**4.5 Kinetic resolution of racemic amines using provisional molecular chirality**

We found that the kinetic resolution of racemic piperidines alkylated at the 2- or 3-position was performed using the provisional enantiomeric conformation of naphthamide **3a** derived from chiral crystals.26) Chiral crystals of naphthamide **3a** were added to a THF solution of racemic lithium amides prepared by the reaction of substituted piperidines with *n*-BuLi at –80°C; the reaction mixture was stirred for 5 hours at –20°C because the substitution reaction did not proceed below –20°C.

When a 2.0 equimolar amount of 2-methylpiperidine was used, 30% of naphthamide **3a** was consumed, and 30% of **16a** was isolated. The reaction conversion was low; however, the reaction was very clean, and 70% of unreacted naphthamide was recovered. Fortunately, **16a** was obtained as the optically active form in 94% *ee*. Based on an increase of the amount of lithium amide to 5 eq., all naphthamide **3a** was consumed and converted to **16a** quantitatively with 81% *ee*. These results indicate that the 2.0 equimolar amounts of lithium amide form a stable intermediacy complex with naphthamide **3a**, and an extra amount of piperidine must be necessary to obtain product **16** in good yield. The intermediacy enantiomeric complex reacts preferentially with one enantiomer of the racemic peridine.

We diminished the amount of piperidines using such additives as diisopropylamine, TMEDA, and HMPA by displacing the complex ligand. When 3.0 eq. of LDA was added to the 2.0 eq. of the piperidine lithium amide, the substitution reaction occurred in a 100% conversion, and **3a**  was isolated almost quantitatively in 73% *ee*. The addition of 1.0 eq. of TMEDA was also effective, and 80% of product was obtained with 80% *ee*. When 3.0 eq. of HMPA was used for the additives, all naphthamide was consumed, and **16a** was obtained in 90% with 69% *ee*.

When racemic 2-ethylpiperidine was reacted with the provisional chiral conformation of **3a**, similar results were obtained as the reaction with 2-methylpiperidine. However, when racemic 3-methylpiperidine was used as a nucleophile, the substitution reaction occurred quantitatively; however, the *ee* value resulted in 17%. The methyl group at the 3-position of the piperidine ring was insufficient to control the stereoselectivity because of the distance between the reacting nitrogen atom and the substituent. On the contrary, the substituent at the 2-positions worked sufficiently as strong chiral flags to control the stereoselectivity.

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 71

Table 3. Asymmetric photosensitized cycloaddition reaction of **4** with alkenes using the

When powdered crystals of **4** (0.02 mol L-1) were dissolved in a cooled MeOH solution (-20°C) containing ethyl vinyl ether (0.1 mol L-1) and irradiated at -20°C with a 365 nm line, optically active adducts **17** were obtained as would be expected. However, the *ee* values were affected by the conversion. High *ee* values of products (82% *ee* of *endo*-**17** and 86% *ee* of *exo*-**17**) were obtained by suppressing the conversion of 18%; however, the *ee* value decreased as the conversion increased. We measured the changes of the CD spectral of an MeOH solution of **4** using a cryostat apparatus by irradiating at -20°C, and it was confirmed that racemization of the starting amide **4** in the singlet-excited state had occurred. Therefore, we examined the triplet-sensitized photocycloaddition of **4** using benzophenone (BP) as a triplet sensitizer to avoid photoracemization from the singlet-excited state. When powdered crystals of **4** were dissolved to a cooled MeOH solution (-20°C) containing ethyl vinyl ether and benzophenone (0.01 mol L-1) and were irradiated at -20°C for 3 h, high optical yields of adducts, 94% *ee* of both *endo*- and *exo*-**17**, were obtained. The use of 0.02 mol L-1 of benzophenone resulted in 100% conversion and a 98% chemical yield of adducts; furthermore, surprisingly high *ee* values of products, 96% *ee* of *endo*-**17** and *exo*-**17**, were obtained. Finally, 98% *ee* of *endo*-**17** and 97% *ee* of *exo*-**17** were isolated by increasing the

The asymmetric cycloaddition using the homochirality in the crystal was also performed by the use of 2-methoxypropene. In this case, only *endo*-**17** was obtained in an almost quantitative yield, and asymmetric synthesis with high *ee*, up to 99%, was performed.

This reaction provided the first example of photosensitized intermolecular cycloaddition with high enantiomeric excess using the homochirality in the crystal generated by

provisional axial chirality

concentration of benzophenone to 0.1 mol/L.

spontaneous crystallization.

Fig. 11. Kinetic resolution of racemic piperidines by provisional molecular chirality of naphthamide **3a**.

#### **4.6 Photosensitized 2+2 cycloaddition reaction using chiral memory**

Achiral *N,N,*4-triethylcoumarin-3-carboxamide **4** crystallized in a chiral space group, *P*212121 (Figure 12).27) The X-ray single crystallographic analysis of the crystals revealed that the amides **12** tend to have a twisted conformation, of which the amide carbonyl group twists almost orthogonally to the coumarin chromophore. There are two enantiomeric conformations as shown in Figure 12 caused by the C-(C=O) bond rotation in fluid media; however, the chiral crystal is composed of a single enantiomer.

