Solvent-induced chirality control in the enantioseparation of 1-phenylethylamine via diastereomeric salt formation

Article abstract of DOI:10.1002/chir.20922

Solvent-induced chirality control in the enantioseparation of 1-phenylethylamine 1 by N-(p-toluenesulfonyl)-(S)-phenylalanine 2 via diastereomeric salt formation was studied. (S)-·(S)-2 was preferentially crystallized as a less-soluble salt from aqueous a

Full text of DOI:10.1002/chir.20922

CHIRALITY 23:326–332 (2011)
Solvent-Induced Chirality Control in the Enantioseparation
of 1-Phenylethylamine via Diastereomeric Salt Formation
KOICHI KODAMA,1 YURIA KIMURA,1 HIROAKI SHITARA,1 MIKIO YASUTAKE,1 RUMIKO SAKURAI,2
1
*
AND TAKUJI HIROSE
1Department of Applied Chemistry, Saitama University, Saitama, Japan
2Faculty of Pharmacy, Iwaki Meisei University, Iwaki, Fukushima, Japan
ABSTRACT
Solvent-induced chirality control in the enantioseparation of 1-phenylethyl-
amine 1 by N-(p-toluenesulfonyl)-(S)-phenylalanine 2 via diastereomeric salt formation was
studied. (S)-1ꢀ(S)-2 was preferentially crystallized as a less-soluble salt from aqueous alco-
hol, while (R)-1ꢀ(S)-2 salt was mainly obtained by addition of solvents with a six-membered
ring such as dioxane, cyclohexane, tetrahydropyran, and cyclohexene to 2-propanol. Further
investigations were carried out from the viewpoints of molecular structures, optical rotation
measurement, and X-ray crystallographic analyses. Crystallographic analyses have revealed
that incorporation of the six-membered ring solvent molecule in (R)-1ꢀ(S)-2 without hydro-
gen bonds changed the molecular conformation of (S)-2 to stabilize the salt, which
C
VV
changed the selectivity of 1 in the enantioseparation. Chirality 23:326–332, 2011.
2010
Wiley-Liss, Inc.
KEY WORDS: optical resolution; enantiomer; amino acids; solvent-switch method; X-ray
crystallographic analysis; hydrogen-bonding network
INTRODUCTION
the mixed solvents, which can inverse the relative stability
of the less and more-soluble diastereomeric salts. Similar
solvent-dependent switch of enantioselectivity has been
reported in a resolution of diastereomeric 1-phenylethyla-
mides of 1,10-binaphthalene-2,20-dicarboxylic acid15 and
enantioselective inclusion of 2-methylpiperidine with a chiral
host compound.16 In most cases, solvent molecules are
included in the crystals by hydrogen bonds to switch the
enantioselectivity.
Previously, we have also reported a solvent dependent
enantioseparation of racemic 1-phenylethylamine 1 by a natu-
ral amino acid derivative, N-(p-toluenesulfonyl)-(S)-phenylala-
nine 2 (Fig. 1).17 In this example, non-solvated diastereo-
meric salt (S)-1ꢀ(S)-2 was preferably obtained from polar
aqueous alcohols, on the other hand, 1,4-dioxane/alcohol
mixed solvents afforded the solvated diastereomeric salt, (R)-
1ꢀ(S)-2ꢀdioxane as a less-soluble salt. Crystallographic analy-
sis has revealed that incorporated dioxane molecules fill the
void space and stabilize the (R)-1ꢀ(S)-2 diastereomeric salt
without any hydrogen-bonding interactions. In this example,
no simple dependency was observed between e and enantio-
meric purity of resolved 1. We have also showed the similar
incorporation of cyclohexane in the diastereomeric salt (R)-
1ꢀ(S)-2ꢀcyclohexane from the X-ray crystallographic analysis.
This observation strongly suggests that (R)-1ꢀ(S)-2 can be
solvated by solvents with a six-membered ring and cyclohex-
ane, which is isostructural to dioxane, is a potential solvent
One of the most attractive methods to achieve enantiosepa-
ration of racemates into their enantiopure forms is a diaster-
eomeric salt formation method with an enantiopure acidic/
basic resolving agent.1–3 This method enables us to obtain
enantiopure compounds both in the laboratory and industrial
scale because of the simple, economical, and reproducible
operation. Recently, it has been reported that application of
the mixture of structurally similar resolving agents can
improve the enantioselectivity.4 Although several research-
ers have been tried to clarify the chiral recognition mecha-
nism from the viewpoint of phase diagrams, computational
method, structural similarity, it is still difficult to predict an
appropriate resolving agent for a racemate.5–7 Therefore, it is
necessary to apply several resolving agents to find a suitable
combination by a trial-and-error approach, and a variety of
new resolving agents have been developed to meet the
demand.8,9 For the design of new resolving agents, natural
compounds are preferable candidates as inexpensive chiral
sources.10 Natural amino acid derivatives are one of the
most widely used resolving agents because both acidic and
basic resolving agents are easily accessible; however, only a
single enantiomer is available from natural sources, and it is
a drawback for efficiently obtaining both enantiomers from
racemates.
