**4.2 Asymmetric reactions using chiral memory derived from asymmetric imides**

We reported the asymmetric reaction using chiral memory owing to the C-N axial chrality derived from the chiral crystal of acyclic imide (Figure 6).19) The imide nitrogen atom has a planar structure, similar to the sp2-hybridized amide nitrogen atom, and can form multiple structures of *EE*, *EZ*, *ZE*, and *ZZ*.14) In imide **2**, the tetrahydronaphthyl group (TENAP) on the nitrogen atom exhibited almost perpendicular conformation to the plane of the imide. Depending on the direction of the TENAP group, each conformation enters an enantiomeric relationship. Racemization rate of the substrate could be determined by measuring the decay of the CD spectra using a cryostat apparatus by dissolved chiral crystals in a cold solvent. Activation free energy of racemization of this imide was 18.4 kcal mol-1 in THF at -20°C, which indicates that the chiral molecular conformation could be retained long enough after the chiral crystals were dissolved in a solvent. We tried the reaction of butyllithium with chiral molecules using this chiral memory. The reaction site is the benzoyl group of the side of the imide plane, and was reacted at -80°C; **9** and **10** were obtained as optically active forms of 83% and 81% *ee*, respectively. Furthermore, when provisional chiral molecule was irradiated in THF at -60°C, optically active oxetanes **11** and **12** were isolated.19)

#### **4.3 Development of chiral crystallization and asymmetric reactions using the chiral crystal of naphthamides**

To perform this asymmetric synthesis, 2-alkoxy-1-naphthamides **3** were chosen because the bond rotation between the naphthalene ring and the amide carbonyl corresponds to enantiomerization of **3**, and the rate is considerably affected by the substituent of both the naphthalene ring and the amide group (Figure 7).20) Naphthamides with a bulky group such as the *N,N*-diisopropyl amide group have stable axial chirality, which is utilized in many

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 67

desired crystals of **3** could be selectively prepared in large quantities by the addition of a

We examined the asymmetric reaction using the provisional molecular chirality of naphthamide **3b (**Figure 8).23) After chiral crystals of **3b** were dissolved in a toluene solution containing diene (0.10 M) at -20°C, the solution was irradiated at the same temperature. Cyclobutane **13** was obtained in an optically active form of 76% *ee* at a 10% conversion of **3b**. Furthermore, with the increase of the conversion of **3b**, the *ee* value of **13** decreased rapidly. The rate of racemization of **3** at -20°C is very slow, and chirality was retained during irradiation. Why did the *ee* values decrease during the progress of the reaction? The amide directly racemized on irradiation via the twisted intramolecular charge transfer (TICT)

Fig. 8. Photochemical cycloaddition of naphthamide **3b** with 2,5-dimethylhexa-2,4-diene

is still 62.6 min. at 20°C. Surprisingly, we could obtain 88% *ee* of the product at 20°C.

We also reported the 4+4 cycloaddition of excited 9-cyanonaphthalene with the ground state of **3,** leading to an optically active 4+4 adduct with high enantioselectivity (Table 2).20) Chiral crystals of **3b** was dissolved in a cooled THF solution of -20°C including 9-CNAN, and the solution was irradiated with an ultra-high pressure mercury lamp for 30 min. Only one cycloadduct **14** was obtained in 100% chemical yield, and the adduct showed optical activity of 95% *ee*. When we used a mixed solvent of MeOH and THF, almost the same *ee* value (94% *ee*) was obtained. Even at 20°C, we were able to obtain 29% *ee* of the adduct from the reaction in THF, in which the enantiomerization occurs competitively with the photocycloaddition. The rate of enantiomerization in alcoholic solvent is more suppressed than in THF, and the half-life

For the stereochemistry of the reaction pathway, the (*S*)-proline derivatives were synthesized. The comparison of the absolute structure of the starting naphthamide and the adduct was studied, and it can be estimated that 9-CNNAP approaches from the vacant site of the carbonyl group to avoid the bulky substituents on the nitrogen atom (Figure 9).24)

corresponding seed crystal during the crystallization process.

mechanism from the singlet excited state.