The rate of racemization was measured according to the changes in the CD spectra using a cryostat apparatus, and the activation free energy and the half-life were calculated. The racemization of **4** in THF was too fast at room temperature to determine the rate. On the other hand, when the crystals of **4** were dissolved in THF at 5°C, the half-life of racemization was 11.9 min. The half-life increased as the temperature was lowered, and *t*1/2 was 30.5 and 82.0 min at the temperatures of 0°C and -5°C, respectively. The activation free energy (ΔG≠) was calculated as the temperature dependence of the kinetic constant (5°C: 4.85 x 10-4, 0°C: 1.89 x 10-4, -5°C: 7.04 x 10-5) to be 20.5-20.7 kcal mol-1. In the case of the racemization in MeOH or DMF, the rate showed a considerably low activation free energy of 22.3-22.4 kcal mol-1, and exhibited 20.2 and 23.6 min of half-life at 25°C, in MeOH and DMF, respectively. These facts indicate that the racemization of **4** is too fast to resolve in the usual manner; however, it can be controlled by lowering the temperature and with the selection of the solvent, and the lifetime becomes long enough for utilization in asymmetric synthesis.

Fig. 12. Racemization of coumarinecarboxamide **4** owing to the rotation of the Ar-(C=O) bond

**a** : R1 = Me, R2 = H **b** : R1 = Et, R2 = H **c** : R1 = H, R2 = Me

Achiral *N,N,*4-triethylcoumarin-3-carboxamide **4** crystallized in a chiral space group, *P*212121 (Figure 12).27) The X-ray single crystallographic analysis of the crystals revealed that the amides **12** tend to have a twisted conformation, of which the amide carbonyl group twists almost orthogonally to the coumarin chromophore. There are two enantiomeric conformations as shown in Figure 12 caused by the C-(C=O) bond rotation in fluid media;

The rate of racemization was measured according to the changes in the CD spectra using a cryostat apparatus, and the activation free energy and the half-life were calculated. The racemization of **4** in THF was too fast at room temperature to determine the rate. On the other hand, when the crystals of **4** were dissolved in THF at 5°C, the half-life of racemization was 11.9 min. The half-life increased as the temperature was lowered, and *t*1/2 was 30.5 and 82.0 min at the temperatures of 0°C and -5°C, respectively. The

constant (5°C: 4.85 x 10-4, 0°C: 1.89 x 10-4, -5°C: 7.04 x 10-5) to be 20.5-20.7 kcal mol-1. In the case of the racemization in MeOH or DMF, the rate showed a considerably low activation free energy of 22.3-22.4 kcal mol-1, and exhibited 20.2 and 23.6 min of half-life at 25°C, in MeOH and DMF, respectively. These facts indicate that the racemization of **4** is too fast to resolve in the usual manner; however, it can be controlled by lowering the temperature and with the selection of the solvent, and the lifetime becomes long enough for utilization

Fig. 12. Racemization of coumarinecarboxamide **4** owing to the rotation of the Ar-(C=O)

G≠) was calculated as the temperature dependence of the kinetic

**16a-c** Up to 94% *ee*

N

R1

\* \* R2

O N


Fig. 11. Kinetic resolution of racemic piperidines by provisional molecular chirality of

(*RS*)-alkylated piperidine *n*-BuLi / additives

chiral crystals of

naphthamide **3a**.

activation free energy (

in asymmetric synthesis.

bond

amide **3a** in THF

N H R1

**4.6 Photosensitized 2+2 cycloaddition reaction using chiral memory** 

however, the chiral crystal is composed of a single enantiomer.

Δ

R2

Table 3. Asymmetric photosensitized cycloaddition reaction of **4** with alkenes using the provisional axial chirality

When powdered crystals of **4** (0.02 mol L-1) were dissolved in a cooled MeOH solution (-20°C) containing ethyl vinyl ether (0.1 mol L-1) and irradiated at -20°C with a 365 nm line, optically active adducts **17** were obtained as would be expected. However, the *ee* values were affected by the conversion. High *ee* values of products (82% *ee* of *endo*-**17** and 86% *ee* of *exo*-**17**) were obtained by suppressing the conversion of 18%; however, the *ee* value decreased as the conversion increased. We measured the changes of the CD spectral of an MeOH solution of **4** using a cryostat apparatus by irradiating at -20°C, and it was confirmed that racemization of the starting amide **4** in the singlet-excited state had occurred. Therefore, we examined the triplet-sensitized photocycloaddition of **4** using benzophenone (BP) as a triplet sensitizer to avoid photoracemization from the singlet-excited state. When powdered crystals of **4** were dissolved to a cooled MeOH solution (-20°C) containing ethyl vinyl ether and benzophenone (0.01 mol L-1) and were irradiated at -20°C for 3 h, high optical yields of adducts, 94% *ee* of both *endo*- and *exo*-**17**, were obtained. The use of 0.02 mol L-1 of benzophenone resulted in 100% conversion and a 98% chemical yield of adducts; furthermore, surprisingly high *ee* values of products, 96% *ee* of *endo*-**17** and *exo*-**17**, were obtained. Finally, 98% *ee* of *endo*-**17** and 97% *ee* of *exo*-**17** were isolated by increasing the concentration of benzophenone to 0.1 mol/L.

The asymmetric cycloaddition using the homochirality in the crystal was also performed by the use of 2-methoxypropene. In this case, only *endo*-**17** was obtained in an almost quantitative yield, and asymmetric synthesis with high *ee*, up to 99%, was performed.

This reaction provided the first example of photosensitized intermolecular cycloaddition with high enantiomeric excess using the homochirality in the crystal generated by spontaneous crystallization.

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 73

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

O

O

O

**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).

**18 19 20**

R1

N

CO2Me

N

Me

O

Me

O N

MeO2C

selectively from the less hindered site of carbonyl group of naphthamide.

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

O N

Fig. 15. CIDT of naphthamide with proline group

MeO2C

OR