Recently, Sakai et al. have reported an interesting enantio-
separation method that both enantiomers are accessible
from racemates using a single enantiomer as a resolving
agent only by changing dielectric constants (e) of the resolu-
tion solvents (dielectrically controlled resolution).11–14 This
method is especially advantageous for the naturally occurred
resolving agents. In this method, a diastereomeric salt that is
more-soluble in non-polar solvents can form hydrated (sol-
vated) less-soluble salt crystals in polar solvents. This solva-
tion phenomenon is dependent on the dielectric constant of
Crystallographic data for the structures reported in this article have been de-
posited with the Cambridge Crystallographic Data Centre.
*Correspondence to: Takuji Hirose, 255 Shimo-Okubo, Sakura-ku, Saitama
338-8570, Japan. E-mail: hirose@apc.saitama-u.ac.jp
Received for publication 26 June 2010; accepted in revised form 26 August
2010
DOI: 10.1002/chir.20922
Published online 12 November 2010 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2010 Wiley-Liss, Inc.

SOLVENT-INDUCED CHIRALITY CONTROL
327
Compound (R)-1ꢀ(S)-4. [a]2D4 5 123.8 (c 1.00, MeOH, T 5 248C);
mp 150.0–152.08C; IR(KBr) cm21: 3335, 1655, 1570, 1497, 1448, 1386,
1322, 1308, 1226, 1159, 1093, 969, 904, 753, 698, 687, 603, 588, 556; 1H
NMR (CDCl3, 300 MHz): d 7.56 (d, J 5 7.5 Hz, 2H), 7.47–7.42 (m, 1H),
7.32–7.27 (m, 7H), 7.13–7.11 (m, 3H), 7.04 (s, 2H), 4.10 (q, J 5 6.6 Hz, 1H),
3.83 (dd, J1 5 5.1 Hz, J2 5 6.9 Hz, 1H), 3.00 (dd, J1 5 4.8 Hz, J2 5 13.8 Hz,
1H), 2.73 (dd, J1 5 7.5 Hz, J2 5 13.8 Hz, 1H), 1.44 (d, J 5 6.6 Hz, 3H).
Compound (S)-1ꢀ(S)-4. [a]2D4 5 117.4 (c 1.00, MeOH, T 5 248C);
mp 159.0–162.08C; IR(KBr) cm21: 2930, 1559, 1449, 1398, 1324, 1163,
1093, 963, 905, 853, 751, 716, 700, 687, 587, 557, 488; 1H NMR (DMSO-d6,
300 MHz): d 7.74 (d, J 5 6.6 Hz, 2H), 7.66–7.19 (m, 13H), 4.30 (q, J 5 6.6
Hz, 1H), 3.46 (t, J 5 5.1 Hz, 1H), 3.01 (dd, J1 5 5.1 Hz, J2 5 13.5 Hz, 1H),
2.93 (dd, J1 5 5.4 Hz, J2 5 13.5 Hz, 1H), 1.44 (d, J 5 6.6 Hz, 3H).
Fig. 1. Chemical structures of 1-phenylethylamine (1) and N-(p-toluene-
sulfonyl)-(S)-phenylalanine (2).
that the solvent switch method can be applied. In this study,
we show the enantioseparation of rac-1 by (S)-2 in cyclohex-
ane/2-propanol mixed solvents and clarify the mechanism of
chirality control that depended on the shape and size of the
solvent on the basis of X-ray crystallographic analyses of the
diastereomeric salts.
Procedure of Enantioseparation via Diastereomeric Salt
Formation
The general enantioseparation experiment was carried out as follows.
Equimolar amounts of racemic 1-phenylethylamine 1 and N-(p-toluene-
sulfonyl)-(S)-phenylalanine 2 were dissolved in an appropriate solvent
under a refluxed temperature. The solution was then left standing at
room temperature to crystallize. The deposited crystals were filtered and
washed with a small amount of solvent, followed by air drying. The
obtained 1ꢀ(S)-2 salt crystals were subjected to acetylation by acetic an-
hydride in the presence of pyridine or triethylamine as a base. Acetyl
amide of 1 was purified by preparative scale TLC, and its enantiomeric
purity was determined by HPLC analysis using Chiralpak AD-H (Daicel
Chemical Ind., eluent: 10% 2-propanol in hexane, flow rate: 0.5 ml/min,
detection: UV 254 nm, retention time: t1 5 12 min(R), t2 5 14 min(S)).
MATERIALS AND METHODS
General
1
The measurement of H NMR spectra was performed on Bruker DPX
200, AVANCE 300, and DRX 400 spectrometers (Molecular Analysis and
Life Science Center, Saitama University). Melting temperatures were
recorded on the MEL-TEMP melting point apparatus and are uncor-
rected. Optical rotation values were measured on the JASCO DIP-370 po-
larimeter. HPLC analyses were performed by using a JASCO Intelligent
HPLC system 900.
Preparation of the Resolving Agents and the
Diastereomeric Salts
Optical Rotation Measurement
The sample solutions for optical rotation measurement were prepared
by mixing equimolar amounts of 1 and 2 in MeOH/dioxane or MeOH/
water at a concentration of 1.0 g /100 ml (c 1.0). The water-jacketed cell
was used to control the measurement temperature at 25.08C. The dielec-
tric constants e of the mixed solvents were calculated as the weighted av-
erage of the mixture components.
Enantiopure resolving agents 2–4 were synthesized from the corre-
sponding amino acids and arylsulfonyl chlorides and characterized
according to the literatures. Enantiopure 1-phenylethylamines were
kindly supplied by Yamakawa Chemical Industry Co.
