An excellent new resolving agent for the diastereomeric resolution of rac-mandelic acid

Article abstract of DOI:10.1016/j.tetasy.2012.06.023

Chiral mandelic acid (S)-1, which is an important precursor for stereoselective transformations and a versatile intermediate for pharmaceuticals, was resolved with the Pope and Peachey method. Enantiopure 1-amino-3-phenoxypropan-2-ol (S)-2, a key intermediate for pharmaceuticals, was used to resolve rac-mandelic acid rac-1 successfully for the first time. The less soluble salt (S)-1·(S)-2·H₂O could be obtained in 77% yield and 98% de (E 75%) using (S)-2 and LiOH in water. The crystal structure of the less soluble salt (S)-1·(S)-2·H₂O showed that the water molecule played a key role in forming the crystals.

Full text of DOI:10.1016/j.tetasy.2012.06.023

Tetrahedron: Asymmetry 23 (2012) 1046–1051
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Tetrahedron: Asymmetry
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An excellent new resolving agent for the diastereomeric resolution
of rac-mandelic acid
Pei Wang a, En Zhang a, Jian-Feng Niu b, Qing-Hua Ren a, Peng Zhao a, Hong-Min Liu a,
⇑
a School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, 450001, PR China
b People’s Hospital of Zhengzhou, 450003, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2012
Accepted 27 June 2012
Chiral mandelic acid (S)-1, which is an important precursor for stereoselective transformations and a ver-
satile intermediate for pharmaceuticals, was resolved with the Pope and Peachey method. Enantiopure
1-amino-3-phenoxypropan-2-ol (S)-2, a key intermediate for pharmaceuticals, was used to resolve rac-
mandelic acid rac-1 successfully for the first time. The less soluble salt (S)-1ꢀ(S)-2ꢀH2O could be obtained
in 77% yield and 98% de (E 75%) using (S)-2 and LiOH in water. The crystal structure of the less soluble salt
(S)-1ꢀ(S)-2ꢀH2O showed that the water molecule played a key role in forming the crystals.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Phenylethylamine and (ꢁ)-phenylglycine butyl ester are relatively
inexpensive. However, the diastereomeric salt needed to be recrys-
Enantiopure mandelic acid (S)-1 and its derivatives are impor-
tant organic molecules, which can be utilized as important precur-
sors for the introduction of a stereogenic center in stereoselective
transformations.1,2 They are also versatile intermediates for phar-
maceuticals3 and resolving agents.4
Several methods for obtaining enantiopure 1 have been devel-
oped to date; these include (i) asymmetric synthesis via metal cat-
alysts or organic catalysts;5 (ii) enzymatic or biomimetic
methods;6 and (iii) diastereomeric resolution.7 With methods (i)
and (ii), (S)-1 can be obtained in high enantiopurity and good yield.
However, scalable processes for industrial synthesis are few, be-
cause the price of the chiral ligands and catalysts is high. The dia-
stereomeric resolution of racemic mixtures remains an economical
and frequently used procedure in the chemical and pharmaceutical
industries, since the resolving agent is recyclable and it is generally
simple, clean, and easy to scale up to an industrial scale.8
tallized 3 times or more to obtain high enantiomeric purity. Thus
searching for new more efficient resolving agents, which are inex-
pensive or easy to synthesize, is necessary.
Enantiopure aryloxypropylamine with an amino group, an
aromatic ring, and a hydroxy group, appears to be a good candidate
for chiral discrimination, which is easy to synthesize.9 In our previ-
ous work, aryloxypropylamine could be kinetically resolved by a C-
12 higher carbon sugar.10 This method was used for the prepara-
tion of the enantiomerically pure b-blockers (S)-Betaxolol and
(S)-Metoprolol.11 Since the use of aryloxypropylamine as a resolv-
ing agent has not been reported, the resolution of rac-1 with aryl-
oxypropylamines was investigated.
2. Results and discussion
2.1. Traditional resolution
For the diastereomeric resolution of rac-1, a number of chiral
resolving agents have been described, which include cinchonine,7a
(ꢁ)-ephedrine,7b (ꢁ)-2-aminobutan-1-ol,7c (+)-1-phenylethyl-
amine,7d and (ꢁ)-phenylglycine butyl ester.7e The uses of alkaloids
and (ꢁ)-2-aminobutan-1-ol are limited due to their cost. (+)-1-
In order to determine the most suitable resolving agent for rac-
1, three aryloxypropylamines were examined: (S)-2, (S)-3 [N-
methyl-substituted (S)-2], and (S)-4 [N-ethyl-substituted (S)-2]
(Fig. 1). The resolving solvent was chosen from water, methanol,
OH
OH
OH
OH
H
N
H
N
O
O
O
NH2
COOH
(S)-2
4
(S)-
1
rac-
(S)-3
Figure 1. Structures of rac-1 and resolving agents (S)-2, (S)-3, and (S)-4.
⇑
Corresponding author.
E-mail address: liuhm@zzu.edu.cn (H.-M. Liu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.023

