Enantioselectivity glycopeptides

The enantioselectivity of the macrocyclic CSPs are different in each of the operating modes, probably because of different separation mechanisms functioning in the different solvent modes. The possible chiral recognition mechanisms for three mobile phase compositions on glycopeptide phases are listed in Table 2-3 in descending order of strength. 

ENANTIOSELECTIVE HPLC SEPARATIONS USING THE GLYCOPEPTIDES CONTAINING CSPs... 

Very recently, ethoxynonafluorobutane (ENFB) was evaluated as a safe and environmentally friendly NP solvent for the enantioselective separation of 15 compounds on two commercially available glycopeptides CSPs (vancomycin and teicoplanin), with APCI-MS detection [126]. 

Another factor that remarkably affects the enantioresolution of given enantiomeric pairs has been shown to be the binding chemistry used for the silica immobilization of glycopeptides (see Section 2.2). This was illustrated in the case of ristocetin A, which was covalently bonded to silica microparticles by immobilization onto epoxy-activated silica under mild conditions [22], and compared with the corresponding commercially available CSP, where the macrocycle was immobilized as previously reported for vancomycin, rifamycin B, thiostrepton [7], and teicoplanin [30]. The comparison proved that immobilization of ristocetin A onto epoxy-activated silica could significantly improve the enantioselectivity and the resolution of the corresponding CSP in the separation of a-amino acids under RP conditions [22]. 

Alcaro, S. et al., Enantioselective semi-preparative HPLC of two 2-arylpropionic acids on glycopeptides containing chiral stationary phases, Tetrahedron Asymmetry, 13, 69, 2002. 

Boesten, J.M.M. et al., Enantioselective high-performance liquid chromatographic separation of A -methyloxycarbonyl unsaturated amino acids on macrocyclic glycopeptide stationary phases, J. Chromatogr. A, 1108, 26, 2006. 

Two EPMEs based on macrocyclic glycopeptide antibiotics—vancomycin and teicoplanin—were designed for the assay of acetyl-L-carnitine [44]. The linear concentration ranges for the proposed electrodes were 10 5-10-2 mol/L for the vancomycin-based electrode and 10 4-10-2 mol/L for the teicoplanin-based electrode, with slopes of 58.1 and 55.0mV/p(acetyl-L-camitine), respectively. The enantioselectivity was determined over D-carnitine. 

Two EPMEs were proposed for the assay of R-baclofen. The electrodes were designed using macrocyclic glycopeptide antibiotic, teicoplanin [45]. Acetonitrile was added to the teicoplanin to design a modified teicoplanin-based electrode. The linear concentration ranges for the proposed enantioselective, membrane electrodes were 10 7-10 4mol/L for teicoplanin-based electrode and 10 6-10 4mol/L for the electrode based on teicoplanin modified with acetonitrile. The slopes of the electrodes were 60.0 and 57.2 mV/pR-baclofen for teicoplanin and teicoplanin modified with acetonitrile-based electrodes, respectively. The enantioselectivity was determined over S-baclofen. The proposed electrodes can be employed reliably for the assay of R-baclofen raw material and from its pharmaceutical formulation, Norton-Baclofen tablets. 

Three EPMEs based on macrocyclic glycopeptide antibiotics— vancomycin and teicoplanin (modified or not with acetonitrile)—were proposed for the determination of l- and D-enantiomers of methotrexate (Mtx) [48]. The linear concentration ranges for the proposed enantioselective membrane electrodes were between 10 6 and 10-3 mol/L for l- and D-Mtx. The slopes of the electrodes were 58.00 mV/pL-Mtx for vancomycin-based electrode, 57.60 mV/pD-Mtx for teicoplanin-based electrode and 55.40 mV/pD-Mtx for teicoplanin modified with acetonitrile-based electrode. The detection limits of the proposed electrodes were of 10 8 mol/L magnitude order. All proposed electrodes proved to be successful for the determination of the enantiopurity of Mtx as raw material and of its pharmaceutical formulations (tablets and injections). 

Davis and Fanelli applied the sulfinimine mediated asymmetric Strecker synthesis to the enantioselective synthesis of the racemization-prone (/ )-(4-methoxy-3,5-dihydroxyphenyl)glycine (134) from 133.81 This amino acid is the central amino acid of the clinically important glycopeptide antibiotic vancomycin as well as related antibiotics. 

In addition to the vancomycin and teicoplanin CSPs, ristocetin A (Chirobiotic R) [289] and recently avoparcin [280] have been evaluated as novel chiral SOs and CSPs. It turned out that within the large family of macrocyclic antibiotics complementarity of enantioselectivity exists for different glycopeptides. As a consequence, very often it is possible to obtain a complete resolution by switching to a congeneric antibiotic CSP, if after optimization no baseline, but partial. separation can be achieved on a certain macrocyclic antibiotic type CSP (see Fig. 9.22). It can be expected that the enantioselectivity potential of closely related antibiotics will be further exploited in the future leading to an increase in the number of macrocyclic antibiotic type CSPs. 

Tesarova and Bosakova [58] proposed an HPLC method for the enantio-selective separation of some phenothiazine and benzodiazepine derivatives on six different chiral stationary phases (CSPs). These selected CSPs, with respect to the structure of the separated compounds, were either based on b-CD chiral selectors (underivatized (J>-CD and hydroxypropyl ether (3-CD) or on macrocyclic antibiotics (vancomycin, teicoplanin, teicoplanin aglycon and ristocetin A). Measurements were carried out in a reversed-phase separation mode. The influence of mobile phase composition on retention and enantio-selective separation was studied. Enantioselective separation of phenothiazine derivatives, including levopromazine (LPZ), promethazine and thioridazine, was relatively difficult to achieve, but it was at least partly successful with both types of CSPs used in this work (CD-based and glycopeptide-based CSP), except for levomepromazine for which only the [CCD-based CSP was suitable. 

Chiral mobile phase additives provide a more versatile and cost-effective approach for enantiomer separations in thin-layer chromatography. Typically, chemically bonded layers with cyclodextrin and its derivatives, bovine serum albumin, or macrocyclic glycopeptides are used as chiral additives in the reversed-phase mode [59,60,172-178]. For [5- and y-cyclodextrins and their derivatives, a 0.1 to 0.5 M aqueous methanol or acetonitrile solution of the chiral selector is used as the mobile phase. Bovine serum albumin is generally used at concentrations of 1-8 % (w/v) in an aqueous acetate buffer of pH 5 to 7 or in a 0.5 M acetic acid solution, in either case with from 3-40 % (v/v) propan-2-ol (or another aliphatic alcohol), added to control retention. Enantioselectivity usually increases with an increase in concentration of the chiral selector, and may be non existent at low concentrations of the chiral selector. 

The AB-biaryl fragment of vancomycin, a glycopeptide antibiotic, was prepared on the basis of this methodology. Furthermore, the method was also applied to the synthesis of natural products without Ci-sustituents next to the biaryl axis such as dioncophylline C or korupensamine B. One of the most recent applications of the concept in natural product synthesis was the first and atropo-enantioselective total synthesis of (+ )-knipholone, an antimalarial phenylanthraquinone. Against the steric hindrance by the C-10 keto function. 

Further analytical applications of glycopeptide antibiotics involve the development of enantioselective poten-tiometric membrane electrodes employed as sensors for chiral drugs. A carbon paste electrode impregnated with vancomycin or teicoplanin was used for detection of 5-flurbiprofen or / -baclofen (Figure 7) with high sensitivity and selectivity." " ... 

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