Enantiomerically Pure Dibenzyl Esters of l-Aspartic and l-Glutamic Acid

Abstract

S)-Dibenzyl aspartate p-toluenesulfonate [(S)-1·TsOH] and (S)-dibenzyl glutamate p-toluenesulfonate [(S)-2·TsOH] were efficiently prepared from the respective L-amino acids and benzyl alcohol with very high yields by using cyclohexane as a water azeotroping solvent instead of benzene, carbon tetrachloride, toluene, or benzyl alcohol itself, as reported in literature methods. Preventively, chiral HPLC methods were developed to determine the enantiomeric excess of the two diesters and DSC analyses were performed on the respective ptoluenesulfonates. With the aid of such investigation tools, we demonstrated that (S)-1·TsOH and (S)-2·TsOH were formed enatiomerically pure in cyclohexane, whereas more or less pronounced racemization occurred both in toluene and in benzyl alcohol. The two one-pot procedures, which did not require crystallization of the product or any other purification step, were accomplished on multigram scale.

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

“…These experiments were not applied to 3 , 7 , 8 , or 10 , which also form racemic compounds, because enantioenrichment was useless or not practically advantageous. In fact, under esterification conditions promoting racemization, l - 8 was invariably obtained without racemization, d - 7 and l - 10 , oppositely, with too high an extent of racemization and l - 3 with poor yield due to degradation. , …”

“…We previously reported the melting points of the racemate and single enantiomers of 1 – 11 . , The melting temperature values, corresponding to the maximum of the melting peak in the DSC trace, are listed in Table with the exception of l - 11 , which is an oil, and the addition of rac- 2 , whose melting point had never been reported. Furthermore, we previously demonstrated by IR and DSC analyses that 1 , whose racemate melts 26 °C lower than the enantiomers, forms a conglomerate . On the basis of the 27 °C lower melting point of the racemate compared to the enantiomer and on their superimposable IR spectra, we later proposed that 6 also forms a conglomerate .…”

“… a Melting peak maximum in the DSC trace. b C: conglomerate; RC: racemic compound. c Of the l enantiomer with the exception of 7 ( d enantiomer). d Of the prevailing enantiomer ( l or, in the only case of 7 , d ); derived from the enantiomeric excesses reported in refs and . e In mg/mL at 20 °C. f Ratio of racemate solubility/enantiomer solubility at 20 °C. g Calculated from α 20 according to ref . …”

“… d Of the prevailing enantiomer ( l or, in the only case of 7 , d ); derived from the enantiomeric excesses reported in refs and . …”

“…Amino acids are very important chiral platform molecules, and the enantiomers of their benzyl esters are key starting materials for the chemical and chemoenzymatic synthesis of dipeptides and polypeptides , and for building more complex nonpeptide molecules including, for instance, mono- or polyheterocyclic diazepinic or azetidinonic substructures. − Recently, we have studied the esterification of 11 amino acids (Asp, Glu, Lys, Ala, Phe, Tyr, Phg, Val, Leu, Met, and Ser) by reaction with excess benzyl alcohol and little more than stoichiometric p -toluenesulfonic acid in boiling solvents, which form heterogeneous water azeotropes and can thus remove water resulting from esterification. , By this procedure, we prepared the dibenzyl ester p -toluenesulfonates of l -aspartic acid ( l - 1 ) and l -glutamic acid ( l - 2 ), the benzyl ester di- p -toluenesulfonate of l -lysine ( l - 3 ), and the benzyl ester p -toluenesulfonates of l -alanine ( l - 4 ), l -phenylalanine ( l - 5 ), l -tyrosine ( l - 6 ), d -phenylglycine ( d - 7 ), l -valine ( l - 8 ), l -leucine ( l - 9 ), l -methionine ( l - 10 ), and l -serine ( l - 11 ) (Chart ).…”