P. Wang et al. / Tetrahedron: Asymmetry 23 (2012) 1046–1051
1047
Table 1
Traditional resolution of rac-1 with (S)-2, (S)-3, and (S)-4
Entry
Resolving agenta
Solvent
Absolute configuration
Yieldb (%)
dec (%)
Ed (%)
1
2
3
4
5
6
7
8
(S)-2
Water
Methanol
Ethanol
Ethyl acetate
Water
Methanol
Ethanol
Ethyl acetate
Water
Methanol
Ethanol
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
109
120
132
167
62
77
84
113
5
12
65
57
50
23
87
77
70
63
12
5
71
68
66
38
54
59
59
71
(S)-3
(S)-4
9
0.6
10
11
12
0.6
0.5
0.3
10
10
5
3
Ethyl acetate
a
b
c
Molar ratio of resolving agent to rac-1 was 1.0, concentration of rac-1 was 152 mg/mL.
Based on half the amount of rac-1 used.
de of the salt was determined by ee of acid 1 liberated from the salt.
Resolution efficiency E(%) = yield (%) ꢂ de (%).
d
ethanol, and ethyl acetate and the volume was 1 mL. The experi-
mental results are summarized in Table 1.
when the ratio of (S)-2 to rac-1 was 1.0 (Table 2, entry 2). However,
the resolution efficiency was relatively low with traditional resolu-
tion (109% yield, 65% de). Therefore, a Pope and Peachey resolution
was carried out in order to improve the resolution efficiency.
We found that (S)-2, (S)-3, and (S)-4 all gave precipitation. In
protic solvents, (S)-2 showed good resolution efficiency (E = 66–
71%, Table 1, entries 1–3), (S)-3 moderate (E = 54–59%, Table 1, en-
tries 5–7), and (S)-4 poor (E = 0.6%, Table 1, entries 9–11). While in
an aprotic solvent, (S)-3 showed the best result (Table 1, entry 8) it
was found that compound (S)-2 in water gave the same resolution
efficiency (E 71%) as (S)-3 in ethyl acetate (Table 1, entries 1 and 8).
From an environmental and industrial point, water was the most
suitable resolving solvent. Therefore, the resolution of rac-1 with
(S)-2 in water was optimized in detail. In order to improve the res-
olution efficiency, the ratio of (S)-2 to rac-1 was next examined;
the experimental results are shown in Table 2.
2.2. Optimization of the resolution conditions based on the
Pope and Peachey method
Pope and Peachey have shown that resolutions can be made
more effective by incorporating an achiral reagent in the resolution
when the solubility differences between the two diastereomeric
salts are relatively small. The achiral reagent competes with the
resolving agent for the enantiomers in the racemic mixture. In
the perfect case, the achiral reagent reacts completely with one
enantiomer and the resolving agent reacts completely with the
other.12 The role of the achiral reagent is to form highly soluble
salts with the enantiomer remaining in the solution.
As shown in Table 2, if the ratio was less or more than 1.0, the
resolution was poor. When the ratio was less, the yield and enan-
As a supplementary base, four types of bases were examined:
LiOH, NaOH, KOH, and Et2NH (DEA). The molar ratio of the base
to rac-1 was set at 0.2 and the results are summarized in
Table 3.
It was found that the addition of a base led to a decrease in the
yield (Table 3, entries 1–4 vs Table 2, entry 2). Among the bases
examined, LiOH and NaOH were extremely efficient as supplemen-
tary bases for obtaining higher resolution efficiency compared with
a traditional resolution (Table 3, entries 1, 2 vs Table 2, entry 2).
Comparing LiOH and NaOH, LiOH was found to be better because
it afforded a higher yield (Table 3, entry 1 vs 2) and as a result,
the best supplementary base was LiOH.
Table 2
Effect of molar ratio of (S)-2 in water
Entry
Ratio of (S)-2 to rac-1a
Yieldb (%)
dec (%)
Ed (%)
1
2
3
4
1.2
1.0
0.7
0.5
91
109
104
95
15
65
18
0
14
71
19
0
a
b
c
Concentration of rac-1 was 152 mg/mL.
Based on half the amount of rac-1 used.
de of the salt was based on ee of acid 1 liberated from the salt.
Resolution efficiency E(%) = yield (%) ꢂ de (%).
d
In order to determine the content of LiOH, the molar ratio of
LiOH to rac-1 was examined. The experimental results are shown
in Table 4.
tiomeric purity both decreased with the ratio (Table 2, entries 2–4).
When the ratio was 0.5, two diastereomeric salts deposited simul-
taneously (Table 2, entry 4). The best resolution was obtained
Table 3
Optimization of the resolution of rac-1 with the Pope and Peachey method
Entry
Ratio of (S)-2 to rac-1a
Supplementary base
Ratio to rac-1
Yieldb (%)
dec (%)
Ed (%)
Base
1
2
3
4
0.8
0.8
0.8
0.8
LiOH
NaOH
KOH
DEA
0.2
0.2
0.2
0.2
99
85
107
91
85
86
18
28
84
73
19
25
a
b
c
Concentration of rac-1 was 152 mg/mL.
Based on half the amount of rac-1 used.
de was based on ee of acid 1 liberated from the salt.
Resolution efficiency E(%) = yield (%) ꢂ de (%).
d

