Limitations of Preferential Enrichment: A Case Study on Tryptophan Ethyl Ester Hydrochloride

Abstract

Since eutomer and distomer show different biological effects, access to pure enantiomers is essential. Preferential enrichment is a relatively new process of chiral resolution developed in the 90s. Extension of its scope was attempted with tryptophan ethyl ester hydrochloride. This salt meets one of the most important requirements for preferential enrichment, namely, a larger solubility for the pure enantiomers with reference to the racemic compound. But, due to the absence of a solid solution, this salt cannot perform preferential enrichment. This impossibility was endorsed by semi-empirical molecular modeling.

Reinvestigating the Preferential Enrichment of DL-Arginine Fumarate: New Thoughts on the Mechanism of This Far from Equilibrium Crystallization Phenomenon

“…For comparison, switching an enantiomer in the structure of DL-Tryptophan Ethyl Ester Hydrochloride structure, a compound that does not show PE although exhibiting all the prerequisites mentioned in the Introduction, costs ca. 30 to 40 kcal.mol −1 [23]. These results are consistent with the possibility for the DL-ArgFum crystal structure to accommodate the deviation from the racemic composition imposed by the mother liquor.…”

“…The energetic cost of such enantiomeric substitutions was then computed by molecular modeling (semi-empirical level of theory) by comparing the lattice energies of the artificial structures to that of the racemic ones. The detailed procedure has been published elsewhere [23] and appears as a satisfactory tool to explain the existence (or the absence) of solid solutions between enantiomers [32]. The details of the modeling calculations performed for DL-ArgFum are given in Figure S6 and Table S5.…”

“…(c) The racemic form should have a solid-solution-like behavior allowing each enantiomer to occupy the same molecular sites, at least to a certain extent. In a recent paper, we demonstrated the importance of this criterion in the case of Tryptophan Ethyl Ester Hydrochloride, a molecular salt that satisfies criterion (a) but which cannot show PE due to the absence of solid solution behavior even under high β (β is defined as the ratio concentration by solubility) [23]. (d) The occurrence of polymorphic transition during crystallization has also been regarded as a prerequisite although no such event has been spotted for second-generation compounds.…”

Spontaneous and Controlled Macroscopic Chiral Symmetry Breaking by Means of Crystallization

“…However, crystals obtained under high supersaturation (i.e., from a clear solution represented by point Ω 8 in Figure 8) clearly reveal, by Second Harmonic Generation (SHG), homochiral domains. If this effect cannot be detected, PE experiments fail [48]. (iii) The first generation of compounds showing PE effect have all exhibited solid-solid transitions between various disordered phases.…”

Temperature Cycling Induced Deracemization of NaClO3 under the Influence of Na2S2O6

“…In the field of resolution by crystallization, different methods were described and can be classified according to their starting equilibrium state. On one hand, processes such as second order asymmetric transformation (SOAT), , preferential crystallization (PC), , and preferential enrichment (PE) , start with different degrees of supersaturated solution, distant from the thermodynamic equilibrium, and rely on a kinetic mechanism to obtain the desired enantiomer. As opposed to PC and PE, the final state in the SOAT process is a thermodynamic equilibrium where the unwanted enantiomer is converted into the desired one by racemization in solution, during the crystallization process.…”