21 Asymmetric Synthesis Involving Dynamic Enantioselective …
449
Prochiral aroylacrylamide 35 has an enone structure, and the photoisomerization
reaction was expected to convert the E-form to the Z-form (Fig. 21.13) [44]. Thermodynamically stable (E)-35 was isomerized to the Z-form by irradiation of light. The
Z-form is much more stable than normal Z-enones due to the intramolecular hydrogen
bond between the carbonyl oxygen of the ketone and the NH group. Furthermore,
the NH of the amide and the nearby carbonyl carbon resulted in an intramolecular
cyclization reaction to give the pyrrolinone 36. It was revealed that 36 formed a
conglomerate with a crystal space group of P2 1 2 1 2 1 . Since pyrrolinone 36 has an
aminal skeleton, a racemization reaction is expected due to the (Z)-35 mediated ringopening process and deracemization by application of the stereoselective dynamic
crystallization method (asymmetric amplification).
The asymmetric center of 36 was stable in low polar solvents such as benzene,
hexane and chloroform and in aprotic solvents, and racemization did not proceed at
room temperature. An increase in racemization rate was observed in methanol, with
a half-life at 20 °C of 161 min. The half-life was shortened to 11.5 min at 35 °C.
When DBU was added as a base catalyst, racemization was further promoted;
however, isomerization from (Z)-35 to (E)-35 was also induced at the same time.
In order to obtain 36 of high optical purity, it was necessary to continue irradiation
with light in order to promote isomerization of the alkenyl group while promoting
racemization by DBU.
The experimental procedure for the actual asymmetric synthesis is very simple.
The prochiral (E)-35 and 0.1 equivalents of DBU were dissolved in a mixed solvent
of methanol and chloroform, and irradiated with light at 365 nm using an LED while
stirring at room temperature until the solvent was completely evaporated. The optical
purity of precipitated 36 after solvent evaporation was analyzed using HPLC with a
chiral column. In all the experiments, 36 was reproducibly obtained at 98–99.9% ee.
The chirality was random in each batch, but by adding a small amount of seed
crystals, it was possible to obtain 36 having the same chirality as the added seed
crystals. We also succeeded in an asymmetric reaction using sunlight. Enamide (E)35 has an absorption edge up to 420 nm and can be isomerized by sunlight. The
prochiral (E)-35 was dissolved in a mixed solvent of methanol and chloroform,
0.1 equivalents of DBU was added, and the mixture was irradiated with sunlight
with stirring until the solvent was completely evaporated. When the experiment was
conducted 10 times, 36 was obtained with an optical purity of 99% ee or more in all,
with 7 in the R-form and 3 in the S-form.
In this reaction system, the pyrrolinone derivative could be obtained with high
enantiomeric purity simply by irradiating the solution of prochiral compound with
LED light or sunlight outdoors (Fig. 21.14). Pyrrolinone is an important skeleton
found in many pharmaceutical intermediates, and the control of the stereochemistry
is an important research topic.
449
Prochiral aroylacrylamide 35 has an enone structure, and the photoisomerization
reaction was expected to convert the E-form to the Z-form (Fig. 21.13) [44]. Thermodynamically stable (E)-35 was isomerized to the Z-form by irradiation of light. The
Z-form is much more stable than normal Z-enones due to the intramolecular hydrogen
bond between the carbonyl oxygen of the ketone and the NH group. Furthermore,
the NH of the amide and the nearby carbonyl carbon resulted in an intramolecular
cyclization reaction to give the pyrrolinone 36. It was revealed that 36 formed a
conglomerate with a crystal space group of P2 1 2 1 2 1 . Since pyrrolinone 36 has an
aminal skeleton, a racemization reaction is expected due to the (Z)-35 mediated ringopening process and deracemization by application of the stereoselective dynamic
crystallization method (asymmetric amplification).
The asymmetric center of 36 was stable in low polar solvents such as benzene,
hexane and chloroform and in aprotic solvents, and racemization did not proceed at
room temperature. An increase in racemization rate was observed in methanol, with
a half-life at 20 °C of 161 min. The half-life was shortened to 11.5 min at 35 °C.
When DBU was added as a base catalyst, racemization was further promoted;
however, isomerization from (Z)-35 to (E)-35 was also induced at the same time.
In order to obtain 36 of high optical purity, it was necessary to continue irradiation
with light in order to promote isomerization of the alkenyl group while promoting
racemization by DBU.
The experimental procedure for the actual asymmetric synthesis is very simple.
The prochiral (E)-35 and 0.1 equivalents of DBU were dissolved in a mixed solvent
of methanol and chloroform, and irradiated with light at 365 nm using an LED while
stirring at room temperature until the solvent was completely evaporated. The optical
purity of precipitated 36 after solvent evaporation was analyzed using HPLC with a
chiral column. In all the experiments, 36 was reproducibly obtained at 98–99.9% ee.
The chirality was random in each batch, but by adding a small amount of seed
crystals, it was possible to obtain 36 having the same chirality as the added seed
crystals. We also succeeded in an asymmetric reaction using sunlight. Enamide (E)35 has an absorption edge up to 420 nm and can be isomerized by sunlight. The
prochiral (E)-35 was dissolved in a mixed solvent of methanol and chloroform,
0.1 equivalents of DBU was added, and the mixture was irradiated with sunlight
with stirring until the solvent was completely evaporated. When the experiment was
conducted 10 times, 36 was obtained with an optical purity of 99% ee or more in all,
with 7 in the R-form and 3 in the S-form.
In this reaction system, the pyrrolinone derivative could be obtained with high
enantiomeric purity simply by irradiating the solution of prochiral compound with
LED light or sunlight outdoors (Fig. 21.14). Pyrrolinone is an important skeleton
found in many pharmaceutical intermediates, and the control of the stereochemistry
is an important research topic.