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P. Wang et al. / Tetrahedron: Asymmetry 23 (2012) 1046–1051
Table 4
Effect of molar ratio of LiOH
Entry
Ratio of (S)-2 to rac-1a
Ratio of LiOH to rac-1
Yieldb (%)
dec (%)
Ed (%)
1
2
3
4
0.7
0.8
0.9
0.95
0.3
0.2
0.1
0.05
92
99
104
125
83
85
82
20
76
84
85
25
a
Concentration of rac-1 was 152 mg/mL.
Based on half the amount of rac-1 used.
de of the salt was based on ee of acid 1 liberated from the salt.
Resolution efficiency E(%) = yield (%) ꢂ de (%).
b
c
d
As shown in Table 4, it was found that a decrease in the ratio of
LiOH led to an increase in the resolution yield (Table 4, entries
1–4). When the LiOH molar ratio was between 0.1 and 0.3, the
enantiomeric purity of the diastereomeric salt remained at a higher
level (82–85% de). Once the LiOH molar ratio decreased to 0.05, the
enantiomeric purity greatly decreased (20% de). As a result, it was
found that the highest resolution efficiency (E 85%) could be ob-
tained when the content of LiOH was 0.1 (Table 4, entry 3). How-
ever, the enantiomeric purity of the diastereomeric salt (82% de)
was relatively low, and so multiple salt recrystallization could
not be avoided. The resolution was further optimized by adjusting
the substrate concentration. The experimental results are summa-
rized in Table 5.
Table 5
Figure 2. Atomic-numbering molecule schemes of the less soluble salt (S)-1ꢀ(S)-
2ꢀH2O.
Effect of substrate concentration in water
Entry
Substrate concentration (mg/mL)a
Yieldb (%)
dec (%)
Ed (%)
1
152
100
76
104
93
76
82
86
98
98
85
80
74
75
2
3e
4f
76
77
a
b
c
d
e
f
rac-1 concentration.
Based on half the amount of rac-1 used.
de was based on ee of acid 1 liberated from the salt.
Resolution efficiency E(%) = yield (%) ꢂ de(%).
The content of rac-1 was 152 mg (1 mmol).
The content of rac-1 was 30 g (197 mmol).
As can be seen from Table 5, decreasing the concentration
caused the yield to decrease and the enantiomeric purity to in-
crease (Table 5, entries 1–3). When the substrate concentration
was 76 mg/mL and the molar ratio of rac-1/(S)-2/LiOH was 1.0/
0.9/0.1, the diastereomeric salt could be obtained in 98% de and
77% yield (Table 5, entry 4). On the other hand, when the resolution
of rac-1 was scaled up from the milligram to the gram scale, a good
resolution could still be obtained (Table 5, entry 3 vs 4).
Figure 3. Crystal structure of (S)-1ꢀ(S)-2ꢀH2O. The hydrogen-bonding pattern
viewed along the a-axis. The dotted lines represent hydrogen bonds.
In the crystal packing of (S)-1ꢀ(S)-2ꢀH2O, water molecules par-
ticipated in the hydrogen-bonding network formation which
worked as connectors between the amine and the acidic molecules
(Fig. 3). Amine, acid, and water molecules were arranged in an or-
derly manner, resulting in the formation of the 21 column parallel
to the b-axis (Fig. 4). Due to the hydrogen bonds, the 21 column ex-
tended infinitely along the b-axis and the columns were inter-
linked along the a-axis (Fig. 4). Thus, the crystal of the less
soluble salt (S)-1ꢀ(S)-2ꢀH2O was formed. In the crystal packing,
the water molecule played an important role for the chiral discrim-
ination, and was essential in forming the salt crystals.
2.3. Crystal structure of the less soluble salt
For a better interpretation of the chiral recognition of (S)-2, we
focused on the crystal structure of the less soluble salt. The less sol-
uble salt was a colorless rod and crystallized in orthorhombic
P212121 space group, the unit cell consisted of four (S)-1, four
(S)-2, and four H2O molecules. The atomic-numbering of the less
soluble salt (S)-1ꢀ(S)-2ꢀH2O13 is shown in Figure 2.
In the crystal packing of (S)-1ꢀ(S)-2ꢀH2O, the CH/
p interaction
between the benzene rings of the acid and the amine was found.
It is generally believed that the pattern of hydrogen-bonding as
It also played an important role in the crystal packing. On one
hand, the CH/p interaction participated in the formation of the 21
columns, while on the other, it also interlinked the 21 columns
along the b-axis (Fig. 5). In addition to the hydrogen-bonding, the
well as the CH/
tion.14 Therefore, special attention was paid to the hydrogen-bond-
ing network and CH/ interactions in the crystal structure.
p interaction accounts for the chiral discrimina-
p

