**3. Chiral memory effects of molecular conformation**

When we start the study for chiral memory and select a molecule with the ability to hold for a certain amount of time the molecular conformation in the crystal lattice, we are focused on

Optically active molecules must crystallize into chiral space groups, but a racemic mixture in solution may either aggregate to form a nonchiral racemic crystal or undergo a spontaneous resolution where the two enantiomers segregate into a conglomerate of enantiopure crystals. Achiral molecules may crystallize into either a nonchiral or a chiral space group. If they crystallize into a chiral space group, the achiral molecules reside in a chiral environment imposed by the lattice. Most achiral molecules are known to adopt interconverting chiral conformations in fluid media, which could lead to a unique conformation upon crystallization. Crystals that have chiral space groups are characterized by being enantiomorphous. They exist in right-handed and left-handed forms that may or may not be visually distinguishable. In spite of impressive work on crystal engineering, predictions on a correlation between crystal symmetry and molecular structures are still

Chiral crystals, like any other asymmetric object, exist in two enantiomorphous equienergetic forms, but careful crystallization of the material can induce the entire ensemble of molecules to aggregate into one crystal, of one-handedness, presumably starting from a single nucleus (Figure 3). However, it is not uncommon to find both

For achieving asymmetric synthesis, we should begin with a compound crystallizing in any one of the chiral space groups. Of the 230 distinct space groups, the most commonly occurring are *P*21/c, *P*-1, *P*212121, *P*21, *C*2/c, and *P*bca, the chiral ones being *P*212121, *P*21, *P*1 and *C*2.13)

The asymmetric crystallization of achiral compounds is stimulated by autoseeding with the first crystal formed. Although the chiral sense of the spontaneously formed chiral crystals cannot be predicted, seed crystals of the preferred chirality can be added in a more practical

When we start the study for chiral memory and select a molecule with the ability to hold for a certain amount of time the molecular conformation in the crystal lattice, we are focused on

enantiomorphs present in a given batch of crystals from the same recrystallization.

procedure to obtain one enantiomorph of a crystal.

Fig. 3. Chiral crystallization with fast enantiomerization

**3. Chiral memory effects of molecular conformation** 

**2. Generation and amplification of chirality by crystallization** 

hard to make.12)

the molecules with the aromatic amide scaffold; this is because they can be synthesized many derivatives with variety substituents, and show considerable stability for the subsequent reaction. Molecules **1-4,** as shown in Figure 4, were designed to consider the development of subsequent asymmetric reactions. Imide **2** has an axial chirality based on the C-N bond; on the contrary, in compounds other than **2**, there is C-C bond axial chirality between the aromatic ring and amide groups. The racemization is inhibited to some extent by the steric repulsion between the aromatic ring and substituent on the amide nitrogen atoms of the planar structure. However, depending on the substituents on the aromatic ring and nitrogen atom, the rotational barrier of the N-C(=O) bond, except in special cases, is 20 ~ 24 kcal mol-1, and the bond can rotate slowly even at room temperature.14) In these substrates, when N-C(=O) bond rotation occurs, the racemization spontaneously proceeds depending on the Ar-(C=O) bond rotation; therefore, the maximum free energy of activation for racemization is also controllable. By changing the size and electronic property of the substituents, we can finely tune the energy of racemization of the aromatic amide.

Azumaya *et al*. also reported an example of retention of the molecular chirality when the chiral crystal of 1,2-bis(N-benzoyl-N-methylamino)benzene **5** was dissolved in cold CDCl3.15) The BIPHOS ligand **6** crystallizes as a conglomerate, and a single crystal in CH2Cl2 at -78°C reacts with [PdCl2(CH3CN)2] to give the enantiomerically pure complex [PdCl2(biphos)]. Tissot *et al*. reported an example of catalytic asymmetric synthesis where the enantiomerically pure complex was used in the catalytic asymmetric allylic substitution of 1,3-diphenylprop-2-enyl acetate with the anion of dimethyl malonate to give product in 93% yield and with 80% *ee*.16)

Fig. 4. Achiral molecules with chiral memory effect

#### **4. Asymmetric reactions using chiral memory derived from chiral crystals**

#### **4.1 Asymmetric nucleophilic addition to carbonyl group using chiral crystals of 2-benzoylbenzamides**

When 2-benzoyl benzamides **1a-d** with various sizes of substituents on the nitrogen atom were synthesized and the crystal structure was analyzed by X-ray crystallographic analysis,

Asymmetric Reaction Using Molecular Chirality Controlled by Spontaneous Crystallization 65

synthesis involving nucleophilic reaction of carbonyl groups using chiral memory with C-C

Table 1. Reaction using the crystal of 2-benzoylbenzamides with n-BuLi

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

irradiated in THF at -60°C, optically active oxetanes **11** and **12** were isolated.19)

**crystal of naphthamides** 

**4.3 Development of chiral crystallization and asymmetric reactions using the chiral** 

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

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

axial chirality.

it was revealed that three substrates **1a-c** afforded chiral crystals (Figure 5).17) As mentioned, achiral materials generally yield chiral crystals in about 10%; however, the designed molecules with the polarity and their round shapes crystallized in the chiral space group in very high proportion.18) In these substrates, the two carbonyl groups are unable to form a planar conformation, but formed a twisted up and down structure, and chiral crystals were obtained by forming crystals of either enantiomer. If the substrate had a relatively fast rate of racemization, the same enantiomeric crystals were obtained in the flask by the usual recrystallization from a solution. It is easy to obtain large quantities of the desired enantiomer crystals by adding seed crystals of one enantiomer during crystallization.

