2.1. Optical Resolution of Racemic 3-Hydroxycarboxylic Acids (1–3) with Enantiopure 2-Amino-1,2-diphenylethanol (ADPE)
The solvents used for crystallization often change the yield and optical purity of the obtained diastereomeric salts. Therefore, the influence of the solvents on the optical resolution of
rac-
1 with (−)-ADPE was investigated (
Table 1). The initial diastereomeric salt mixture was prepared by dissolving equimolar quantities of
rac-
1 and (−)-ADPE in methanol followed by evaporation. It was then recrystallized from various solvents as described below. The solvents were listed in the order of log P
ow as a parameter of polarity. The yield of the deposited salt was calculated based on half the amount of initial salt. A small quantity of the deposited salt was utilized to extract
1. The recovered
1 was converted to methyl ester and its enantiopurity was determined by HPLC analysis.
In the crystallization of the diastereomeric salt of
rac-
1 and (−)-ADPE in less polar solvents, CHCl
3 and THF preferentially afforded the (
R)-
1 salt as a less-soluble salt with an overall good efficiency (entries 1 and 2). The stereochemical arrangement on the chiral center of
1 in the salt was consistent with that of 3-hydroxy-3-phenylpropionic acid previously studied [
22]. In particular, CHCl
3 afforded the highest efficiency although a large amount of the solvent was necessary. However, crystallization with more polar solvents, AcOEt, 2-PrOH, and aqueous 50% EtOH afforded the (
R)-
1 salt with moderate to low efficiency (entries 3–5).
The effects of solvents used for recrystallization on the optical resolution of
rac-
2 with (+)-ADPE (the antipode of (−)-ADPE) were investigated (
Table 2). Crystallization of the diastereomeric salt of
rac-
2 and (+)-ADPE in all the tested solvents afforded the (
S)-
2 salt with good to high enantiopurity and efficiency. It is worth noting that crystallization with THF produced the (
S)-
2 salt with high yield and enantiopurity thereby contributing to an exceptionally high efficiency up to 68% (entry 2). Although the structure of the acid
2 is closely related to that of
1, resolution of
rac-
2 gave better results than the resolution of
rac-
1.
The effects of solvents used for recrystallization during the optical resolution of
rac-
3 with (−)-ADPE were investigated (
Table 3). Crystallization of the diastereomeric salt of
rac-
3 and (−)-ADPE consistently afforded the (
R)-
3 salt regardless of the solvents, except in the case of EtOH, which showed no selectivity (entry 6). Although the enantiopurity and resolution efficiency were low in most solvents, less polar solvents afforded the (
R)-
3 salt with a good enantiopurity and an overall good efficiency (entries 1–3). Despite the fact that
3 has an additional methylene group compared to
1, the absolute configuration did not change during the resolution of
rac-
3 with (−)-ADPE, and the (
R)-
3 salt was obtained. In both the cases, less polar CHCl
3 afforded the maximum resolution efficiency; however, the value for (
R)-
3 salt was lower than that of (
R)-
1.
2.2. Optical Resolution of Racemic 3-Hydroxycarboxylic Acids (1–3) with Cinchonidine
The effects of solvents used for recrystallization during the optical resolution of
rac-
1 with cinchonidine were investigated. The experimental procedure was the same as that used for the resolution of
1 with (−)-ADPE (
Table 4). Crystallization of the diastereomeric salt of
rac-
1 and cinchonidine afforded the (
R)-
1 salt with an overall high efficiency compared to the resolution by (−)-ADPE (
Table 1). It was found that polar AcOEt, alcohol solvents, and 1,4-dioxane afforded the (
R)-
1 salt with high efficiency up to 63% (entries 2–5), whereas less polar THF yielded the (
R)-
1 salt with only a moderate efficiency (entry 1). In this case, polar solvents afforded the (
R)-
1 salt efficiently. Such a solvent effect is in contrast with the resolution of
rac-
1 with (−)-ADPE.
