Enantioresolution of dl‐penicillamine

Abstract

Penicillamine (PenA) is a nonproteinogenic amino acid containing a thiol group. The three functional groups in penicillamine undergo characteristic chemical reactions and differ in their ability to participate in various chemical and biochemical reactions. d-penicillamine is more active pharmacologically, while the l-isomer occurs 'naturally'. This review deals with the enantioresolution of PenA both by direct and indirect methods using liquid chromatography. HPLC separation of its diastereomers prepared with different chiral derivatizing reagents (on reversed-phase columns) and separation of the derivatives prepared with achiral reagents (on chiral columns or via ligand exchange mode) has been discussed. Separation of enantiomers tagged with achiral reagent (to add a chromophore for ehanced detection) when there is no diastereomer formation has been considered separately. In addition, application of PenA and its derivatives as chiral selector for enentioresolution of certain other compounds has also been discussed.

Enantioresolution of Amino Acids: A Decade’s Perspective, Prospects and Challenges

“…Copper chelation of d-PenA has been shown to generate reactive oxygen species that are cytotoxic to human leukemia and breast cancer cells [20]. A detailed review on direct and indirect methods of enantioseparation of PenA using liquid chromatography, along with a brief comparison of the two approaches, has been published by Bhushan and Kumar [21]; it suggests that there is a scope for development of methods for determination of enantiomers of PenA in biological specimens.…”

Possible factors influencing the separation mechanism of diastereomeric amino acid derivatives obtained from s-triazine type reagents

“…The mobile phase pH of about 2 produced by trifluoroacetic acid (TFA) used for the chromatographic studies [1,2] is low enough where at least partial protonation of one of the triazine nitrogens will likely occur. The presence of a population of protonated species could influence the conformational equilibria depending on the proximity of the counterion relative to the substituents on the triazine ring.…”

“…Recently, it has been suggested that the separation mechanism for s-triazine derivatives is essentially the same as for MR derivatives [2]. This proposal is based on the same elution order, implicating that the D-L diastereomer has the same complimentary arrangement of hydrophobic groups on one face and hydrophilic groups on the opposite face, analogous to MR derivatives.…”

“…The use of s-triazine reagents has been shown to be of significant analytical utility for the optical purity analysis of ␣-amino acids [1,2]. The first reported example demonstrated the effectiveness of mono-chloro s-triazine (MCT) reagents [1], which were produced from cyanuric chloride by substituting one chloride with an alkoxy or aryloxy group followed by substitution of a second chloride with an optically pure amino acid such as alanine or valine.…”

“…More recently, it was shown that the analogous dichloro s-triazine (DCT) reagents are also effective, which are similar to MCT derivatives except that no alkoxy/aryloxy group is introduced, and consequently a chloro substituent remains in the final diastereomeric derivative. The chloro triazine derivatives obtained with DCT reagents were shown to give even better diastereoselectivity than the corresponding methoxy triazine derivatives obtained with MCT reagents [2].…”