Phase Diagrams to Evaluate the Opportunity for Enantiomeric Enrichment of Some Nonracemic Mixtures of Amino Acid Benzyl Esters by Crystallization as p-Toluenesulfonate Salts

Abstract

A number of amino acids undergo moderate-to-high racemization when converted to benzyl ester under inadequate conditions. As they are usually recovered and purified at the end of the esterification by precipitating/crystallizing the p-toluenesulfonate salt, it is of most importance to be aware that such isolation procedures can improve but also lessen the enatiomeric excess of the product. To predict the chance of enantioenrichment by crystallization, it is necessary to define whether the enantiomers of these ester salts form conglomerates or racemic compounds in the solid state and, in case of racemic compounds, to know the enantiomeric composition of the eutectics and to verify that it is similar to the eutectic composition obtained from ternary solubility curves. We constructed the binary melting point phase diagrams of a number of amino acid benzyl ester p-toluenesulfonates showing that most of them form racemic compounds. Of these, we studied those of Ala, Phe, Leu, and Glu, in particular, demonstrating that when prepared in l form with moderate racemization the first three cannot be enantioenriched by crystallization because their l fraction is much higher at the ternary solubility eutectic than at the binary eutectic, whereas the last one can be isolated enantiopure by crystallization because its l fractions at both the ternary solubility and binary eutectics are accordingly low.

1H NMR spectroscopy in the presence of Mosher acid to rapidly determine the enantiomeric composition of amino acid benzyl esters, chirons susceptible to easy racemization

“…Recently, we have reported the Fischer-Speier efficient preparation of several amino acid benzyl esters with very high enantiomeric excess in cyclohexane or in the green ether Me-THF at reflux (Bolchi et al 2017a;Bolchi et al 2018). Differential scanning calorimetry investigations and development of chiral HPLC analytical methods specific for any amino acid benzyl ester allowed us to validate these new procedures and to discard unsuitable solvents such as toluene, but also as the high boiling ether CPME (Bolchi et al 2017a;Bolchi et al 2018;Bolchi et al 2017b). NMR spectroscopy associated to the use of chiral auxiliaries can be alternative to chiral HPLC and its attractiveness is much higher if enantiodifferentiation is achieved by simply adding chiral solvating agents (CSA), which form rapidly reversible diastereomeric complexes with the two dissolved enantiomers of the analyte via noncovalent interactions and thus without need of any substrate derivatization (Wenzel and Chisholm 2011;Parker 1991;Seco et al 2004;Seco et al 2012;Perez-Trujillo et al 2013).…”