K. Kodama et al. / Tetrahedron: Asymmetry 28 (2017) 460–466
461
(1R,2S)-2-amino-1,2-diphenylethanol salt prepared from its etha-
nol solution is shown in Figure 1. As suggested from the 1H NMR
result mentioned above, no solvent was included and a 1:1 salt
of (S)-2 and (1R,2S)-2-amino-1,2-diphenylethanol was formed. A
columnar hydrogen-bonding network was constructed with a 2-
fold screw axis, which is similar to previously reported (S)-1Á
(1R,2S)-2-amino-1,2-diphenylethanol salt.6 The space group of
the crystal was P21 and the neighboring columns were packed in
parallel. In addition to the charge-assisted hydrogen bonds
between the ammonium group of (1R,2S)-2-amino-1,2-dipheny-
lethanol and the carboxylate group of (S)-2, the molecules were
combined by hydrogen bonds between the hydroxy groups of
(S)-2 and (1R,2S)-2-amino-1,2-diphenylethanol to reinforce the
columnar network.
H
OH
H
CH2OH
COOH
H
OH
COOH
CH2COOH
2
mandelic acid
1
H3C
OH
COOH
H
OH
C
COOH
H2
H2N
OH
(1R,2S)-2-amino-1,2-diphenylethanol
3
4
Furthermore, there are two CH/
stituents of (S)-2. One is between the para-CH of (S)-2 and the phe-
p interactions to fix the sub-
2. Results and discussion
nyl ring of (1R,2S)-2-amino-1,2-diphenylethanol of the
Optically active 3-hydroxy-3-phenylpropionic acid 2, which has
a methylene group between the carboxy group and the stereogenic
center of mandelic acid, has been applied to the stereoselective
synthesis of chiral drugs such as (S)-dapoxetine.9 Its enantiosepa-
ration is not easy due to the flexible methylene group but has been
achieved by diastereomeric salt formation with morphine, a highly
toxic alkaloid.10
neighboring column (the CÁ Á Á
p
-plane and CHÁ Á Á
p-plane distances
were 3.67 and 2.74 Å, respectively) and the other is the intra-
columnar interaction between the methylene hydrogen atom and
the phenyl ring of (S)-2 (the CÁ Á Á
p
-plane and CHÁ Á Á
p
-plane dis-
interac-
tances were 3.61 and 3.00 Å, respectively).12 These CH/
p
tions probably played an important role to fix the substituents of
(S)-2 and recognize the chirality. The bulky phenyl group of 2 is
one-carbon more remote from the carboxylate group than in man-
delic acid, and the resulting flexibility allowed dense molecular
packing without incorporation of the solvent molecules to form a
stable salt.
Racemic 2 was synthesized from ethyl benzoylacetate accord-
ing to a reported method and purified by recrystallization from
toluene.11 The salt of rac-2 and (1R,2S)-2-amino-1,2-diphenyletha-
nol was prepared in advance by evaporation of the methanol solu-
tion of their equimolar mixture. The salt was recrystallized once
from various solvents and the deposited solid was filtered and
dried before characterization by 1H NMR spectroscopy. Part of
the salt was decomposed and the enantiopurity of recovered 2
was determined by HPLC analysis after derivatization to its methyl
ester. The results are summarized in Table 1. Seven types of sol-
vents with different polarities were tested and all of them prefer-
entially afforded the (S)-2Á(1R,2S)-2-amino-1,2-diphenylethanol
salt. No chirality switching was observed, which was in accordance
with the fact that none of the tested solvents was included in the
precipitated salt crystals, although the presence of water was
unknown (entry 1). It is noteworthy that the resolution efficiency
(=yield  ee) was as high as 0.5; the less polar THF and 1,4-dioxane
afforded the highest efficiencies (entries 6 and 7), while (S)-2 was
obtained with the highest enantiopurity by recrystallization from
50% EtOH (entry 2). According to this method, enantiopure (S)-2
was prepared after repeated recrystallization of the initial salt (4
times) from 50% EtOH (27% overall yield, >99% ee).
In order to examine the structure of the corresponding more-
soluble (R)-2Á(1R,2S)-2-amino-1,2-diphenylethanol salt, its anti-
pode (S)-2Á(1S,2R)-2-amino-1,2-diphenylethanol salt was prepared
from enantiopure (S)-2 and commercially available (1S,2R)-2-
amino-1,2-diphenylethanol. The structure of the salt crystallized
from aqueous ethanol solution is shown in Figure 2. The columnar
hydrogen-bonding network was constructed from (S)-2 and
(1S,2R)-2-amino-1,2-diphenylethanol, which was similar to
the less-soluble (S)-2Á(1R,2S)-2-amino-1,2-diphenylethanol salt.
However, a water molecule was embedded in the center of the
columnar structure to afford the (S)-2Á(1S,2R)-2-amino-1,2-
diphenylethanolÁ0.5H2O salt. Moreover, two CH/p interactions
were present in the same parts as was the less-soluble (S)-2Á
(1R,2S)-2-amino-1,2-diphenylethanol salt. Although the two
diastereomeric salts have similar molecular orientations, the space
group of the hemihydrated more-soluble salt crystal was C2 and
the structure appeared to be less symmetrical. Preferential crystal-
lization of (S)-2Á(1R,2S)-2-amino-1,2-diphenylethanol salt during
enantioseparation in aqueous solvents probably resulted from this
subtle difference.
While the solvent-induced chirality switching method was not
achieved with 2, X-ray crystallographic analyses of the diastere-
omeric salts were performed in order to elucidate the mechanism
of chiral recognition of 2. The structure of the less-soluble (S)-2Á
When the more-soluble (S)-2Á(1S,2R)-2-amino-1,2-dipheny-
lethanol salt was recrystallized from 1,4-dioxane, a crystal with a
Table 1
Enantioseparation of rac-2 with (1R,2S)-2-amino-1,2-diphenylethanola
Entry
Solvent (L/mol)
Solvent inclusionb (%)
Yieldc (%)
Eed (%)
Eff.e
1
2
3
4
5
6
7
H2O (21)
50% EtOH (11)
EtOH (9)
2-PrOH (13)
Acetone (10)
THF (17)
–
80
47
95
61
59
68 (S)
83 (S)
58 (S)
68 (S)
74 (S)
72 (S)
56 (S)
0.54
0.39
0.55
0.42
0.44
0.56
0.56
Not included
Not included
Not included
Not included
Not included
Trace
78
100
1,4-Dioxane (20)
a
b
c
rac-2 and (1R,2S)-2-amino-1,2-diphenylethanol (1.0 mmol) were used.
The solvent inclusion was determined by 1H NMR analysis.
Yield is based on the half of the salt amount.
Ee was determined by HPLC analysis after derivatization to its methyl ester.
Eff. = Yield (%) Â Ee (%)/10,000.
d
e