The present paper describes characteristics and application of Marfey's reagent (MR) including general protocols for synthesis of the reagent and diastereomers along with advantages, disadvantages and the required precautions. Applications, and comparison with other derivatizing agents, for the resolution of complex mixtures of DL-amino acids, amines and non-proteinogenic amino acids, peptides/amino acids from microorganisms, cysteine residues in peptides, and evaluation of racemizing characteristics have been discussed. Separation mechanisms of resolution of amino acid diastereomers and replacement of Ala-NH2 by suitable chiral moieties providing structural analogs and different chiral variants and their application as a derivatizing agent to examine the efficiency, and reactivity of the reagent have been focussed. Use of MR for preparing CSPs for direct enantiomeric resolution has also been included.

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Twelve chiral derivatizing reagents (CDRs) were synthesized by substituting one of the fluorine atoms in 1,5-difluoro-2,4-dinitrobenzene (DFDNB) with three optically pure amines [(R)-(-)-1-cyclohexylethylamine, (+)-dehydroabietylamine and (S)-(-)-alpha,4-dimethylbenzylamine], six amino acid amides [L-Ala-NH(2), L-Phe-NH(2), L-Val-NH(2), L-Leu-NH(2), L-Met-NH(2) and D-Phg-NH(2)] and three amino acids [L-Ala, L-Val and L-Leu]. In addition, dinitrophenyl-L-Pro-N-hydroxysuccinimide ester and N-succinimidyl-(S)-2-(6-methoxynaphth-2-yl) propionate were also synthesized and used as CDR. Keeping in view the presence of an amino group, diastereomers of six beta-blockers (atenolol, propranolol, bisoprolol, metoprolol, salbutamol, and carvedilol) were synthesized by reaction with these 14 CDRs. The diastereomers were separated by RP-HPLC. The method was validated for linearity, accuracy, limit of detection and limit of quantification.

The syntheses of optically active compounds (whether of pharmaceutical or synthetic importance, or as promising candidates as chiral ligands and auxiliaries in asymmetric syntheses) result in the formation of a mixture of products with one enantiomer predominating. Usually, the practice is to use standard open‐column chromatography for the first purification step in an enantioselective synthesis; the workup of the reaction product by crystallization or achiral chromatography would mask the real efficiency of the enantioselective methodology, since enantiomeric ratio (er) of the product may change by any of these methods. Most of the synthetic organic chemists are aware of the influence of crystallization on the er value.Majority of synthetic organic chemists are, however, not aware, while employing standard chromatography, that there may be an increase or decrease of er value. In other words, an undesired change in er goes unnoticed when such a mixture of enantiomers is isolated by chromatography on an achiral‐phase because of the prevalent concept of basic stereochemistry. Such unnoticed errors in enantioselective reactions may lead to misinterpretations of the enantioselective outcome of the synthesis. The scientific issue is, what is the difference between a racemic and nonracemic mixture in achiral environment (e.g., achiral‐phase chromatography) that leads to enantiomeric enrichment, amounting to separation of one particular enantiomer?There are sporadic reports on enantiomer separation of nonracemic mixtures in an achiral environment particularly from the scientists working in analytical chemistry. To cover/discuss all these reports is out of the scope of this article.The aim of the present report is to draw attention to the following points: i) How should the synthetic organic chemists and analytical chemists take care of the unexpected separation of enantiomers from nonracemic mixtures in a totally achiral environment? ii) What are the technical terms used in recent literature? iii) The requirement of revisiting definitions/terms (introduced in recent years, in particular) to describe such separations of enantiomers in light of prevalent scientific/chemical terminology used in the ‘language of chemistry’, the text book concept, and IUPAC background. iv) To propose logical scientific terminology or phrases for explaining the possible mechanism of separation under these conditions. v) To discuss briefly the concept/possibile phenomenon responsible for these enantioselective effects. It is also attempted to explain the effect of change of physical parameters influencing the separation from nonracemic mixture in achiral‐phase chromatography.

Diastereomers of (RS)-propranolol were synthesized using (S)-levofloxacin-based new chiral derivatizing reagents (CDRs). Levofloxacin was chosen as the pure (S)-enantiomer for its high molar absorptivity (εo  ∼ 24000) and availability at a low price. Its -COOH group had N-hydroxysuccinimide and N-hydroxybenzotriazole, which acted as good leaving groups during nucleophilic substitution by the amino group of the racemic (RS)-propranolol; the CDRs were characterized by UV, IR, (1) H-NMR, high resolution mass spectrometry (HRMS) and carbon, hydrogen, nitrogen, and sulphur fundamental elemental components analyser (CHNS). Diastereomers were separated quantitatively using open column chromatography; absolute configuration of the diastereomers was established and the reagent moiety was detagged under microwave-assisted acidic conditions. (S)- and (R)-propranolol as pure enantiomers and (S)-levofloxacin were separated, isolated and characterized. Optimized lowest-energy structures of the diastereomers were developed using Gaussian 09 Rev. A.02 program and hybrid density functional B3LYP with 6-31G* basis set (based on density functional theory) for explanation of elution order and configuration. In addition, RP HPLC conditions for separation of diastereomers were optimized with respect to pH, concentration of buffer, flow rate of mobile phase and nature of organic modifier. HPLC separation method was validated as per International Conference on Harmonization guidelines. With the systematic application of various analytical techniques, absolute configuration of the diastereomers (and the native enantiomers) of (RS)-propranolol was established. Copyright © 2016 John Wiley & Sons, Ltd.

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