N-(p-toluenesulfonyl)-(S)-phenylalanine (2).18 [a]D25 5 12.10 (c
1.00, MeOH, T 5 258C); mp 168.08C; IR(KBr) cm21: 3321, 3030, 1711,
1331, 1158; 1H NMR (CDCl3, 200 MHz): d 7.60 (d, J 5 8.2 Hz, 2H), 7.26–
7.05 (m, 7H), 5.00 (d, J 5 8.6 Hz, 1H), 4.27–4.17 (m, 1H), 3.16–2.95 (m,
2H), 2.40 (s, 3H).
X-Ray Crystallographic Analyses
X-ray crystallographic data were collected on a Bruker SMART APEX
diffractometer with graphite monochromated Mo Ka radiation (Table 1).
The crystal structures were determined by a direct method using
N-(p-toluenesulfonyl)-(R)-phenylglycine (3).19 [a]D22 5 2113.4 (c
1.00, MeOH, T 5 228C); mp 181.0–182.08C; IR(KBr) cm21: 3591, 3293,
1725, 1600, 1460, 1344, 1326, 1290, 1258, 1210, 1167, 1091, 1069, 926,
899, 814, 725, 690, 594, 571, 533; 1H NMR (CDCl3/CD3OD, 400 MHz): d
7.61 (d, J 5 8.4 Hz, 2H), 7.25–7.18 (m, 7H), 4.98 (s, 1H), 3.38 (s, 1H),
2.38 (s, 3H).
TABLE 1. Crystallographic data for the diastereomeric salts
(R)-1ꢀ(S)-2
(R)-1ꢀ(S)-2ꢀtetrahydropyran
Formula
FW
C
24H28N2O4S
440.54
293
C29H38N2O5S
526.67
123
Orthorhombic
P212121
6.1431(12)
20.043(4)
22.181(4)
90
N-benzenesulfonyl-(S)-phenylalanine (4).20 [a]D24 5 10.50 (c 1.00,
MeOH, T 5 248C); mp 135.58C; IR(KBr) cm21: 3342, 3173, 3061, 2967,
1735, 1697, 1447, 1376, 1347, 1294, 1171, 1109, 1093, 955, 835, 756, 720,
701, 688, 640, 586, 541; 1H NMR (CDCl3, 400 MHz): d 7.72 (d, J 5 7.6
Hz, 2H), 7.54 (t, J 5 7.2 Hz, 1H), 7.44 (t, J 5 7.8 Hz, 2H), 7.25–7.24 (m,
3H), 7.09–7.07 (m, 2H), 5.02 (d, J 5 8.8 Hz, 1H), 4.28–4.22 (m, 1H), 3.11
(dd, J1 5 5.6 Hz, J2 5 14 Hz, 1H), 3.02 (dd, J1 5 6.4 Hz, J2 5 14 Hz, 1H).
Temperature (K)
Crystal system
Space group
Monoclinic
P21
˚
a (A)
13.184(2)
5.8641(10)
15.511(3)
109.623(4)
1129.5(3)
2
˚
b (A)
˚
c (A)
Compound (R)-1ꢀ(R)-3. [a]2D4 5 2105.7 (c 1.00, MeOH, T 5
248C); mp 185.0–186.08C; IR(KBr) cm21: 3313, 1655, 1595, 1519, 1457,
1365, 1342, 1321, 1225, 1157, 1090, 1065, 921, 809, 729, 699, 667, 564,
546; 1H NMR (DMSO-d6, 300 MHz): d 7.64 (d, J 5 8.4 Hz, 2H), 7.46–
7.17 (m, 12H), 4.34 (q, J 5 6.9 Hz, 1H), 4.16 (s, 1H), 2.39 (s, 3H), 1.45
(d, J 5 6.6 Hz, 3H).
b (8)
3
˚
V (A )
2731.0(9)
4
Z
Dc (g/cm3)
R
Rw
1.295
1.281
0.0536
0.1340
6588
3780
3295
3780
298
776840
0.0592
0.1691
29767
6251
5661
6251
352
776841
Measured reflns
Unique reflns
Observed refluns
Refluns used
parameters
Number CCDC
Compound (S)-1ꢀ(R)-3. [a]2D4 5 2110.4 (c 1.00, MeOH, T 5
248C); mp 168.0–170.08C; IR(KBr) cm21: 3316, 1648, 1583, 1496, 1456,
1376, 1358, 1344, 1325, 1231, 1159, 1090, 1063, 915, 896, 808, 777, 734,
718, 696, 669, 564, 548; 1H NMR (DMSO-d6, 300 MHz): d 7.64 (d, J 5 8.4
Hz, 2H), 7.48–7.17 (m, 12H), 4.33 (q, J 5 6.6 Hz, 1H), 4.20 (d, J 5 6.6
Hz, 1H), 2.39 (s, 3H), 1.45 (d, J 5 6.6 Hz, 3H).
Chirality DOI 10.1002/chir

328
KODAMA ET AL.