Fig. 7. Racemization of 2-alkoxy-1-naphthamides by Ar-(C=O) bond rotation

asymmetric synthesis.21) Therefore, achiral naphthamides possessing a relatively compactsize amide group derived from pyrrolidine and piperidine, **3a** and **3b**, were prepared for our purpose. The X-ray single crystallographic analyses of the crystals revealed that both amides tend to have almost the same molecular conformation; remarkably, each carbonyl group twists almost orthogonally to the naphthalene plane.

Fig. 6. Chiral crystallization of achiral acyclic imide and asymmetric synthesis using the chiral memory

Fortunately, both **3a** and 3**b** crystallized in a chiral space group, *P*212121, and the constituent molecules adopted a chiral and helical conformation in the crystal lattice. The rate of racemization of **3** after dissolving the chiral crystals in a solvent was measured based on the changes in the CD spectra. The activation free energy (Δ*G≠*) was calculated from the temperature dependence of the kinetic constant between 5 and 15°C as 21.2 ± 0.2 kcal mol-1 in THF. These facts indicate that the racemization of **3b** is too fast to be resolved in the usual manner. The lifetime can be lengthened by lowering the temperature so that the racemization is sufficiently slow and the reaction can be used to accomplish asymmetric synthesis.

The crystals of naphthamide **3** used for the asymmetric reaction were prepared by stirred crystallization from the melt.22) The samples were completely melted at 120°C, which greatly exceeds their melting points (mp of **3b**: 110-112°C), cooled and solidified by lowering the temperature by stirring to 100°C. High reproducibility of both the chiral crystallization and asymmetric reaction was achieved by this method; however, the direction of the optical rotation of the photoproduct was inconsistent and appeared randomly. Of course, the

asymmetric synthesis.21) Therefore, achiral naphthamides possessing a relatively compactsize amide group derived from pyrrolidine and piperidine, **3a** and **3b**, were prepared for our purpose. The X-ray single crystallographic analyses of the crystals revealed that both amides tend to have almost the same molecular conformation; remarkably, each carbonyl

Fig. 6. Chiral crystallization of achiral acyclic imide and asymmetric synthesis using the

changes in the CD spectra. The activation free energy (

Fortunately, both **3a** and 3**b** crystallized in a chiral space group, *P*212121, and the constituent molecules adopted a chiral and helical conformation in the crystal lattice. The rate of racemization of **3** after dissolving the chiral crystals in a solvent was measured based on the

temperature dependence of the kinetic constant between 5 and 15°C as 21.2 ± 0.2 kcal mol-1 in THF. These facts indicate that the racemization of **3b** is too fast to be resolved in the usual manner. The lifetime can be lengthened by lowering the temperature so that the racemization is sufficiently slow and the reaction can be used to accomplish asymmetric

The crystals of naphthamide **3** used for the asymmetric reaction were prepared by stirred crystallization from the melt.22) The samples were completely melted at 120°C, which greatly exceeds their melting points (mp of **3b**: 110-112°C), cooled and solidified by lowering the temperature by stirring to 100°C. High reproducibility of both the chiral crystallization and asymmetric reaction was achieved by this method; however, the direction of the optical rotation of the photoproduct was inconsistent and appeared randomly. Of course, the

Δ

*G≠*) was calculated from the

group twists almost orthogonally to the naphthalene plane.

chiral memory

synthesis.

desired crystals of **3** could be selectively prepared in large quantities by the addition of a corresponding seed crystal during the crystallization process.

Fig. 7. Racemization of 2-alkoxy-1-naphthamides by Ar-(C=O) bond rotation

We examined the asymmetric reaction using the provisional molecular chirality of naphthamide **3b (**Figure 8).23) After chiral crystals of **3b** were dissolved in a toluene solution containing diene (0.10 M) at -20°C, the solution was irradiated at the same temperature. Cyclobutane **13** was obtained in an optically active form of 76% *ee* at a 10% conversion of **3b**. Furthermore, with the increase of the conversion of **3b**, the *ee* value of **13** decreased rapidly. The rate of racemization of **3** at -20°C is very slow, and chirality was retained during irradiation. Why did the *ee* values decrease during the progress of the reaction? The amide directly racemized on irradiation via the twisted intramolecular charge transfer (TICT) mechanism from the singlet excited state.

