Bruce C. Hamper

A rational approach to the design of highly effective chiral stationary phases for the liquid chromatographic separation of enantiomers.

Abstract The design and rationale of some novel chiral stationary phases (CSPs) are discussed with respect to methods for determining enantiomeric purity, absolute configuration and for obtaining enantiomerically pure materials by liquid chromatography. The commercially-available dinitrobenzoylamino CSP type 1 is discussed with respect to the chiral recognition mechanisms which may operate in the resolution of some polycyclic and heterocyclic aromatic molecules and some benzodiazepines. N-Acyl α-arylalkylamines are also employed as models to formulate mechanisms for the chiral properties of type 1 CSPs in terms of enantiomeric stacking of the most stable conformations in solution. The properties of new types of ‘reciprocal’ CSPs are discussed and illustrated by enantiomeric separation of some amino acid and amino phosphoric acid derivatives, and by the separation of the following enantiomeric drugs as their 3,5-dinitrobenzoyl derivatives: metoprolol, oxoprenolol, ephedrine and alprenolol.

Chromatographic separation of the enantiomers of 1,3-dithiolane-1-oxides

Abstract The enantiomers of 2,2-disubstituted 1,3-dithiolane- 1 -oxides (type 1 and 2) are separable by direct high-performance liquid chromatography on commercially available chiral stationary phases derived from the N-3,5-dinitrobenzoyl derivatives of α-amino acids. The chromatographic data for a series of dithiolane oxides is presented. Two chiral recognition models are advanced to account for the structure—enantio-selectivity relationships observed for these series. Using these models, absolute configurations of the enantiomers are assigned on the basis of chromatographic elution order. These assignments are consistent with those determined by independent chemical and spectroscopic means. Resolutions of the enantiomers are compared on nine different chiral stationary phases.

Chapter 7 The Direct Preparative Resolution Of Enantiomers By Liquid Chromatography On Chiral Stationary Phases

Publisher Summary This chapter considers recent developments in the liquid chromatographic separation of enantiomers on a preparative scale. The chapter focuses on methods which allow the isolation of enantiomerically pure rather that slightly enriched materials. The recent development of chiral stationary phases (CSPs) effective for preparative work can be attributed largely to research done at the analytical level, for example, the separability of enantiomers on a given CSP can be evaluated quickly using a small quantity of racemate. Well-separated enantiomers are potential candidates for incorporation into “reciprocal” CSPs which should resolve compounds of the type used in the initial CSP. Any CSP which performs well at the analytical level can be used in preparative columns. Because the properties desired in a preparative chiral column are not unlike those required for any preparative separation, any treatment of preparative liquid chromatographic technique is relevant to the separation of enantiomers. The chapter discusses several chromatographic parameters specifically applied to CSPs.

Parallel solid-phase synthesis and high-throughput 1H NMR evaluation of a 96-member 1,2,4-trisubstituted-pyrimidin-6-one-5-carboxylic acid library.

A solid-phase organic synthesis method has been developed for the preparation of trisubstituted pyrimidin-6-one carboxylic acids 12, which allows elaboration to a 3-dimensional combinatorial library. Three substituents are introduced by initial Knoevenagel condensation of an aldehyde and malonate ester resin 7 to give resin bound 1. Cyclization of 1 with an N-substituted amidine 10, oxidation, and cleavage afforded pyrimidinone 12. The initial solid-phase reaction sequence was followed by gel-phase (19)FNMR and direct-cleavage (1)H NMR of intermediate resins to determine the optimal conditions. The scope of the method for library production was determined by investigation of a 3 x 4 pilot library of twelve compounds. Cyclocondensation of N-methylamidines and 7 followed by CAN oxidation gave mixtures of the resin bound pyrimidin-6-one 11 and the regioisomeric pyrimidin-4-one 15, which after cleavage from the resin afforded a nearly 1:1 mixture of pyrimidin-6-one and pyrimidin-4-one carboxylic acids 12 and 16, respectively. The regiochemical assignment was confirmed by ROESY1D and gHMBC NMR experiments. A library was prepared using 8 aldehydes, 3 nitriles, and 4 amines to give a full combinatorial set of 96 pyrimidinones 12. Confirmation of structural identity and purity was carried out by LCMS using coupled ELS detection and by high-throughput flow (1)H NMR.