TABLE 2. Enantioseparation of rac-1 with (S)-2 in 2-propanol/cyclohexane mixed solvents
Solvent 2-propanol/
cyclohexane (v/v)
Solvent volume
(ml/mmol of rac-1)
Yield
(g)a
Ee
Absolute
configuration
Dielectric
constant
Entry
Initial salt (g)
(%)b
1
2
3
4
5
6
7
8
9
10
100:0
90:10
80:20
70:30
60:40
50:50
40:60
30:70
20:80
10:90
4.2
5.7
7.0
6.5
8.0
11.0
13.0
42.0
65.0
144.0
0.440
0.929
0.899
0.458
0.436
0.451
0.446
0.458
0.454
0.447
0.154
0.351
0.221
0.145
0.138
0.173
0.165
0.144
0.147
0.137
68.4
28.3
48.0
46.9
69.1
33.3
24.0
35.0
34.5
53.7
S
S
S
S
S
R
R
R
R
R
19.9
18.1
16.4
14.6
12.8
11.0
9.2
7.4
5.6
3.8
aMaterial yield of the deposited diastereomeric salts.
bDetermined by chiral HPLC analysis (Daicel Chiralpak AD-H) after derivatizing to its acetyl amide.
SIR9721 and refined by the full-matrix least squares method using
Enantioseparation of rac-1 with (S)-2 in Various Solvents
with Five- or Six-Membered Ring Structures
SHELXL-97.22
Since the inversion of enantioselectivity by dioxane and
cyclohexane appeared to be mainly due to incorporation of
the solvent molecules in (R)-1ꢀ(S)-2 salt, the phenomenon
would be generally observed in the solvents with similar
size and shape. Considering the structure of the crystalliza-
tion solvents, we expected that tetrahydropyran (THP),
cyclohexene, and tetrahydrofuran(THF) were also potential
solvents to inverse the enantioselectivity of 1. The results of
enantioseparation of rac-1 with (S)-2 in a mixed solvent of
2-propanol/cyclic solvents 5 10:90 (v/v) are summarized in
Table 3. The ratio of the mixed solvents used was fixed to
afford appropriate solubility and make comparisons with the
result obtained for cyclohexane. THP is composed of a satu-
rated six-membered ring like dioxane and cyclohexane. 2-
Propanol/THP (10:90, v/v) afforded the diastereomeric salt
incorporating THP with about 30 mol % inclusion ratio esti-
mated from the 1H NMR measurement. As we expected,
the mainly obtained 1 was R-isomer (56.2% ee), and addition
of THP to 2-propanol in the crystallization solvent has also
changed the enantioselectivity of 1 from S to R. Cyclohex-
ene has a similar but more rigid and planar structure than
cyclohexane due to an unsaturated carbon–carbon bond in
the six-membered ring. 2-Propanol/cyclohexene (10:90, v/v)
also afforded (R)-1 with 42.1% ee. On the other hand, (S)-1
was mainly obtained from 2-propanol/THF (10:90, v/v),
which is composed of one less carbon atom compared with
THP. These results suggest that size and shape of the crys-
tallization solvents are crucial factors to determine the enan-
tioselectivity of 1 and that the solvents with a six-membered
ring structure generally change the enantioselectivity of 1
from S to R.
RESULTS AND DISCUSSION
Enantioseparation of rac-1 with (S)-2 in Cyclohexane/
2-Propanol
First, we investigated the enantioseparation of rac-1 with
(S)-2 in a mixed solvent of cyclohexane and 2-propanol with
changing their mixing ratio by 10% based on their volume.
Enantiopure (S)-2 was synthesized from L-phenylalanine and p-
toluenesulfonyl chloride according to the literature.18 Both rac-
1 and (S)-2 (1 or 2 mmol) were added in the crystallization sol-
vents and dissolved at refluxed temperature, then left at room
temperature to crystallize the salt. After the salt was separated
and air-dried to measure the yield, 1 was derivatized to its ace-
tyl amide before the determination of enantiomeric excess(ee)
by chiral HPLC analysis. The results are summarized in Table
2. Although low solubility of the salt prevented crystallization
from 100% cyclohexane, the salt of 1ꢀ(S)-2 was obtained as
white solids for all the solvent systems examined. It was shown
that (S)-1ꢀ(S)-2 was obtained from the solvents with low cyclo-
hexane content; on the other hand, an increase of cyclohexane
ratio in the crystallization solvent changed the mainly obtained
enantiomer of 1 from S to R-isomer. (R)-1 was obtained from
the solvents with more than 50% of cyclohexane ratio and 2-pro-
panol/cyclohexane 5 10:90 (v/v) gave (R)-1 in the best selec-
tivity. This chirality inversion is in accordance with the result
performed in dioxane/2-propanol mixed solvents while only
25% of dioxane in 2-propanol changed the selectivity.17 It is sug-
gested that subtle difference of the molecular structures
between dioxane and cyclohexane affect the stability of the dia-
stereomeric salts and efficiency of the enantioseparation.
TABLE 3. Enantioseparation of rac-1 with (S)-2 in 2-propanol/cyclic compound mixed solvents
Solvent volume
(ml/mmol of rac-1)
Absolute
configuration
Entry
Solvent (v/v)
2-Propanol
2-Propanol/THP (10:90)
2-Propanol/cyclohexene (10:90)
2-Propanol/THF (10:90)
Initial salt (g)
Yield (g)a
Ee (%)b
1
2
3
4
4.2
21.2
120.8
1.1
0.440
0.541
0.091
1.585
0.154
0.187
0.024
0.564
68.4
56.2
42.1
47.9
S
R
R
S
aMaterial yield of the deposited diastereomeric salts.
bDetermined by chiral HPLC analysis (Daicel Chiralpak AD-H) after derivatizing to its acetyl amide.
