21 Asymmetric Synthesis Involving Dynamic Enantioselective …
435
them, the chiral space groups are P2 1 2 1 2 1 , P2 1 , P1, C2, which is 14.1% of the
total [14]. Since this data includes crystal structure analysis data of optically active
compounds, the ratio of chiral crystallization of achiral compounds and formation of
conglomerates is considered to be somewhat lower, around 5-10%. However, there
are some substance groups where only half crystallize in a chiral space group, and
there are cases where the synthesis of 50 types of derivatives does not afford any
chiral space groups. Although the intermolecular interactions of both enantiomers
can be predicted to some extent, they are still not fully elucidated but are dependent
on chance.
Therefore, when performing a reaction using a chiral crystal or utilizing optical
resolution by crystallization, it is preferable to target a substance group whose
substituents can be easily changed. Unlike studies applying to a variety of derivatives with different substituents, such as asymmetric synthesis using chiral catalysts, chiral crystallization is a bottleneck for asymmetric synthesis using crystal
chirality. In order to avoid this bottleneck, a diastereomeric reaction can be used
by introducing optically active substituents into the molecule, or by forming chiral
ion pairs (salts), co-crystals, or chiral inclusion compounds (host–guest complexes).
Many valuable methods have been adopted that lead to chiral environments in crystal
lattices [15–20].
21.2 Total Resolution from Racemates by Dynamic
Crystallization
Pasteur was able to manually separate sodium ammonium tartrate crystals to obtain
an enantiopure compound, based on the geometric chirality of the contours of the
conglomerate crystal. However, it is difficult to visually divide most crystals, because
they do not show geometric chirality by such an outline [21]. So far, conglomerate
crystals have been used for optical resolution of racemates by general preferential
crystallization methods, which are important methods indispensable for resolution
processes on an industrial scale, especially in the fields of medicine, agrochemicals,
and foods [22].
In the industrial preferential crystallization process, various improvements have
been made to obtain crystals with as high an enantiomeric purity as possible, but
it is necessary to reduce the amount of crystals obtained by one crystallization,
because the opposite enantiomer that is excessive in the mother liquor crystallizes.
(Fig. 21.1a). Furthermore, the maximum resolution is only 50:50, and there is a
problem that one enantiomer must be discarded. Therefore, total resolution to selectively obtain only the required enantiomer by crystallization under conditions where
racemization occurs rapidly has been performed with some substrates (Fig. 21.1b).
When a racemic mixture of a conglomerate is crystallized from a supersaturated
solution, the molecule repeatedly aggregates and dissolves, until the first chiral crystal
nucleus is eventually formed. As molecules of the same enantiomer gather further
435
them, the chiral space groups are P2 1 2 1 2 1 , P2 1 , P1, C2, which is 14.1% of the
total [14]. Since this data includes crystal structure analysis data of optically active
compounds, the ratio of chiral crystallization of achiral compounds and formation of
conglomerates is considered to be somewhat lower, around 5-10%. However, there
are some substance groups where only half crystallize in a chiral space group, and
there are cases where the synthesis of 50 types of derivatives does not afford any
chiral space groups. Although the intermolecular interactions of both enantiomers
can be predicted to some extent, they are still not fully elucidated but are dependent
on chance.
Therefore, when performing a reaction using a chiral crystal or utilizing optical
resolution by crystallization, it is preferable to target a substance group whose
substituents can be easily changed. Unlike studies applying to a variety of derivatives with different substituents, such as asymmetric synthesis using chiral catalysts, chiral crystallization is a bottleneck for asymmetric synthesis using crystal
chirality. In order to avoid this bottleneck, a diastereomeric reaction can be used
by introducing optically active substituents into the molecule, or by forming chiral
ion pairs (salts), co-crystals, or chiral inclusion compounds (host–guest complexes).
Many valuable methods have been adopted that lead to chiral environments in crystal
lattices [15–20].
21.2 Total Resolution from Racemates by Dynamic
Crystallization
Pasteur was able to manually separate sodium ammonium tartrate crystals to obtain
an enantiopure compound, based on the geometric chirality of the contours of the
conglomerate crystal. However, it is difficult to visually divide most crystals, because
they do not show geometric chirality by such an outline [21]. So far, conglomerate
crystals have been used for optical resolution of racemates by general preferential
crystallization methods, which are important methods indispensable for resolution
processes on an industrial scale, especially in the fields of medicine, agrochemicals,
and foods [22].
In the industrial preferential crystallization process, various improvements have
been made to obtain crystals with as high an enantiomeric purity as possible, but
it is necessary to reduce the amount of crystals obtained by one crystallization,
because the opposite enantiomer that is excessive in the mother liquor crystallizes.
(Fig. 21.1a). Furthermore, the maximum resolution is only 50:50, and there is a
problem that one enantiomer must be discarded. Therefore, total resolution to selectively obtain only the required enantiomer by crystallization under conditions where
racemization occurs rapidly has been performed with some substrates (Fig. 21.1b).
When a racemic mixture of a conglomerate is crystallized from a supersaturated
solution, the molecule repeatedly aggregates and dissolves, until the first chiral crystal
nucleus is eventually formed. As molecules of the same enantiomer gather further