The effects of solvents used for recrystallization during the optical resolution of
rac-
2 with cinchonidine were investigated (
Table 5). Crystallization of the diastereomeric salt of
rac-
2 and cinchonidine afforded the (
R)-
2 salt in all the solvents. Polar solvents gave high efficiency (entries 3–6) although less polar CHCl
3 and THF afforded rather low efficiency (entries 1 and 2). When compared with the resolution results of
rac-
1, similar solvent effects were observed for the resolution of
rac-
2 with cinchonidine, and the (
R)-
2 salt was obtained. Although 1,4-dioxane yielded good results, it appears ADPE is a more suitable resolving agent for the resolution of
rac-
2.
Finally, the effects of solvents used for recrystallization during the optical resolution of
rac-
3 using cinchonidine were investigated (
Table 6). Crystallization of the diastereomeric salt of
rac-
3 and cinchonidine consistently afforded the (
R)-
3 salt as less-soluble salt. The absolute configuration did not change, when compared with the resolution of
rac-
1. In particular, both the less polar toluene and polar solvents afforded the (
R)-
3 salt with high efficiency up to 56% (entries 1, 7 and 8). The salt was highly soluble in the examined solvents and only a little amount of EtOH afforded no salt crystal (entry 6).
As far as the solvent effects are concerned, it appears that the solvent polarity influences resolution efficiency to a significant extent. When ADPE was used as the resolving agent, it was almost the case that less polar solvents yielded good results. This is probably due to more effective hydrogen bonds to form the less-soluble salt in less polar solvents. On the other hand, when cinchonidine was used as the resolving agent, more polar solvents have a tendency to yield good results.
Furthermore, in the case of
rac-
1 and
rac-
2, both the resolving agents, ADPE and cinchonidine, have afforded good results (
Table 1,
Table 2,
Table 4 and
Table 5). However, in the case of
rac-
3, cinchonidine has afforded better resolution results (
Table 6) than (−)-ADPE (
Table 3). This would be attributed to the smaller structure of ADPE than cinchonidine, which was not suitable for the chiral recognition of longer chain carboxylic acid,
rac-
3. On the other hand, cinchonidine is rigid and bulky and, although it is remote from the functional group, it can well distinguish (
R) or (
S) in the chiral center, thereby contributing to high resolution efficiency.
2.3. Crystallographic Analysis of the Less-Soluble Diastereomeric Salts
Crystallographic investigations were performed to elucidate the structures of less-soluble diastereomeric salts obtained during the optical resolution of 1–3 using ADPE and cinchonidine.
The resolution of
rac-
2 with (+)-ADPE in THF afforded the (
S)-
2 salt with the highest efficiency (
Table 2, entry 2). The structures of the (
S)-
2 · (+)-ADPE salt crystal obtained in THF are shown in
Figure 2. It was revealed that the absolute configuration of
2 was inferred to be (
S), which was consistent with the resolution results. An array of periodic tubular structures was present along the
b-axis. A typical columnar hydrogen-bonding network, which was found in other carboxylate salts with enantiopure ADPE [
26,
27,
28], was constructed with a two-fold screw axis (2
1) from (
S)-
2 and (+)-ADPE. The ammonium hydrogens of (+)-ADPE were linked to the adjacent carboxylate oxygen atoms of (
S)-
2 via intermolecular hydrogen bonds. The hydroxy hydrogen of (+)-ADPE was connected to the oxygen of the hydroxy group of (
S)-
2 via an intermolecular hydrogen bond. The hydroxy hydrogen of (
S)-
2 was also involved in an intermolecular hydrogen bonding with the carboxylate oxygen of other (
S)-
2. It was noteworthy that the crystallization solvent was incorporated in the salt, and the
2: (+)-ADPE: THF ratio was 1:1:1. The THF molecules were not connected to the tubular structures via hydrogen bonds and remained isolated between the tubular structures to fill the void space. Such an incorporation of cyclic ethers was also be observed for other diastereomeric salts of ADPE and a hydroxycarboxylic acid [
29]. In addition to hydrogen bonds, the structure was reinforced by three CH/
π interactions [
30,
31], which contributed to its stability. The stereoselectivity of (
S)-
2 was achieved by fixing its carboxymethyl and hydroxy groups on the stereogenic center by hydrogen bonds as well as by fixing its benzyl group with CH/
π interactions between the
meta-CH of (
S)-
2 and the phenyl group of (+)-ADPE and between the
ortho-CH of (
S)-
2 and the phenyl group of other (
S)-
2. Such an incorporation of THF in the salt was not observed in the case of
1, which indicates that the steric effect of the chlorine atom on
2 contributed to create the void space.