Chirality DOI 10.1002/chir

SOLVENT-INDUCED CHIRALITY CONTROL
329
Fig. 3. Chemical structures of N-(p-toluenesulfonyl)-(R)-phenylglycine (3)
and N-benzenesulfonyl-(S)-phenylalanine (4).
Fig. 2. Crystal structure of (R)-1ꢀ(S)-2ꢀtetrahydropyran viewed from the
columnar axis. The dotted lines and colored circles show hydrogen bonds
and columnar structures, respectively. Hydrogen atoms are omitted for
clarity. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
the selectivities of 49.6% ee and 47.3% ee, respectively
(entries 3 and 4). Similarly, 1ꢀ(S)-4 crystallized from 2-propa-
nol and 2-propanol/cyclohexane (10:90, v/v) consistently
afforded homochiral (S)-1ꢀ(S)-4 as a less-soluble salt in
46.6% and 47.8% selectivities (entries 5 and 6). It was sug-
gested that chirality inversion phenomenon was not
observed by the addition of cyclohexane when (R)-3 and (S)-
4 were applied as a resolving agent. This is in sharp contrast
to the result that heterochiral diastereomeric salt (R)-1ꢀ(S)-2
was crystallized from 2-propanol/cyclohexane 5 10:90 (v/v)
mixed solvent (entry 2).
It is well known that even a slight modification of the
resolving agents can drastically change the enantioselectiv-
ity.8,9 In this case, a decrease of only one carbon atom in the
resolving agent has made it difficult to switch the enantiose-
lectivity of 1 dependent on the solvents. We have reported
that appropriate flexibility of the molecular conformation is
seemed to play a key role to apply the solvent-induced chiral-
ity switch in the enantioseparation by changing the molecu-
lar conformation to include solvent molecules and form
densely packed salt crystals.23,24 As discussed below,25–28 it
is probable that 1ꢀ(R)-3 and 1ꢀ(S)-4 have similar hydrogen-
bonding networks as 1ꢀ(S)-2, however, slight differences
such as more rigid structure of (R)-3 and less bulky struc-
ture of (S)-4 have changed the molecular packing in the salt
crystals to prevent their heterochiral diastereomeric salts
from incorporating cyclohexane molecules in the void space
to switch the enantioselectivity.
To know the reason of chirality inversion caused by the
addition of THP, X-ray crystallographic analysis was per-
formed for the single crystal of (R)-1ꢀ(S)-2 prepared from
THP/2-propanol (Fig. 2). As observed for the cases that diox-
ane and cyclohexane were included in (R)-1ꢀ(S)-2, THP mol-
ecules were included in the one dimensional void space to
form (R)-1ꢀ(S)-2ꢀTHP ternary inclusion crystal. The molecu-
lar arrangements of (R)-1 and (S)-2 were quite similar to
those of other inclusion crystals, and THP molecules were
included without any hydrogen bonds. It was revealed that
THP molecules also effectively filled the void space to stabi-
lize the (R)-1ꢀ(S)-2 diastereomeric salt and contributed to
switch the enantioselectivity of 1.
Structural Modification of the Resolving Agents
It was found that the solvents with a six-membered molec-
ular structure were potential to switch the enantioselectivity
of 1 resolved with (S)-2. In the next step, we investigated
the effect of the structures of resolving agents. We prepared
two structurally related resolving agents, N-(p-toluenesul-
fonyl)-(R)-phenylglycine(3) and N-benzenesulfonyl-(S)-phe-
nylalanine(4), which have one less carbon atom compared
with 2 (Fig. 3). Enantiopure 3 and 4 were synthesized from
the corresponding amino acids and arylsulfonyl chlorides by
the similar manner to (S)-2. The results of the enantiosepara-
tion of rac-1 with (S)-2, (R)-3 and (S)-4 in 2-propanol and 2-
propanol/cyclohexane 5 10:90 (v/v) mixed solvent are sum-
marized in Table 4. When (R)-3 was used as a resolving
agent, addition of cyclohexane to 2-propanol gave little differ-
ence in the enantioseparation, and the homochiral diastereo-
meric salt (R)-1ꢀ(R)-3 was obtained as a less-soluble salt in
Comparison of Crystal Structures of the Diastereomeric
Salts: (R)-1ꢀ(S)-2, (S)-1ꢀ(S)-2, (R)-1ꢀ(S)-2ꢀSolvent
To investigate the mechanism of this solvent dependent
resolution system in detail, we compared the crystal struc-
tures of the three salt crystals, (R)-1ꢀ(S)-2, (S)-1ꢀ(S)-2,17
and (R)-1ꢀ(S)-2ꢀdioxane17 (Fig. 4). The single crystal of
TABLE 4. Enantioseparation of rac-1 with (S)-2, (R)-3 and (S)-4 in a 2-propanol/cyclohexane mixed solvent
Resolving
agents
Solvent 2-propanol/
cyclohexane (v/v)
Solvent volume
(ml/mmol of rac-1)
Absolute
configuration
Homo/
heteroc
Entry
Initial salt (g)
Yield (g)a
Ee (%)b
1
2
3
4
5
6
(S)-2
(S)-2
(R)-3
(R)-3
(S)-4
(S)-4
100:0
10:90
100:0
10:90
100:0
10:90
4.2
144.0
8.8
312
3.7
0.440
0.447
0.289
0.274
0.115
0.081
0.154
0.137
0.086
0.099
0.017
0.030
68.4
53.7
49.6
47.3
46.6
47.8
S
R
R
R
S
S
Homo
Hetero
Homo
Homo
Homo
Homo
63.2
aMaterial yield of the deposited diastereomeric salts.
bDetermined by chiral HPLC analysis (Daicel Chiralpak AD-H) after derivatizing to its acetyl amide.
cChirality of the resolving agents and 1 in the less-soluble diastereomeric salts.