Fig. 8. Photochemical cycloaddition of naphthamide **3b** with 2,5-dimethylhexa-2,4-diene

We also reported the 4+4 cycloaddition of excited 9-cyanonaphthalene with the ground state of **3,** leading to an optically active 4+4 adduct with high enantioselectivity (Table 2).20) Chiral crystals of **3b** was dissolved in a cooled THF solution of -20°C including 9-CNAN, and the solution was irradiated with an ultra-high pressure mercury lamp for 30 min. Only one cycloadduct **14** was obtained in 100% chemical yield, and the adduct showed optical activity of 95% *ee*. When we used a mixed solvent of MeOH and THF, almost the same *ee* value (94% *ee*) was obtained. Even at 20°C, we were able to obtain 29% *ee* of the adduct from the reaction in THF, in which the enantiomerization occurs competitively with the photocycloaddition. The rate of enantiomerization in alcoholic solvent is more suppressed than in THF, and the half-life is still 62.6 min. at 20°C. Surprisingly, we could obtain 88% *ee* of the product at 20°C.

For the stereochemistry of the reaction pathway, the (*S*)-proline derivatives were synthesized. The comparison of the absolute structure of the starting naphthamide and the adduct was studied, and it can be estimated that 9-CNNAP approaches from the vacant site of the carbonyl group to avoid the bulky substituents on the nitrogen atom (Figure 9).24)

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 69

obtained. When the crystals of (+)-**3a** or **3b** were used for the *SNAr* reaction, (+)-**15a,b** were obtained. Both amides **15a** and **15b** have stable axial chirality and did not racemize at room

Fig. 10. Asymmetric *SNAr* reaction of **3** with *t*-butyllithium using the provisional axial

**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

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.

temperature for several months.

reaction did not proceed below –20°C.

chirality

Table 2. Asymmetric photochemical cycloaddition reaction of **3b** with 9-cyanoanthracene using the provisional axial chirality

Fig. 9. Reaction course of the photocycloaddition of chiral conformation of (*S*)-**3b** with excited state of 9-CNAN

#### **4.4 Chiral lock of the provisional chiral memory of naphthamides**

Next, we examined how to lock the bond rotation affecting racemization of the amides **3**.25) The racemization should be suppressed by substitution of the methoxy group at the 2 position of the naphthalene ring with the more bulky group.

A THF solution containing 3.0 eq. of *t*-BuLi was cooled to -80°C and was followed by the addition of chiral crystals of **3a**. After reaction for 1 h at the same temperature, the reaction mixture was treated in the usual manner. Analysis of the reaction product showed the formation of 2-*t*-butyl derivatives **15a** in a 97% yield and in an optically active form of 85% *ee*. When the chiral crystal of **3b** was used for the *SNAr* reaction, nearly similar results were

Table 2. Asymmetric photochemical cycloaddition reaction of **3b** with 9-cyanoanthracene

Fig. 9. Reaction course of the photocycloaddition of chiral conformation of (*S*)-**3b** with

Next, we examined how to lock the bond rotation affecting racemization of the amides **3**.25) The racemization should be suppressed by substitution of the methoxy group at the 2-

A THF solution containing 3.0 eq. of *t*-BuLi was cooled to -80°C and was followed by the addition of chiral crystals of **3a**. After reaction for 1 h at the same temperature, the reaction mixture was treated in the usual manner. Analysis of the reaction product showed the formation of 2-*t*-butyl derivatives **15a** in a 97% yield and in an optically active form of 85% *ee*. When the chiral crystal of **3b** was used for the *SNAr* reaction, nearly similar results were

**4.4 Chiral lock of the provisional chiral memory of naphthamides** 

position of the naphthalene ring with the more bulky group.

using the provisional axial chirality

excited state of 9-CNAN

obtained. When the crystals of (+)-**3a** or **3b** were used for the *SNAr* reaction, (+)-**15a,b** were obtained. Both amides **15a** and **15b** have stable axial chirality and did not racemize at room temperature for several months.

Fig. 10. Asymmetric *SNAr* reaction of **3** with *t*-butyllithium using the provisional axial chirality
