Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

Abstract

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second‐order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate‐forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

Spontaneous Deracemizations

“…Also the first step of the identification of the crystals belonging to one of the 65 Sohncke groups and despite the help that CBD offers generally requires previous X-ray diffraction studies. In this respect, there is a lack of studies of phase diagrams for knowing the range of concentrations or type of solvent where the racemic conglomerate is the stable form: a recent report constitutes an example of this type of necessary preliminary work . Most of the reported works are based on α-amino acid derivatives by converting them into imines, which then by tautomerization racemize the H atom bearing a stereogenic center (example of Figure ).…”

“…In this respect, there is a lack of studies of phase diagrams for knowing the range of concentrations or type of solvent where the racemic conglomerate is the stable form: a recent report constitutes an example of this type of necessary preliminary work. 203 Most of the reported works are based on α-amino acid derivatives by converting them into imines, 204 which then by tautomerization racemize the H atom bearing a stereogenic center (example of Figure 9). However, other racemization procedures, through a redox reaction, 205 thermal sigmatropic rearrangement, 206 atropisomerism, 207 and photoisomerization 208,209 are being reported.…”

Spontaneous and Controlled Macroscopic Chiral Symmetry Breaking by Means of Crystallization

“…When a fast racemization takes place in solution under the same condition as the crystallization of a conglomerate, it is possible to observe a spontaneous macroscopic break in symmetry. The corresponding phase diagrams are no longer those displayed in Figure 1A-D, as detailed in [20,21]. Indeed, the phase diagrams are degenerated because the liquid phase can only contain an equimolar amount of enantiomers (i.e., a racemic composition see Figures 1E and 2).…”

Crystallization-Induced Deracemization: Experiments and Modeling

“…We remark in passing that another nonlinear cooling profile, different from that proposed here, was investigated in the literature to improving the performance of the CID process: more specifically, a cubic trajectory. 25 Such a trajectory was proposed by Mullin for cooling crystallization assuming a constant rate of growth in the absence of nucleation and under the condition that the temperature derivative of solubility is not temperature dependent: i.e. assuming the solubility is a linear funtion of temperature 29 (note that in this work, we use the exponential dependence of solubility on temperature).…”

“… 17 , 23 − 25 These earlier works showed that, by application of the appropriate temperature profile, this simple technique enabled the collection of a pure product with higher productivity in comparison to deracemization via temperature cycles. 17 , 25 However, a systematic analysis of the effect of the operating conditions, which aims at understanding how to tune them to target high purity and productivity, is still lacking.…”