Eugene J. Billiot

Enantiomeric separations by use of polymeric surfactant electrokinetic chromatography

This review surveys the enantiomeric separation of drugs by electrokinetic chromatography using polymeric chiral surfactant pseudostationary phases. These phases have recently been shown to provide better mass transfer and increased rigidity and stability than regular micelles in micellar capillary electrophoresis. Characterization of the polymeric chiral surfactants is presented. Solution interactions of the pseudostationary phases via thermodynamics and fluorescence probe studies are evaluated. Also, case studies of enantiomeric separation of drugs using a single amino acid surfactant and the synergistic effect of the addition of gamma-cyclodextrin to the buffer is discussed. The use of dipeptide surfactants for chiral drug separations is described as well.

Chiral separation with dipeptide-terminated polymeric surfactants: the effect of an extra heteroatom on the polar head group.

Chiral recognition of two binaphthyl derivatives and three benzodiazepines were studied by use of polymeric surfactants in electrokinetic chromatography. Four specific dipeptide terminated (multichiral) micelle polymers were synthesized for this study. These include poly (sodium‐N‐undecanoyl‐L‐alanyl‐leucinate)‐(poly L‐SUAL), poly (sodium‐N‐undecanoyl‐L‐valyl‐leucinate) (poly L‐SUVL), poly (sodium‐N‐undecanoyl‐L‐seryl‐leucinate) (poly L‐SUSL), and poly(sodium‐N‐undecanoyl‐L‐threonyl‐leucinate) (poly L‐SUTL). In addition to the chiral separation study, the physicochemical properties (critical micelle concentration and specific rotation) of each polymer were investigated. The molecular weights of the various dipeptide‐terminated micelle polymers were determined using analytical ultracentrifugation. These dipeptide‐terminated micelle polymers were designed to study the effect of the extra heteroatom at the polar head group of the micelle polymer (i.e., poly L‐SUSL compared to poly L‐SUAL and poly L‐SUTL compared to poly L‐SUVL) on the enantiomeric separation of the binaphthyl derivatives and benzodiazepines. The synergistic effect of three chiral centers (poly L‐SUTL) provided improved resolution over that of two chiral centered dipeptide‐terminated micelle polymer in the case of (±)‐temazepam, (±)‐oxazepam, (±)‐binaphthol, and (±)‐binaphthol phosphate. The chiral recognition mechanisms in these cases were additionally controlled by the presence of the extra heteroatom located on the polar head group of the micelle polymers.

Chiral separations using polymeric dipeptide surfactants: effect of number of chiral centers and steric factors

Two polymeric dipeptide chiral surfactants (PDCSs), poly sodium N-undecanoyl isoleucyl-valinate (SUILV) with three chiral centers and poly sodium N-undecanoyl leucyl-valinate (SULV) with two chiral centers, have been evaluated and compared as chiral pseudo-stationary phases in electrokinetic capillary chromatography. The performance of these surfactants, in terms of enantioselectivity was examined using anionic, cationic and neutral analytes. Analyses of the data suggest that the enantiomeric resolutions of the analytes with these two PDCSs are dependent upon steric factors rather than number of stereogenic centers.

Enantiomeric separations using poly(L-valine) and poly(L-leucine) surfactants. Investigation of steric factors near the chiral center

This study examined the effect of steric factors near the stereogenic center on polymerized surfactants, sodium N-undecyl-L-leucine, sodium N-undecyl-L-norleucine, sodium N-undecyl-L-tert.-butyl leucine, sodium N-undecyl-L-isoleucine. sodium N-undecyl-L-valine, sodium N-undecyl-L-norvaline. and sodium N-undecyl-L-proline. The effect of steric factors near the chiral center of the polymeric surfactants were examined using binaphthyl derivatives, aminoglutethimide, and 2,2,2-trifluoro-1-(9-anthryl)ethanol. In addition, fluorescence spectroscopy was used to determine the hydrophobicities of these surfactants using the environmentally-sensitive probe pyrene.

Improved chiral separation using achiral modifiers in cyclodextrin modified capillary zone electrophoresis

The influence of achiral modifiers on the chiral separation of propranolol is examined by cyclodextrin modified capillary zone electrophoresis. The improved chiral separation of propranolol is by molecules previously identified in our group as forming ternary complexes with cyclodextrin and pyrene. The polarity, chain size and heteroatom composition of the functional groups on the comodifiers was systematically varied in order to study the influence of these variables on the separation of propranolol. The improved chiral separation is accompanied by a decrease in retention time. The decrease in retention time is suggestive of a decrease in the association of beta-cyclodextrin (beta-CD) with propranolol which was verified by calculation of apparent association constants using fluorometric methods.

Investigation of chiral recognition by molecular micelles with molecular dynamics simulations

ABSTRACT Molecular dynamics simulations were used to characterize the binding of the chiral drugs chlorthalidone and lorazepam to the molecular micelle poly-(sodium undecyl-(L)-leucine-valine). The project’s goal was to characterize the nature of chiral recognition in capillary electrophoresis separations that use molecular micelles as the chiral selector. The shapes and charge distributions of the chiral molecules investigated, their orientations within the molecular micelle chiral binding pockets, and the formation of stereoselective intermolecular hydrogen bonds with the molecular micelle were all found to play key roles in determining where and how lorazepam and chlorthalidone enantiomers interacted with the molecular micelle. GRAPHICAL ABSTRACT

Using molecular dynamics simulations to identify the key factors responsible for chiral recognition by an amino acid-based molecular micelle

Abstract Molecular dynamics (MD) simulations were used to investigate the binding of six chiral compounds to the amino acid-based molecular micelle (MM) poly-(sodium undecyl-(L)-leucine-leucine) or poly(SULL). The MM investigated is used as a chiral selector in capillary electrophoresis. The project goal was to characterize the chiral recognition mechanism in these separations and to move toward predictive models to identify the best amino acid-based MM for a given separation. Poly(SULL) was found to contain six binding sites into which chiral compounds could insert. Four sites had similar sizes, shapes, and electrostatic properties. Enantiomers of alprenolol, propranolol, 1,1′-bi-2-naphthyl-2,2′-diyl hydrogen phosphate, 1,1′-bi-2-naphthol, chlorthalidone, or lorazepam were separately docked into each binding pocket and MD simulations with the resulting intermolecular complexes were performed. Solvent-accessible surface area calculations showed the compounds preferentially associated with binding sites where they penetrated into the MM core and shielded their non-polar atoms from solvent. Furthermore, with five of the six compounds the enantiomer with the most favorable free energy of MM association also experienced the most favorable intermolecular hydrogen bonding interactions with the MM. This result suggests that stereoselective intermolecular hydrogen bonds play an important role in chiral discrimination in separations using amino acid-based MMs.GRAPHICAL ABSTRACT