Chirality DOI 10.1002/chir

330
KODAMA ET AL.
Fig. 4. Structures of the three diastereomeric salt crystals: (a) (R)-1ꢀ(S)-2, (b) (S)-1ꢀ(S)-2, (c) (R)-1ꢀ(S)-2ꢀdioxane viewed from the columnar axis, respectively. Co-
lumnar hydrogen-bonding network of (d) (R)-1ꢀ(S)-2, (e) (R)-1ꢀ(S)-2ꢀdioxane, respectively. The dotted lines and colored circles show hydrogen bonds and columnar
structures, respectively. Hydrogen atoms are omitted for clarity. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(R)-1ꢀ(S)-2 was prepared by slow evaporation of the tolu-
ene/THF solution of (R)-1ꢀ(S)-2. Figure 4 shows that a
one dimensional columnar hydrogen-bonding network is
commonly constructed in the three salt crystals, which is
an often observed supramolecular structure in primary
ammonium-carboxylate salt crystals.25–28 In (R)-1ꢀ(S)-
2ꢀdioxane, dioxane molecules were included in the void
space formed between the columnar structures without
any hydrogen-bonding interaction as mentioned above for
(R)-1ꢀ(S)-2ꢀTHP (Fig. 4c).
ylic acid (S)-2 itself.13 On the other hand, it is necessary
for (S)-2 to adopt trans-gauche or gauche-gauche conforma-
tion to maintain a columnar hydrogen-bonding network
formed with primary amine 1. These two conformations
are commonly observed in the salts of (S)-2 and other
primary amines.13 In (R)-1ꢀ(S)-2, (S)-2 takes a gauche-
gauche conformation and the columnar network was
formed between the ammonium hydrogen atom of (R)-1
and carboxylate oxygen atom of (S)-2 (Fig. 4d). On the
other hand, trans-gauche orientation is adopted in (R)-
1ꢀ(S)-2ꢀdioxane and the one dimensional columnar struc-
ture is maintained not only by the hydrogen bonds
between the ammonium hydrogen atom of (R)-1 and car-
boxylate oxygen atom of (S)-2 but the additional hydro-
gen bond between carboxylate oxygen atom and amide
hydrogen atom of (S)-2 (Fig. 4e). It was found that this
additional intermolecular hydrogen bond between (S)-2
One critical difference between these crystal structures
is the molecular conformation of (S)-2. Three possible
conformers of (S)-2 are described in Figure 5. In general,
gauche-trans conformation appears to be the most stable
form because two bulky groups, phenyl and p-toluenesul-
fonyl amide groups adopt trans-position to avoid their
steric repulsion. This is the case for the crystal of carbox-
Chirality DOI 10.1002/chir

SOLVENT-INDUCED CHIRALITY CONTROL
331
Fig. 5. Three possible conformers of (S)-2. The first designation denotes the relationship between phenyl and carboxylate groups, second one denotes that of
phenyl and tosylamide groups.
molecules stabilized the columnar structure of (R)-1ꢀ(S)-
2ꢀdioxane.
tle effect on the stability of the inclusion crystals and
results of enantioseparation.
In addition, gauche-gauche conformation of (S)-2 appears
to be disadvantageous for efficient packing of columns
than that with trans-gauche conformation. Viewed from the
columnar axis of (R)-1ꢀ(S)-2, the orientation of two aro-
matic rings of gauche-gauche (S)-2 is almost perpendicular
and packed less densely (Fig. 4a); on the other hand,
parallel orientation is observed in trans-gauche (S)-2, and
more dense and efficient packing of columnar structures
was achieved for (R)-1ꢀ(S)-2ꢀdioxane (Fig. 4c). In (S)-
1ꢀ(S)-2 diastereomeric salt, (S)-2 takes both gauche-gauche
and trans-gauche conformations and shows conformational
isomorphism (Fig. 4b). One column is constructed from
(S)-2 with gauche-gauche conformation, and the other col-
umn is constructed from (S)-2 with trans-gauche confor-
mation. These conformational differences may reflect the
order of the stability of the three salts ((R)-1ꢀ(S)-
2ꢀdioxane > (S)-1ꢀ(S)-2 > (R)-1ꢀ(S)-2). In the presence
of an appropriate solvent as a space filler, (R)-1ꢀ(S)-
2ꢀsolvent ternary crystals become favorable than (S)-1ꢀ(S)-
2 and the enantioselectivity of 1 has changed from S to
R. The crystals obtained from cyclohexane and THP are
isostructural to (R)-1ꢀ(S)-2ꢀdioxane, except for the align-
ment of the columns: parallel alignment for the dioxane
inclusion crystal (space group: P21) and antiparallel align-
ment for the other two inclusion crystals (space group:
P212121). This subtle difference is seemed to be caused
by the presence of two oxygen atoms; however, it has lit-
Comparison of the Dependence of Optical Rotation of
Diastereomeric Salts for the Solvents
Previously, we have shown that a large difference of
optical rotation values between two diastereomeric salts
was often observed when dielectrically controlled resolu-
tion is applicable.23,24 Optical rotation measurements
reflect conformational change of the molecules in solution.
