21 Asymmetric Synthesis Involving Dynamic Enantioselective …
439
at 200 °C, a small amount of seed crystals was added and crystallization was carried
out while gradually cooling to obtain crystals with high optical purity of 90% ee or
more.
In addition, there is a substrate suitable for deracemization by crystallization.
Pyrimidinethione 21 having a naphthyl group on the nitrogen atom forms a conglomerate. The solvent is gradually evaporated from the toluene solution at 100 °C to give
91% ee of crystals [50, 51].
Nicotinamide 22 also gave a conglomerate (P2 1 space group) and has a half-life of
racemization of about 3 h in chloroform at 20 °C. It was melted at 160 °C (mp 148 °C),
gradually cooled to 125 °C with stirring, and solidified by adding a small amount
of seed crystals, giving 83–92% ee of crystals [52]. To obtain a high ee of crystals
with good reproducibility by deracemization from the melt, seeding is necessary,
because only 6-42% ee was obtained without seeding. On the other hand, attrition
with stirring in hexane at 70 °C always gave 99% ee crystals after 3 days.
Similar aromatic amide derivatives 23–25 exhibited axial chirality, and afforded
conglomerate crystals [53–55]. Their activation free energies are around 20–
22 k cal mol
−1 , which means that their axial chirality can be easily controlled thermodynamically. Optically active compounds were easily obtained by enantioselective
crystallization from the melt with specific ees; however, the chirality was gradually
lost by dissolving into solvent even at room temperature. The chirality was efficiently
utilized for many asymmetric reactions at low temperature and by using adequate
solvent properties.
21.3 Absolute Asymmetric Synthesis by the Combined
Methodology of Chiral Center Generation
and Dynamic Enantioselective Crystallization
Focusing on developing a more effective and convenient absolute asymmetric
synthesis using crystal chirality, an asymmetric synthetic method combining a reaction that generates a chiral center from a prochiral molecule with dynamic crystallization was developed (Fig. 21.3). Optically active materials can be obtained by simultaneously carrying out the chemical reaction and dynamic crystallization without an
external chiral source. This approach starts with prochiral materials that can provide
chiral products via reversible condensation reactions. Application to the Mannich
reaction has been reported by Tsogoeva et al. [37] and to an aldol condensation by
Bolm et al. [56]. We also developed some new reaction systems and summarize them
together with some valuable results developed by other groups.
439
at 200 °C, a small amount of seed crystals was added and crystallization was carried
out while gradually cooling to obtain crystals with high optical purity of 90% ee or
more.
In addition, there is a substrate suitable for deracemization by crystallization.
Pyrimidinethione 21 having a naphthyl group on the nitrogen atom forms a conglomerate. The solvent is gradually evaporated from the toluene solution at 100 °C to give
91% ee of crystals [50, 51].
Nicotinamide 22 also gave a conglomerate (P2 1 space group) and has a half-life of
racemization of about 3 h in chloroform at 20 °C. It was melted at 160 °C (mp 148 °C),
gradually cooled to 125 °C with stirring, and solidified by adding a small amount
of seed crystals, giving 83–92% ee of crystals [52]. To obtain a high ee of crystals
with good reproducibility by deracemization from the melt, seeding is necessary,
because only 6-42% ee was obtained without seeding. On the other hand, attrition
with stirring in hexane at 70 °C always gave 99% ee crystals after 3 days.
Similar aromatic amide derivatives 23–25 exhibited axial chirality, and afforded
conglomerate crystals [53–55]. Their activation free energies are around 20–
22 k cal mol
−1 , which means that their axial chirality can be easily controlled thermodynamically. Optically active compounds were easily obtained by enantioselective
crystallization from the melt with specific ees; however, the chirality was gradually
lost by dissolving into solvent even at room temperature. The chirality was efficiently
utilized for many asymmetric reactions at low temperature and by using adequate
solvent properties.
21.3 Absolute Asymmetric Synthesis by the Combined
Methodology of Chiral Center Generation
and Dynamic Enantioselective Crystallization
Focusing on developing a more effective and convenient absolute asymmetric
synthesis using crystal chirality, an asymmetric synthetic method combining a reaction that generates a chiral center from a prochiral molecule with dynamic crystallization was developed (Fig. 21.3). Optically active materials can be obtained by simultaneously carrying out the chemical reaction and dynamic crystallization without an
external chiral source. This approach starts with prochiral materials that can provide
chiral products via reversible condensation reactions. Application to the Mannich
reaction has been reported by Tsogoeva et al. [37] and to an aldol condensation by
Bolm et al. [56]. We also developed some new reaction systems and summarize them
together with some valuable results developed by other groups.