Resolution of a Metastable Racemic Compound of Anhydrous Phencyphos by Hydrate Formation

The resolution of 2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinan 2-oxide (phencyphos) was achieved by dissolution of anhydrous racemic phencyphos, a racemic compound, accompanied by simultaneous secondary nucleation of the dissolved racemate on to enantiopure seeds of phencyphos hydrate, a conglomerate. The seeds were placed in separate compartments and the pure enantiomers could be conveniently collected from these compartments after the dissolution of the anhydrous racemate.

A new twist in eutectic composition: deracemization of a racemic compound amino acid by Viedma ripening and temperature fluctuation.

Viedma ripening and temperature fluctuation are processes based on solution phase racemization and dissolution-growth of racemic or scalemic conglomerates resulting in solid-phase deracemization. The dissolution-growth process is performed by abrasive grinding in the first case and by the temperature fluctuation in the second. But both methods have the intrinsic drawback of being only applicable to conglomerates, accounting for only 10% of all chiral molecules and are not suitable for the 90% of chiral compounds that crystallize as racemic compound. Herein we show that the enantiomeric excess of the solution in the eutectic mixture formed by a racemic compound and one of its enantiomers in suspension changes dramatically by growth-dissolution of the crystals through grinding and temperature fluctuation, converting the racemic compound into the desired enantiomer. With this new finding the scope of Viedma ripening and temperature fluctuation could be significantly expanded and can shed new ideas about the origin of biological homochirality on earth.

Possibilities of Exploiting Kinetic Control in the Continuous Fractional Crystallization of Diastereomeric Mixtures

For rapid and kinetic control-influenced resolutions, it is advisable to choose a resolving agent with the highest possible eutectic composition (eeEuResAg). It may also be advantageous to add the crystalline resolving agent directly to the solution of the racemic compound. In addition, the use of a quasi-racemic resolving agent or amphoteric resolving agent can provide kinetic resolution. In some cases, the continuous fractional crystallization of diastereomeric salts requires the salt of the resolving agent (Ca2+, Na+, etc.) or other achiral additives (thiourea) that cause rapid crystallization and provide high diastereomeric purity. A further advantage may be the sequential use of the same resolving agent that is capable of forming crystalline diastereomers with both enantiomers when using kinetic control (tandem resolution).

The Stoichiometry, Structure and Possible Formation of Crystalline Diastereomeric Salts

Knowing the eutectic composition of the binary melting point phase diagrams of the diastereomeric salts formed during the given resolution, the achievable F (F = eeDia*Y) value can be calculated. The same value can also be calculated and predicted by knowing the eutectic compositions of the binary melting point phase diagrams of enantiomeric mixtures of the racemic compound or the resolving agent. An explanation was sought as to why and how the crystalline precipitated diastereomeric salt—formed in the solution between a racemic compound and the corresponding resolving agent—may be formed. According to our idea, the self-disproportionation of enantiomers (SDE) has a decisive role when the enantiomers form two nonequal ratios of conformers in solution. The self-organized enantiomers form supramolecular associations having M and P helicity, and double helices are formed. Between these double spirals, with the formation of new double spirals, a dynamic equilibrium is achieved and the salt crystallizes. During this process between acids and bases, chelate structures may also be formed. Acids appear to have a crucial impact on these structures. It is assumed that the behavior of each chiral molecule is determined by its own code. This code validates the combined effect of constituent atoms, bonds, spatial structure, charge distribution, flexibility and complementarity.

Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation of Enantiomers and Enantiomeric Mixtures

This perspective is focused on the main parameters determining the results of crystallization of enantiomers or enantiomeric mixtures. It was shown that the ratio of supramolecular and helical associations depends on the eutectic composition of the corresponding enantiomeric mixture. The M and P ratios together with the self-disproportionation (SDE) of enantiomers define the reaction of the racemic compound with the resolving agent. Eventually, each chiral molecule reacts with at least two conformers with different degrees of M and P helicity. The combined effect of the configuration, charge distribution, constituent atoms, bonds, flexibility, and asymmetry of the molecules influencing their behavior was also summarized.