To further investigate this solvent-dependent enantiosepa-
ration, we measured optical rotation values of (S)-1ꢀ(S)-2
and (R)-1ꢀ(S)-2 in MeOH/H2O and MeOH/dioxane sol-
vents with various mixed ratio (Fig. 6). It was revealed
that little difference was observed between the two dia-
steremeric salts (|[f]SS–[f]RS| 5 0–36) in a whole range
of the dielectric constants, though the solvent-dependent
chirality inversion was observed by the addition of diox-
ane. This is probably because the chirality inversion is
attributed to the inclusion of the solvent molecules in the
crystalline state without any hydrogen bonds and there-
fore, solvents make little difference on the conformation
of 1 and 2 in a solution state.
CONCLUSIONS
Control of the functionality of organic salt crystals by
the included solvents is studied by other groups from the
viewpoint of supramolecular chemistry.29,30 In this study,
we demonstrated that size and shape of the solvents are
crucial factors to switch the selectivity of the enantiosepa-
ration of rac-1 via the diastereomeric salt formation with
(S)-2. The enantioselectivity of 1 dramatically changed
from S to R with increasing the cyclohexane ratio of the
crystallization solvents. The similar phenomena were com-
monly observed when solvents with a six-membered ring
structure such as THP and cyclohexene were used. How-
ever, the chirality switch phenomenon was not observed
when structurally similar resolving agents (R)-3 and (S)-4
were applied. Crystallographic analysis has revealed that
THP was included in the salt (R)-1ꢀ(S)-2 and stabilized it
without any hydrogen bonds. It was shown from the com-
parison of the three salt crystals that the difference in
the conformation of (S)-2 plays an important role for their
relative stability and enantioselectivity of 1. Although the
efficiency of enantioseparation of rac-1 by (S)-2 is not
very high, the commonly observed chirality inversion phe-
nomenon will help us to design more efficient separation
systems controlled by crystallization solvents.
Fig. 6. Solvent dependence of molar rotation of the diastereomeric salts
in MeOH/dioxane and MeOH/water: (R)-1ꢀ(S)-2 (square), (S)-1ꢀ(S)-2
(circle). [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

332
KODAMA ET AL.
16. Toda F, Tanaka K, Miyahara I, Akutsu S, Hirotsu K. Role of methanol in
LITERATURE CITED
chiral combinations of host-guest molecules in the inclusion crystal:
structure determination by X-ray crystallography. J Chem Soc Chem
Commun 1994:1795–1796.
1. Jacques J, Collet A, Wilen SH. Enantiomers, racemates, and resolutions.
Malabar: Krieger; 1981.
2. Kozma D. Optical resolutions via diastereomeric salt formation. London:
CRC Press; 2002.
17. Hirose T, Begum M, Islam MS, Taniguchi K, Yasutake M. Resolution of
a-methylbenzylamine via diastereomeric salt formation using the natu-
rally based reagent N-tosyl-(S)-phenylalanine together with a solvent
switch technique. Tetrahedron Asymmetry 2008;19:1641–1646.
3. Faigl F, Fogassy E, Nogradi M, Palovics E, Schindler J. Strategies in opti-
cal resolution: a practical guide. Tetrahedron Asymmetry 2008;19:519–536.
4. Kellogg RM, Nieuwenhuijzen JW, Pouwer K, Vries TR, Broxterman QB,
Grimbergen RFP, Kaptein B, La Crois RM, de Wever E, Zwaagstra K,
van der Laan AC. Dutch resolution: separation of enantiomers with fami-
lies of resolving agents. A status report. Synthesis 2003;10:1626–1638.
18. Han ZJ, Wang R, Zhou YF, Liu L. Simple derivatives of natural amino
acids as chiral ligands in the catalytic asymmetric addition of phenylace-
tylene to aldehydes. Eur J Org Chem 2005;2005:934–938.
19. Salas-Coronado R, Vasquez-Badillo A, Medina-Garcia M, Garcia-Colon
JG, Noth H, Contreras R, Flores-Parra A. Hydrogen bonds and preferred
5. Anandamanoharan PR, Cains PW, Jones AG. Separability of diastereomer
salt pairs of 1-phenylethylamine with enantiomeric 2-substituted phenyl-
acetic acids by fractional crystallization, and its relation to physical and
phase properties. Tetrahedron Asymmetry 2006;17:1867–1874.
conformation of optically active amides.
2001;543:259–275.
J Mol Struct (Theochem)
20. Schuller WH, Niemann C. The papain-catalyzed synthesis of acyl-D- and
L-phenylalanylphenylhydrazides from a series of enantiomorphic paris of
acylated phenylalanines. J Am Chem Soc 1951;73:1644–1646.
