Comparison of Chiral Separations of Aminophosphonic Acids and Their Aminocarboxylic Acid Analogs Using a Crown Ether Column

Abstract

Crown ethers are capable of complexing with primary amines and have been utilized in chromatography to separate amino acid racemates. This application has been extended to resolve (1-amino-1-phenylmethyl)phosphonic acid and (1-aminoethyl)phosphonic acid racemates, along with their aminocarboxylic acid analogs (2-phenylglycine and alanine, respectively), via a ChiroSil RCA crown ether based chiral stationary phase. Effects of the organic modifier, temperature, and acid type and concentration on retention and selectivity were also investigated. Trends in retention and selectivity varied between aminophosponic acids and their aminocarboxylic analogs. Computer modeling and (1)H NMR analyses were performed to potentially gain a better understanding of interactions of the aforementioned molecules with the ChiroSil RCA chiral stationary phase. Theoretical predictions of the most stable conformations for (R)- and (S)-enantiomers were compared to elution order; it was found that the elution order agreed with molecular modeling such that the longest retention correlated with the predicted most stable complex between the enantiomer and crown ether. (1)H NMR demonstrated interactions of aminophosphonic and aminocarboxylic racemates with (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid in solution and was utilized to determine enantiomeric excess of (1-amino-1-phenylmethyl)phosphonic acid after its enantioenrichment via crystallization through diastereomeric salt formation with the crown ether followed by filtration.

Development of HPLC Chiral Stationary Phases Based on (+)‐(18‐Crown‐6)‐2,3,11,12‐tetracarboxylic Acid and Their Applications

“…CSP 1 was also successfully applied to the resolution of aminophosphonic acids (see Fig. for the structure), analogs of α‐amino acids, which have been known to show various biological activities including antibacterial, antifungal, and enzyme‐inhibiting properties . Actually, (1‐amino‐1‐phenylmethyl)phosphonic acid (R = Phenyl) and (1‐aminoethyl)phosphonic acid (R = Methyl) were resolved on CSP 1 with the use of 2.0% perchloric or trifluoro acetic acid (v/v) in water:methanol (20:80 or 30:70) as a mobile phase .…”

Resolution of Enantiomers of Novel C2‐Symmetric Aminobisphosphinic Acids via Diastereomeric Salt Formation With Quinine

“…α‐Aminoalkylphosphinic acids are considered structural analogs of α‐amino acids and possess potential biological activities applicable to antibiotics, enzyme inhibitors, pharmacological agents, antiviral agents, and herbicides (Figure ) . Since the structure of the phosphinic functional group mimics the unstable tetrahedral intermediates formed in enzyme‐mediated peptide bond cleavage, some pseudo‐peptides derived from α‐aminophosphinic acids are known to act as inhibitors of proteolytic enzymes such as metallo‐ and serine‐proteases …”