444
M. Sakamoto
in equal amounts. As the reaction progressed, the solution became saturated with the
poorly soluble product, and both enantiomers of the product precipitated in equal
amounts as racemic conglomerate crystals. The solid of 28 was gradually replaced
with the solid of product 29. The initial symmetry of this solid state was broken due
to either local statistical fluctuations in ee or a local difference in crystal size distribution between the enantiomers. Subsequently, grinding of the crystals in combination
with solution-phase racemization caused complete deracemization of the solids. The
reaction proceeded quantitatively, and the yield of the filtered solid product was 90
with 99% ee.
As described above, moderate chiral induction of 45% ee was achieved in a couple
of days by conjugate addition followed by the dynamic preferential crystallization
method. On the other hand, a considerably higher ee value was obtained with the
second method by using Viedma ripening, although several days were required for
effective deracemization even in the presence of DBU. Therefore, we examined
combining the methodology of both procedures to obtain optically pure crystals in
a short period of time. First, benzoylacrylamide 28 and phenethylamine (1.3 eq)
were reacted in a mixed solvent of MeOH and hexane, and the reaction mixture was
vigorously stirred while evaporating solvent at 40 °C. It took about a half-day to
remove all the solvent. The ee value of the solid of adduct 29 was around 15%. To
the solid, ethanol as a solvent, DBU (0.5 eq), and glass beads were added, and the
suspended mixture was stirred vigorously. The changes in ee values for the reaction
mixture (including both mother liquor and crystals) were plotted. Deracemization
began in a short time and the ee increased to 95% in only 8 or 9 days. In all cases, the
final ee value of the separated solid was 99%. Thus, we shortened the reaction time
significantly by dynamic preferential crystallization followed by attrition-enhanced
deracemization.
The next example is the asymmetric synthesis of an aspartic acid derivative,
succinopyridine 30 (Fig. 21.8) [59]. This material crystallizes in the chiral space
group of P2 1 2 1 2 1 and is used as an optical element due to its second-harmonic generation (SHG) properties. As described above, the aza-Michael addition is reversible
and is successful in chiral amplification by dynamic crystallization. The pyridinium
cation of 30 adjacent to the carboxylate anion also suggests that direct deprotonation
would lead to racemization of this material.
The racemization rate of optically active 30 was measured in 90 °C water, and
the half-life was found to be 115 min. The use of 10% aqueous AcOH reduced the
half-life to 20 min. In this case, when D 2 O was used instead of H 2 O, deuterated 30
was formed at the chiral center accompanied by small amounts of maleic acid and
fumaric acid. These facts suggested that the racemization of the chiral center did
not occur by a reversible reaction but by deprotonation involving the enol form as a
major pathway.
When an equal amount of maleic acid and pyridine was reacted in water at 90 °C,
succinopyridine precipitated readily. Acetic acid was added to form a 60% aqueous
acetic acid solution, and the reaction mixture maintained suspension with stirring at
the same temperature using glass beads. The ee value rose after 8 days and reached
99% ee after 16 days. A higher concentration of acetic acid, about 75% in water,
M. Sakamoto
in equal amounts. As the reaction progressed, the solution became saturated with the
poorly soluble product, and both enantiomers of the product precipitated in equal
amounts as racemic conglomerate crystals. The solid of 28 was gradually replaced
with the solid of product 29. The initial symmetry of this solid state was broken due
to either local statistical fluctuations in ee or a local difference in crystal size distribution between the enantiomers. Subsequently, grinding of the crystals in combination
with solution-phase racemization caused complete deracemization of the solids. The
reaction proceeded quantitatively, and the yield of the filtered solid product was 90
with 99% ee.
As described above, moderate chiral induction of 45% ee was achieved in a couple
of days by conjugate addition followed by the dynamic preferential crystallization
method. On the other hand, a considerably higher ee value was obtained with the
second method by using Viedma ripening, although several days were required for
effective deracemization even in the presence of DBU. Therefore, we examined
combining the methodology of both procedures to obtain optically pure crystals in
a short period of time. First, benzoylacrylamide 28 and phenethylamine (1.3 eq)
were reacted in a mixed solvent of MeOH and hexane, and the reaction mixture was
vigorously stirred while evaporating solvent at 40 °C. It took about a half-day to
remove all the solvent. The ee value of the solid of adduct 29 was around 15%. To
the solid, ethanol as a solvent, DBU (0.5 eq), and glass beads were added, and the
suspended mixture was stirred vigorously. The changes in ee values for the reaction
mixture (including both mother liquor and crystals) were plotted. Deracemization
began in a short time and the ee increased to 95% in only 8 or 9 days. In all cases, the
final ee value of the separated solid was 99%. Thus, we shortened the reaction time
significantly by dynamic preferential crystallization followed by attrition-enhanced
deracemization.
The next example is the asymmetric synthesis of an aspartic acid derivative,
succinopyridine 30 (Fig. 21.8) [59]. This material crystallizes in the chiral space
group of P2 1 2 1 2 1 and is used as an optical element due to its second-harmonic generation (SHG) properties. As described above, the aza-Michael addition is reversible
and is successful in chiral amplification by dynamic crystallization. The pyridinium
cation of 30 adjacent to the carboxylate anion also suggests that direct deprotonation
would lead to racemization of this material.
The racemization rate of optically active 30 was measured in 90 °C water, and
the half-life was found to be 115 min. The use of 10% aqueous AcOH reduced the
half-life to 20 min. In this case, when D 2 O was used instead of H 2 O, deuterated 30
was formed at the chiral center accompanied by small amounts of maleic acid and
fumaric acid. These facts suggested that the racemization of the chiral center did
not occur by a reversible reaction but by deprotonation involving the enol form as a
major pathway.
When an equal amount of maleic acid and pyridine was reacted in water at 90 °C,
succinopyridine precipitated readily. Acetic acid was added to form a 60% aqueous
acetic acid solution, and the reaction mixture maintained suspension with stirring at
the same temperature using glass beads. The ee value rose after 8 days and reached
99% ee after 16 days. A higher concentration of acetic acid, about 75% in water,