6. Karamertzanis PG, Anandamanoharan PR, Fernandes P, Cains PW, Vick-
ers M, Tocher DA, Florence AJ, Price SL. Toward the computational
design of diastereomeric resolving agents: an experimental and computa-
21. Altomare A, Burla MC, Camalli M, Cascarano GL, Giacovazzo C, Gua-
gliardi A, Moliterni AGG, Polidori G, Spagna R. SIR97: a new tool for
tional study of 1-phenylethylammonium-2-phenylacetate derivatives.
Phys Chem B 2007;111:5326–5336.
J
crystal structure determination and refinement.
1999;32:115–119.
J Appl Crystallogr
7. Bereczki L, Bombicz P, Balint J, Egri G, Schindler J, Pokol G, Fogassy E,
Marthi K. Optical resolution of 1-(1-naphthyl)ethylamine by its dicarbox-
ylic acid derivatives: structural features of the oxalic acid derivative dia-
stereomeric salt pair. Chirality 2009;21:331–338.
22. Sheldrick GM. SHELXL97, program for the refinement of crystal struc-
tures. Germany: University of Go†ttingen; 1997.
23. Taniguchi K, Sakurai R, Sakai K, Yasutake M, Hirose T. Optical rotation
study on solvent dependenc of diastereomeric salt discrimination proper-
ties. Bull Chem Soc Jpn 2006;79:1084–1090.
8. Kinbara K, Saigo K. Chiral discrimination during crystallization. In: Denmark
SE, editor. Topics in stereochemistry, Vol. 23. Chapter 4. Chichester: Wiley;
2003. p 207–265.
24. Taniguchi K, Aruga M, Yasutake M, Hirose T. Solvent control of optical
resolution of 2-amino-1-phenylethanol using dehydroabietic acid. Org Bio-
mol Chem 2008;6:458–463.
9. Kinbara K. Design of resolving agents based on crystal engineering. Syn-
lett 2005;5:732–743.
10. Ogawa R, Fujino T, Hirayama N, Sakai K. Practical resolution of racemic
trans-2-benzylaminocyclohexanol with di-p-toluoyl-L-tartaric acid via dia-
stereomeric salt formation based on the Pope and Peachey method. Tet-
rahedron Asymmetry 2008;19:2458–2461.
25. Kodama K, Kobayashi Y, Saigo K. Two-component supramolecular heli-
cal architectures: creation of tunable dissymmetric cavities for the inclu-
sion and chiral recognition of the third components. Chem Eur
2007;13:2144–2152.
J
11. Sakurai R, Yuzawa A, Sakai K, Hirayama N. Dielectrically controlled
enantiomeric resolution (DCR) of (R)- and (S)-2-methylpyrrolidine by
(R,R)-tartaric acid. Cryst Growth Des 2006;6:1606–1610.
26. Kobayashi Y, Saigo K. The role of CH/p interaction in the stabilization of
less-soluble diastereomeric salt crystals. Chem Rec 2007;7:47–56.
27. Sada K, Inoue K, Tanaka T, Tanaka A, Epergyes A, Nagahama S, Matsumoto
A, Miyata M. Organic layered crystals with adjustable interlayer distances of
1-naphthylmethylammonium n-alkanoates and isomerism of hydrogen-bond
networks by steric dimension. J Am Chem Soc 2004;126:1764–1771.
12. Sakai K, Sakurai R, Hirayama N. Molecular mechanism of DCR phenom-
enon observed in (RS)-1-cyclohexylethylamine-mandelic acid resolution
system. Tetrahedron Asymmetry 2006;17:1812–1816.
13. Sakai K, Sakurai R, Akimoto T, Hirayama N. Molecular mechanism of
dielectrically controlled optical resolution (DCR). Org Biomol Chem
2005;3:360–365.
28. Koshima H, Nagano M, Asahi T. Optical activity induced by helical
arrangement of tryptamine and 4-chlorobenzoic acid in their cocrystal. J
Am Chem Soc 2005;127:2455–2463.
14. Sakai K, Sakurai R, Nohira H, Tanaka R, Hirayama N. Practical resolution
of 1-phenyl-2-(4-methylphenyl)-ethylamine using a single resolving agent
controlled by the dielectric constant of the solvent. Tetrahedron Asym-
metry 2004;15:3495–3500.
29. Mizobe Y, Hinoue T, Miyata M, Hisaki I, Hasegawa Y, Tohnai N. Distinct
guest-dependent changes in arrangements of a fluorophore and the corre-
sponding emission modes in a ternary system: transcription and translation
of guest molecular information. Bull Chem Soc Jpn 2007;80:1162–1172.
15. Kato Y, Kitamoto Y, Morohashi N, Kuruma Y, Oi S, Sakai K, Hattori T.
Crystallization-based optical resolution of 1,10-binaphthalene-2,20-dicar-
boxylic acid via 1-phenylethylamides: control by the molecular structure
and dielectric property of solvent. Tetrahedron Lett 2009;50:1998–2002.
30. Imai Y, Kido S, Kamon K, Kinuta T, Sato T, Tajima N, Kuroda R, Matsu-
bara Y. A charge-transfer complex of 10,100-dihydroxy-9,90-biphenanthryl
and methylviologen as
2007;9:5047–5050.
a visual inclusion host system. Org Lett
Chirality DOI 10.1002/chir