Fig. 5. Achiral 2-benzolybenzamides studied for chiral crystallization and asymmetric synthesis.

When the chiral crystals were dissolved in a solvent at room temperature, the molecular chirality disappeared in an instant. How long chiral molecular conformation is retained after the crystals were dissolved in a cold solvent? There are several techniques to measure the rate of racemization, and it can be obtained from the decay of optical rotation or CD spectra by longer life to some extent. However, these substrates have very fast rates of racemization, and the Cotton effect was not observed by the CD spectra immediately after dissolving the crystals in a solvent of -80°C by using a cryostat apparatus. Therefore, the rate of racemization for **1b** was determined using VT-NMR techniques. Methylene protons of the diethyl group on the nitrogen atom of **1b** are observed at the two different positions of anti and syn at room temperature; however, the protons in the diastereomeric relationship will be observed as four peaks at low temperatures. Activation free energy of racemization was calculated from the chemical shift, the coalescence temperature was 10.3 kcal mol-1 in toluene at -60°C, and the half-life could be reached in 2.2 x 10-3 sec. The half-life is very short; however, asymmetric synthesis of a sufficiently high stereoselectivity was expected to be achieved by selecting a stereospecific reaction faster than racemization.

Nucleophilic addition reactions to the carbonyl group were examined. When the chiral crystals of **1** were added to a cooled toluene solution containing butyllithium, the adduct **7** was obtained in high yield. Optical purity of the product was determined after induction to phthalide **8** by treatment with acetic acid (Table 1). The product from **1a** showed optical activity of 17% *ee* because of the significantly faster rate of racemization of **1a** having small steric hindrance of dimethyl groups on the nitrogen atom. On the other hand, when using the chiral crystals of **1b** and **1c**, the product could be obtained with optical purity of more than 80% *ee*. As a matter of course, when using the crystals of racemic **1d**, **7d** and **8d** were obtained as racemates. Whereas compound **1** showed short-lived chiral memory, it was enough to react with butyllithium. These results prepared unprecedented asymmetric

it was revealed that three substrates **1a-c** afforded chiral crystals (Figure 5).17) As mentioned, achiral materials generally yield chiral crystals in about 10%; however, the designed molecules with the polarity and their round shapes crystallized in the chiral space group in very high proportion.18) In these substrates, the two carbonyl groups are unable to form a planar conformation, but formed a twisted up and down structure, and chiral crystals were obtained by forming crystals of either enantiomer. If the substrate had a relatively fast rate of racemization, the same enantiomeric crystals were obtained in the flask by the usual recrystallization from a solution. It is easy to obtain large quantities of the desired

enantiomer crystals by adding seed crystals of one enantiomer during crystallization.

Fig. 5. Achiral 2-benzolybenzamides studied for chiral crystallization and asymmetric

be achieved by selecting a stereospecific reaction faster than racemization.

When the chiral crystals were dissolved in a solvent at room temperature, the molecular chirality disappeared in an instant. How long chiral molecular conformation is retained after the crystals were dissolved in a cold solvent? There are several techniques to measure the rate of racemization, and it can be obtained from the decay of optical rotation or CD spectra by longer life to some extent. However, these substrates have very fast rates of racemization, and the Cotton effect was not observed by the CD spectra immediately after dissolving the crystals in a solvent of -80°C by using a cryostat apparatus. Therefore, the rate of racemization for **1b** was determined using VT-NMR techniques. Methylene protons of the diethyl group on the nitrogen atom of **1b** are observed at the two different positions of anti and syn at room temperature; however, the protons in the diastereomeric relationship will be observed as four peaks at low temperatures. Activation free energy of racemization was calculated from the chemical shift, the coalescence temperature was 10.3 kcal mol-1 in toluene at -60°C, and the half-life could be reached in 2.2 x 10-3 sec. The half-life is very short; however, asymmetric synthesis of a sufficiently high stereoselectivity was expected to

Nucleophilic addition reactions to the carbonyl group were examined. When the chiral crystals of **1** were added to a cooled toluene solution containing butyllithium, the adduct **7** was obtained in high yield. Optical purity of the product was determined after induction to phthalide **8** by treatment with acetic acid (Table 1). The product from **1a** showed optical activity of 17% *ee* because of the significantly faster rate of racemization of **1a** having small steric hindrance of dimethyl groups on the nitrogen atom. On the other hand, when using the chiral crystals of **1b** and **1c**, the product could be obtained with optical purity of more than 80% *ee*. As a matter of course, when using the crystals of racemic **1d**, **7d** and **8d** were obtained as racemates. Whereas compound **1** showed short-lived chiral memory, it was enough to react with butyllithium. These results prepared unprecedented asymmetric

synthesis.

synthesis involving nucleophilic reaction of carbonyl groups using chiral memory with C-C axial chirality.


Table 1. Reaction using the crystal of 2-benzoylbenzamides with n-BuLi
