Elucidation of the enantioselective recognition mechanism of a penicillin G acylase‐based chiral stationary phase towards a series of 2‐aryloxy‐2‐arylacetic acids

Abstract

A series of structurally related 2-aryloxy-2-arylacetic acids (1-3, 5-16) together with a thioisostere derivative (4) have been synthesized and characterized by GC-MS and 1H NMR. The designed compounds were analyzed on a Penicillin G Acylase chiral stationary phase (PGA-CSP) and the influence of the structure variations on retention and enantioselectivity was investigated. The chromatographic study includes the direct separation of the enantiomers of the synthesized compounds and the determination of the elution order of selected racemic mixtures. 10 out of 16 racemates were separated; high chromatographic enantioseparation factors (alpha > 2) were achieved for some compounds. For the enantiomers of four compounds whose absolute configuration was known (1, 3, 12, 16), the elution order was R:S with the exception of 2-(4-chloro-phenoxy)phenylacetic acid (1), for which the elution order was reversed. Preliminary molecular modeling studies suggest that both polar and charge-transfer interactions as well as steric effects play an important role in determining the retention factors and the enantioselectivities observed.

Penicillin G acylase as chiral selector in LC and CE: Exploring the origins of enantioselectivity☆

“…A series of 2-aryloxy-2-arylacetic acids (Set 1; compounds 2-16, Table 1 ) together with a thioisostere derivative was designed staring from the observation that only the enantiomers of one analyte 2-(4-chloro-phenoxy)phenyl acetic acid (reported in Table 1 as compound 1), presented a reversed elution order (S:R) [40].…”

“…The set included some derivatives characterized by the presence into the side chain of a phenyl ring (compounds 17-24) or a further Table 1 Chemical structure of 2-aryloxy-2-arylacetic acids and chromatographic parameters obtained for racemates analyzed on PGA-CSP [40,41] Compound k1˛Rs phenoxy group (compounds 25-30) at a different distance from the chiral center. Moreover, half of these compounds had an additional chlorine atom in the para-position of the side chain benzene ring, whereas different atoms or groups with different size, shape and electronic properties were considered for the para-position of the phenoxy group directly linked to the chiral center.…”

Recent progresses in protein-based chiral stationary phases for enantioseparations in liquid chromatography

“…Furthermore, chiral recognition mechanism on PGA was investigated using molecular modeling and docking studies [29][30][31]. As depicted in Fig.…”

A novel lipase-based stationary phase in liquid chromatography

“…Although there has been much research on protein based chiral stationary phase [9][10][11][12], we demonstrate for the first time to immobilize CALB and use it as liquid chromatography stationary phase for direct chiral separation.…”

“…In recent years, several new chiral selectors such as penicillin G acylase (PGA), antibodies, fatty acid binding protein (FABP) and streptavidin have been introduced in liquid chromatography. Temporini and Massolini et al separated a series of chiral acids using PGA-based chiral stationary phase [11,12].…”