Enantiomeric resolution conglomerates

Spontaneous asymmetric synthesis has been envisaged by theoretical models for more than 50 years [1-7]. This process features the generation and amplification of optical activity during the course of a chemical reaction. It stands in contrast to asymmetric procedures, such as stoichiometric resolution, conglomerate crystallization, or chiral chromatography, in which the optical activity can be increased but no additional chiral product is formed [8]. It is also different from classical asymmetric synthesis, in which new chiral product is obtained but the resulting enantiomeric excess (ee) is usually less than or, at most, equal to that of the chiral initiator or catalyst1. 

It is quite common in EPC synthesis either by asymmetric synthesis or by optical resolution via diastereomers (vide infra) that chiral compounds arc obtained in an enantiomerically enriched, yet optically impure, form. In these cases the optical purity may be increased by crystallization if the compound forms either a conglomerate or a racemic mixture. In the case of conglomerates. one simply adds the amount of solvent necessary for dissolving the racemate. The excess enantiomer remains in crystalline form. 

A related phenomenon can also occur when the crystal lattice packing is chiral. This intrinsic handedness can result in formation of a 1 1 mixture of enantiomeric crystals. In this case, although there has been self-resolution into (+)- and (—)-crystals, both molecular enantiomers remain unseparated in each crystal. The fundamental distinction is that a conglomerate single crystal contains only one molecular enantiomer and therefore would be optically active in solution, while, for the latter, a single crystal contains both molecular enantiomers and its solution would be optically inactive. 

The helical tubuland (HT) diols are a group of alicyclic dialcohols that show characteristic crystallisation behaviour [32,35], When a racemic sample is crystallised, then enantiomeric self-resolution occurs, yielding a conglomerate of (+)- and... 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

When a racemic compound in solution crystallizes in an enantiomorphic unit cell, thus forming a conglomerate, several possibilities can arise. In the ideal case, the crystals that are formed are of a reasonable size and the enantiomeric forms have distinct geometries. This was the situation that Pasteur encountered with sodium ammonium tartrate tetra-hydrate (2.5), and also that which allowed Wemer " to separate by hand the complex [Rh C204)3]K3 (2.24)-K3. It must be noted, however, that even in this case the spontaneous resolution must be accompanied by an asymmetric manual sorting operation. 

Similar to the experiences shown at the recrystaUization of enantiomeric mixtures, the conglomerate behaviour can also be observed at fractioned predpitation. An apphcation of this method was effectuated at the resolution of racemic tiserdne (IIS) with half an equivalent of (R,R)-tartaric acid. The (S)-TIS enantiomer, the active pharmaceutical ingredient, remained in the filtrate of the diastereoisomeric salt formation process. Consequently, it contaminated with its mirror imge isomer. The enantiomeric enrichment was accomplished by selective precipitation. The (S>R)-TIS mixture was dissolved in water as a hydrochloric acid salt, then less than an equivalent amount of potassium hydroxide was added to the solutionin order to liberate the excess of (S)-TIS. The pure (S)-TIS base precipitated from the solution and an almost racemic hydrochloride salt remained in the solution..33... 

Resolution of a racemic mixture was discovered by Pasteur in the last century. It remains an useful method to prepare enantiomerically pure compounds, although the yield in the desired enantiomw cannot exceed 50%. It is realized by the reaction of stoichiometric amounts of a chiral auxiliary which will produce a I I mixture of diastereomers, generally easy to separate. Removal of the chiral auxiliary graerates the desired enantiomer. A special case of resolution is one in which the racemic compound crystallizes as a conglomerate. Here, a chiral seed can propagate the production of... 

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