21 Asymmetric Synthesis Involving Dynamic Enantioselective …
437
As mentioned above, chiral amplification using dynamic enantioselective crystallization is a very effective resolution method because the desired enantiomer
can be completely resolved in one crystallization [7, 8]. Several successful examples of chiral amplification have been reported so far, and their application to
amino acid derivatives and in the pharmaceutical field is particularly remarkable
(Fig. 21.2). The amino acid derivatives 1–11 [5, 26, 29–38] and the naproxen derivative 12 [39, 40] all use a racemization reaction via deprotonation at the α-position
of the carbonyl group. The required optically active enantiomers are selectively
obtained with high enantiomeric purity by filtration, and some compounds have
been developed industrially.
Deracemization of racemic diarylsuccinamides 13 affording a conglomerate was
also developed under basic conditions by the solvent evaporation method or attritionenhanced deracemization with specific ee values [41, 42].
The racemization reaction is most frequently reported by abstraction of the acidic
protons at the α-position of carbonyl groups, but asymmetric amplification accompanied by racemization of quaternary chiral centers has also been reported. The
chiral center of isoindolinone 14 is an aminal structure and is stable in nonpolar
solvents; however, racemization proceeds under basic conditions or in an alcoholic solvent. Asymmetric amplification from a racemate to over 90% ee has been
achieved by crystallization while promoting racemization in the presence of 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) [43]. Similarly, for the racemization by ringopening and ring-closing of the aminal carbon, 100% ee optical purity has been
reported even for asymmetric amplification of pyrrolinone 15 [44].
Spiropyrans 16 and spirooxazines 17 also have quaternary chiral centers. These
compounds are photochromic materials that undergo reversible color change owing
to ring-opening and ring-closing reactions by photolysis or thermal reaction. Asymmetric amplification has been achieved by dynamic crystallization of racemic
spiropyrans and spirooxazines, which afforded racemic conglomerate crystals by
the solvent evaporation method or attrition-enhanced deracemization [45].
Deracemization of allylsulfoxide 18 was developed by Meekes under grinding
conditions in ether refluxing conditions, where the racemization process involved
2,3-sigmatropic rearrangement [46].
An example of preferential crystallization accompanied by racemization (atropisomerization) by axial rotation has been reported [47]. Pincock et al. reported that
binaphthyl 19 was melted and crystallized at 150 °C to obtain an optically active solid.
Binaphthyl is a racemic crystal upon crystallization from solution, but deracemization
is achieved by satisfying two conditions: forming a conglomerate at high temperature and rapid racemization by axial rotation during crystallization. Furthermore,
when the melted materials were stirred during crystallization, the reproducibility of
obtaining high purity crystals improved with high optical purity of 90% ee or more
[48].
We found that an analog of pyrimidine bases 20 having aryl groups on the nitrogen
atom formed conglomerates [49]. These compounds have stable C–N axial chirality
and do not racemize at room temperature; however, axial rotation occurs at high
temperature. A small amount of solvent was added to crystals of 20. After dissolution
437
As mentioned above, chiral amplification using dynamic enantioselective crystallization is a very effective resolution method because the desired enantiomer
can be completely resolved in one crystallization [7, 8]. Several successful examples of chiral amplification have been reported so far, and their application to
amino acid derivatives and in the pharmaceutical field is particularly remarkable
(Fig. 21.2). The amino acid derivatives 1–11 [5, 26, 29–38] and the naproxen derivative 12 [39, 40] all use a racemization reaction via deprotonation at the α-position
of the carbonyl group. The required optically active enantiomers are selectively
obtained with high enantiomeric purity by filtration, and some compounds have
been developed industrially.
Deracemization of racemic diarylsuccinamides 13 affording a conglomerate was
also developed under basic conditions by the solvent evaporation method or attritionenhanced deracemization with specific ee values [41, 42].
The racemization reaction is most frequently reported by abstraction of the acidic
protons at the α-position of carbonyl groups, but asymmetric amplification accompanied by racemization of quaternary chiral centers has also been reported. The
chiral center of isoindolinone 14 is an aminal structure and is stable in nonpolar
solvents; however, racemization proceeds under basic conditions or in an alcoholic solvent. Asymmetric amplification from a racemate to over 90% ee has been
achieved by crystallization while promoting racemization in the presence of 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) [43]. Similarly, for the racemization by ringopening and ring-closing of the aminal carbon, 100% ee optical purity has been
reported even for asymmetric amplification of pyrrolinone 15 [44].
Spiropyrans 16 and spirooxazines 17 also have quaternary chiral centers. These
compounds are photochromic materials that undergo reversible color change owing
to ring-opening and ring-closing reactions by photolysis or thermal reaction. Asymmetric amplification has been achieved by dynamic crystallization of racemic
spiropyrans and spirooxazines, which afforded racemic conglomerate crystals by
the solvent evaporation method or attrition-enhanced deracemization [45].
Deracemization of allylsulfoxide 18 was developed by Meekes under grinding
conditions in ether refluxing conditions, where the racemization process involved
2,3-sigmatropic rearrangement [46].
An example of preferential crystallization accompanied by racemization (atropisomerization) by axial rotation has been reported [47]. Pincock et al. reported that
binaphthyl 19 was melted and crystallized at 150 °C to obtain an optically active solid.
Binaphthyl is a racemic crystal upon crystallization from solution, but deracemization
is achieved by satisfying two conditions: forming a conglomerate at high temperature and rapid racemization by axial rotation during crystallization. Furthermore,
when the melted materials were stirred during crystallization, the reproducibility of
obtaining high purity crystals improved with high optical purity of 90% ee or more
[48].
We found that an analog of pyrimidine bases 20 having aryl groups on the nitrogen
atom formed conglomerates [49]. These compounds have stable C–N axial chirality
and do not racemize at room temperature; however, axial rotation occurs at high
temperature. A small amount of solvent was added to crystals of 20. After dissolution