**5. Diastereoselective reaction using memory effect of molecular chirality controlled by crystallization**

Asymmetric chiral transfer techniques using chiral memory derived from chiral crystals can be applied to diastereoselective reaction (Figures. 13, 14). We used the aromatic amides **18- 20** with an optically active proline goup as the chiral source to give the chiral memory capabilities. Four diastereomers are possible in these compounds owing to the rotational isomer of C(=O)-N and C-(C=O) bonds. When we used diastereomeric mixture in asymmetric reactions, we obtained the mixture of products reflecting the ratio of starting diastereomers, and high stereoselective reaction could not be achieved. However, when diastereomixture of amides were crystallized, epimerization owing to the bond rotation was promoted, and the mixture automatically converged to a single diastereomer by Crystallization-Induced Diastereomer Transformation (CIDT) (Figure 13).

## **5.1 Diastereoselective reaction using memory effect of naphthamides**

In the NMR spectrum of naphthamide **18**, several peak pairs were observed derived from diastereomixtures, which suggested that this amide existed as a mixture of diastereomers in the solution.24) After evaporating the solution to solidify the amide, NMR spectrum measured immediately after dissolving the solid to CDCl3 showed only peaks derived from single diastereomers. This fact indicated that diastereomixture crystallized by converging to single crystalline diastereomer by simple solidification (Figure 15). Conformation in the crystal was determined as (*S,aR*)-**18-A** by single crystal X-ray crystallographic analysis. Moreover, this chiral molecular conformation in solution was also retained at low temperature for long enough time to be used as a chiral memory.

Fig. 13. Asymmetric synthesis using chiral memory derived from CIDT

Asymmetric chiral transfer techniques using chiral memory derived from chiral crystals can be applied to diastereoselective reaction (Figures. 13, 14). We used the aromatic amides **18- 20** with an optically active proline goup as the chiral source to give the chiral memory capabilities. Four diastereomers are possible in these compounds owing to the rotational isomer of C(=O)-N and C-(C=O) bonds. When we used diastereomeric mixture in asymmetric reactions, we obtained the mixture of products reflecting the ratio of starting diastereomers, and high stereoselective reaction could not be achieved. However, when diastereomixture of amides were crystallized, epimerization owing to the bond rotation was promoted, and the mixture automatically converged to a single diastereomer by

In the NMR spectrum of naphthamide **18**, several peak pairs were observed derived from diastereomixtures, which suggested that this amide existed as a mixture of diastereomers in the solution.24) After evaporating the solution to solidify the amide, NMR spectrum measured immediately after dissolving the solid to CDCl3 showed only peaks derived from single diastereomers. This fact indicated that diastereomixture crystallized by converging to single crystalline diastereomer by simple solidification (Figure 15). Conformation in the crystal was determined as (*S,aR*)-**18-A** by single crystal X-ray crystallographic analysis. Moreover, this chiral molecular conformation in solution was also retained at low

**5. Diastereoselective reaction using memory effect of molecular chirality** 

Crystallization-Induced Diastereomer Transformation (CIDT) (Figure 13).

**5.1 Diastereoselective reaction using memory effect of naphthamides** 

temperature for long enough time to be used as a chiral memory.

Fig. 13. Asymmetric synthesis using chiral memory derived from CIDT

**controlled by crystallization** 

Diastereoselective photocycloaddition reaction with 9-CNAN was examined. Irradiation of amides **18a-b** before solidification in the presence of 9-CNAN gave adduct**s 21a** and **21b** with the *de* values of 63% and 53%, respectively. On the other hand, when the crystals of amides obtained by CIDT were dissolved in THF at -20℃, 96% *de* of adduct **21a** and 100% *de* of **21b** were obtained. The molecular conformation of **18** was retained in a cold solution after dissoving the crystals, and could act as a chiral molecular memory; 9-CNNAP approached selectively from the less hindered site of carbonyl group of naphthamide.

Fig. 14. Aromatic amides with chiral memory effect derived from CIDT

Fig. 15. CIDT of naphthamide with proline group
