSPs. In contrast, only a few mechanistic studies on chiral discrimination at the molecular... 

Various endeavors have been undertaken to get insight into the 3D selector-selectand complex structures and to elucidate chiral recognition mechanisms of cinchonan carbamate selectors for a few model selectands (in particular, DNB-Leu). Such studies comprised NMR [92-94], ET-IR [94-96], X-ray diffraction [33,59,92,94], and molecular modeling investigations (the latter focusing on molecular dynamics [92,93,97], and 3D-QSAR CoMFA studies [98]). 

Many researchers have put a considerable amount of effort into studies of the chiral recognition mechanisms (using, e.g., NMR and molecular modeling), but yet the choice of chiral selector or chiral phase for a new compound is often based on trial and error. Different strategies for chiral method development have been presented by many of the retailers of chiral columns as a service for the customers. In addition to the information supplied by these retailers, another source of knowledge is Chirbase, a database that contains more than 50,000 HPLC separations of more than 15,000 different chiral substances [61], which also can provide guidance to the analytical chemist. 

Very recently, nice recognition of free and AT-acetylated amino acids (Gly, Ala, Phe) and some structurally related guests by a dicationic cyclophane-type A/,Ar -dibenzylated chiral derivative (4) of a bisisoquinoline alkaloid S,S-(+)-tetrandine (3 DBT) has been studied by NMR titration in water [31]. In contrast to other macrocyclic hosts, DBT shows high affinity and large enan-tioselectivity (K(S)/K(R)> 10) toward the smaller N-acetylalanine and binds the larger phenylalanine more weakly and nonselectively. The binding specificity of DBT was rationalized on the basis of molecular mechanics calculations. 

The mechanism of chiral recognition in permethyl-p-cyclodextrin has been thoroughly studied by Lipkowitz et al. [269] employing a molecular modelling approach. Not surprisingly, the host s most enantiodiscriminating domain was found to be inside the macrocyclic cavity. 

The computational studies described above are representative examples meant to illustrate the diversity of computational techniques used to assess chiral recognition by cyclodextrins in chiral chromatography. Other published examples include the use of molecular mechanics to describe shapes of aminoalkylphosphonic acids binding to a covalently linked acetylated cyclodextrin [72], the computation of free energies of atenolol binding to a perphenylcarbamate-p-cyclodextrin likewise covalently bound to silica gel [73], and studies of cyclodextrins used as chiral mobile phase additives in reverse-phase HPLC [74] and in capillary electrophoresis [75]. 

Lu, Y. Li, Ch. Zhang, H. Liu, X. Study on the mechanism of chiral recognition with molecularly imprinted polymers. Anal. Chem. Acta 2003,489, 33 3. 

The many data which have accumulated through chromatographic studies of resolution permit a) to single out systems which seem suitable for more detailed investigations of the intimate molecular mechanism of chiral recognition by methods such as X-ray crystallography and b) to correlate the influence of structural factors of selectors and selectands on stereoselectivity. 

This chapter will focus on chiral recognition mechanisms and molecular interactions. The commercialized macrocyclic glycopeptides ristocetin, R, vancomycin, V, teicoplanin, T and its aglycon form, teicoplanin aglycon, TAG will be the main subject of the study since a large database is available in the literature [3-7]. However, non-commercialized avoparcin, balhimycin, and the recently introduced eremomycin macrocyclic glycopeptides [8] are also included in the study for more information on possible mechanisms. 

The mechanism of molecular recognition and chiral discrimination of cellulose-and amylose-derived chiral selectors is difficult to study due to the complexity of the macromolecule and their multiple binding sites. However, some knowledge of binding mechanisms exist for selected selectands from NMR spectroscopy ] 165.166], molec-... 

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