The structure of the needle-like crystals (
R)-
1 · cinchonidine obtained in EtOH is illustrated in
Figure 3. The ratio of
1: cinchonidine was found to be 1:1. The absolute configuration of
1 was inferred to be (
R), which was consistent with the resolution results (
Table 4, entry 4). One carboxylate oxygen of (
R)-
1, which points towards the cinchonidine molecule, formed an intermolecular hydrogen bond with the ammonium hydrogen of the azabicyclo[2.2.2]octane group of cinchonidine. The same carboxylate oxygen was held by another intermolecular hydrogen bond that connected it to the hydroxy hydrogen of another cinchonidine. Another carboxylate oxygen of (
R)-
1, which points away from the cinchonidine molecule, was also involved in the intermolecular hydrogen bonding with the hydroxy hydrogen of other (
R)-
1. Thus, an array of structures with ribbon-like hydrogen-bonding patterns was present along the
a-axis. These hydrogen-bonding interactions are responsible for reinforcing the crystal structure. The crystal structure was also reinforced by continuous CH/
π interactions on the aromatic rings of
1 and cinchonidine. The phenyl group of (
R)-
1 and the quinoline group of cinchonidine were arranged in an edge-to-face orientation. One CH/
π interaction was present between the CH of the quinoline group of cinchonidine and the quinoline group of other cinchonidine. Three CH/
π interactions were present on the phenyl group of (
R)-
1: one is between the CH of the quinoline group of cinchonidine and the phenyl group of (
R)-
1; the other is between the
meta-CH of (
R)-
1 and the quinoline group of cinchonidine. Moreover, the CH of the vinyl group of cinchonidine was involved in the CH/
π interaction with the phenyl group (
R)-
1. These CH/
π interactions were responsible for the recognition of the benzyl group on the chiral center of (
R)-
1.
The crystal structure of (
R)-
2 · cinchonidine salt, which was obtained in EtOH/toluene, is shown in
Figure S1. The ratio of
2: cinchonidine was found to be 1:1. The structure was analogous to that of (
R)-
1 · cinchonidine despite the presence of a chlorine substituent in
2, which explains its high efficiency during the resolution of
rac-
2.
The crystal structure of (
R)-
3 · cinchonidine salt obtained using AcOEt is illustrated in
Figure 4. The ratio of
3: cinchonidine was found to be 1:1. The absolute configuration of
3 was inferred to be (
R), which was consistent with the resolution results (
Table 6, entry 4). Although the carboxylate moiety of (
R)-
3 was partly disordered, one carboxylate oxygen of (
R)-
3, which points towards the cinchonidine molecule, formed an intermolecular hydrogen bond with the ammonium hydrogen of the azabicyclo[2.2.2]octane group of cinchonidine. Another carboxylate oxygen of (
R)-
3, which points away from the cinchonidine molecule, was involved in the intramolecular hydrogen bonding with the hydroxy hydrogen of (
R)-
3. There are less intermolecular interactions in (
R)-
3 · cinchonidine than in the (
R)-
1 · cinchonidine salt, which probably contributed to its high solubility. They featured ribbon-like networks but only weakly connected along the
a-axis. Moreover, (
R)-
3 · cinchonidine exhibited different packing patterns of arrays due to an additional methylene group. The phenyl group of (
R)-
3 and the quinoline group of cinchonidine were positioned remote to each other. Nevertheless, the crystal structure was reinforced by the same type of continuous CH/
π interactions as exhibited in (
R)-
1 · cinchonidine and (
R)-
2 · cinchonidine. Together with the fixation of carboxyl and hydroxy groups by hydrogen bonds, the terminal phenyl group of (
R)-
3 was fixed with three kinds of CH/
π interactions by cinchonidine. Despite its flexibility,
rac-
3 was efficiently resolved using a large and rigid chiral structure, cinchonidine.