**5.2 Diastereoselective reaction using memory effect of coumarinecarboxamides**

We found that coumarin carboxamide **19** also existed as a mixture of diastereomers in solution, and could be converged to (*S,aR*)-conformer by solidification.28) When the crystals of **19** were dissolved in MeOH at -20°C and irradiated in the presence of electron-rich alkenes, perfectly stereo-controlled 1:1 photoadduct **22** was obtained in 100% *de* (Figures 16, 17).

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 75

isomer was easier to crystallize than the major isomer, and they converged to almost a single diastereomer in a ratio of a*R*:a*S* = 95:5 (*de* = 90%). Furthermore, recrystallization of the crystals once from ether easily gave 99% *de* of amide **20**. Axial chirality was stable for several days at room temperature; however, heating the chloroform solution of (*S*,a*R*)-**20** at 55°C for

Next, the homochiral crystals were utilized for subsequent diastereoselective reactions. Diastereoselective 2+2 photocycloaddition reaction of amide **20** with methacrylonitrile was examined. The reaction with methacrylonitrile proceeded effectively, stereo-, and regiospecifically. The amide **20** before crystallization was irradiated in the presence of methacrylonitrile with a high-pressure mercury lamp at 20°C until most of the starting amide was consumed (2 hrs). The photochemical reaction occurred effectively, and 2 + 2 cycloadducts were obtained in 100% chemical yields; both diastereomers were *endo* isomers, minor (1*S*,2a*R*,8b*R*)-**23**, major (1*R*,2a*S*,8b*S*)-**23**, and the *de* value was -25%. Since epimerization was not observed at 20°C, it seems that the *de* value of the photoproducts should be attributed

12 hrs gave the exact same diastereomixture as before crystallization.

to the ratio of the diastereomers of the amide **20** before crystallization (-20% *de*).

Fig. 18. Epimerization of quinolonecarboxamide with chiral handle and stereoselective

Furthermore, we examined a photocycloaddition reaction using the homochiral molecular conformation converged by CIDT. The crystals were expected to be composed of a single diastereomer of (*S*,a*R*)-conformation, and the epimerization in the solution caused by the bond rotation between the quinolone and the carbonyl group was restricted at room temperature. In other words, conformation in the crystals may be retained as frozen after dissolving them in the solvent at room temperature, and molecular homochirality can be

photoaddition using chiral memory.

Table 4. Diastereoselective photocycloaddition using chiral memory derived from CIDT

Fig. 16. Epimerization of coumarinecarboxamide with chiral handle

Fig. 17. Stereoselective photocycloaddition using chiral memory derived from CIDT

#### **5.3 Diastereoselective reaction using memory effect of quinolonecarboxamides**

2-Quinolone-4-carboxamide **20** possessing (*S*)-proline methyl ester as a chiral handle was chosen for the purpose.29) Amide **20** exists as a mixture of two diastereomers in the ratio of a*R*:a*S* = 40:60 (diastereomeric excess, *de* = -20%) before crystallization (Figure 18). When the mixture was crystallized from a THF solution by evaporating solvent at 70°C, the minor

h -20oC THF 0.5 h

conv. of **18** (%)

solidification

before before after after

Fig. 16. Epimerization of coumarinecarboxamide with chiral handle

yield of **21** (%)

NC

**21**

RO

O N CO2Me

*de* of **21** (%)

>99 >99 >99 >99

Table 4. Diastereoselective photocycloaddition using chiral memory derived from CIDT

Fig. 17. Stereoselective photocycloaddition using chiral memory derived from CIDT

**5.3 Diastereoselective reaction using memory effect of quinolonecarboxamides** 

2-Quinolone-4-carboxamide **20** possessing (*S*)-proline methyl ester as a chiral handle was chosen for the purpose.29) Amide **20** exists as a mixture of two diastereomers in the ratio of a*R*:a*S* = 40:60 (diastereomeric excess, *de* = -20%) before crystallization (Figure 18). When the mixture was crystallized from a THF solution by evaporating solvent at 70°C, the minor

+

9-CNAN

**18-A** Crystal

amide **18-A**

**18a** (R = Me) **18b** (R = Et) **18a** (R = Me) **18b** (R = Et)

isomer was easier to crystallize than the major isomer, and they converged to almost a single diastereomer in a ratio of a*R*:a*S* = 95:5 (*de* = 90%). Furthermore, recrystallization of the crystals once from ether easily gave 99% *de* of amide **20**. Axial chirality was stable for several days at room temperature; however, heating the chloroform solution of (*S*,a*R*)-**20** at 55°C for 12 hrs gave the exact same diastereomixture as before crystallization.

Next, the homochiral crystals were utilized for subsequent diastereoselective reactions. Diastereoselective 2+2 photocycloaddition reaction of amide **20** with methacrylonitrile was examined. The reaction with methacrylonitrile proceeded effectively, stereo-, and regiospecifically. The amide **20** before crystallization was irradiated in the presence of methacrylonitrile with a high-pressure mercury lamp at 20°C until most of the starting amide was consumed (2 hrs). The photochemical reaction occurred effectively, and 2 + 2 cycloadducts were obtained in 100% chemical yields; both diastereomers were *endo* isomers, minor (1*S*,2a*R*,8b*R*)-**23**, major (1*R*,2a*S*,8b*S*)-**23**, and the *de* value was -25%. Since epimerization was not observed at 20°C, it seems that the *de* value of the photoproducts should be attributed to the ratio of the diastereomers of the amide **20** before crystallization (-20% *de*).

Fig. 18. Epimerization of quinolonecarboxamide with chiral handle and stereoselective photoaddition using chiral memory.

Furthermore, we examined a photocycloaddition reaction using the homochiral molecular conformation converged by CIDT. The crystals were expected to be composed of a single diastereomer of (*S*,a*R*)-conformation, and the epimerization in the solution caused by the bond rotation between the quinolone and the carbonyl group was restricted at room temperature. In other words, conformation in the crystals may be retained as frozen after dissolving them in the solvent at room temperature, and molecular homochirality can be

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 77

activation free energy of racemization from 10 to 30 kcal mol-1 for chiral memory. It is not an unusual technique, but a rather typical approach that can be widely utilized in asymmetric reactions. We have found many more applications to this method using chiral memory; we will present them in future work. In addition, this method could be applied to the diastereoselective reaction using chiral memory derived from CIDT. These findings suggest that the molecular information in the crystal can be widely applied to a variety of chemistry,

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**7. References** 

215-230

effectively transferred to the products. The THF solution of (*S*,a*R*)-**20** containing methacrylonitrile was irradiated with a high-pressure mercury lamp for 2 hrs until the starting amide was consumed. When the reaction was performed at 20°C, two 2 + 2 adducts, major (1*S*,2a*R*,8b*R*)-**23** and minor (1*R*,2a*S*,8b*S*)-**23** were obtained in 99% yield. As expected, epimerization was strongly controlled at this temperature, and a high *de* of 89% was achieved. Even at low temperature, the reaction proceeded effectively, and after decreasing the temperature, the *de* values improved; the best *de* of 98% was obtained in the reaction at -80°C. The axial chirality evoked by crystallization directed the course of the approach of the reacting molecules, and a fully controlled diastereoselective intermolecular photocycloaddition reaction was performed.