P. Wang et al. / Tetrahedron: Asymmetry 23 (2012) 1046–1051
1049
Figure 4. Crystal structure of (S)-1ꢀ(S)-2ꢀH2O. a1 Two 21 columns viewed along a-axis. a2 Two 21 columns viewed along b-axis. The dotted lines represent hydrogen bonds.
CH/
2ꢀH2O.
p
interaction also helped with the stability of the salt (S)-1ꢀ(S)-
soluble salt crystals. In the crystal of (S)-1ꢀ(S)-2ꢀH2O, the hydro-
gen-bonding and CH/p interactions aided the stability of the salt.
3. Conclusion
4. Experimental
4.1. General
Enantiopure 1-amino-3-phenoxypropan-2-ol (S)-2,
a new
resolving agent, has been used to resolve rac-1 with good chiral-
recognition ability and high resolution efficiency. A new resolution
process for rac-1 based on the Pope and Peachey method has been
established. Compound (S)-2, LiOH, and water were found to be a
suitable resolving agent, supplementary base, and solvent, respec-
tively. When rac-1/(S)-2/LiOH was 1.0/0.9/0.1, the less soluble salt
(S)-1ꢀ(S)-2ꢀH2O was obtained in 77% yield and 98% de (E 75%). A
water molecule was found to play a key role in forming the less
Compound rac-1 was purchased from Sinopharm Chemical Re-
agent Co., Ltd, the resolving agents (S)-2, (S)-3, and (S)-4 were syn-
thesized according to the reported method10 and determined by
NMR and HPLC. 1H NMR and 13C NMR were recorded at 400 MHz
and 100 MHz on a Bruke Avance II, and spectroscopic data are re-
ported in ppm relative to tetramethylsilane (TMS) as the internal
standard. IR spectra were measured on a JASCO FT/IR-230 spec-
Figure 5. Crystal structure of (S)-1ꢀ(S)-2ꢀH2O. a1 CH/
angle. a3 CH/ interaction between two 21 columns viewed along the a-axis. a4 CH/
indicate short CH/
p
interaction in one 21 column viewed along the a-axis. a2 CH/
p interaction in one 21 column viewed from a certain
p
p
interaction between two 21 columns viewed from a certain angle. The dotted lines
0
p
distances Datm (ÅA).

1050
P. Wang et al. / Tetrahedron: Asymmetry 23 (2012) 1046–1051
trometer in KBr pellets. Melting points were obtained on a YAMA-
TO apparatus MLDEL MP-21.
(S)-2 (150 mg, 0.9 mmol), LiOH (2.4 mg, 0.1 mmol), and water
(1 mL). The solution was then kept at 70 °C for 0.5 h. The solution
was gradually cooled to 25 °C and kept for 12 h. The precipitate
was filtered and washed with cooled water (3 ꢂ 0.3 mL) to afford
(S)-1ꢀ(S)-2ꢀH2O (128 mg, 0.38 mmol, yield 76%, 98% de, E 74%).
(S)-1ꢀ(S)-2ꢀH2O: mp: 127–129 °C; IR (KBr) cmꢁ1: 3489, 3414,
3230, 3065, 2925, 1611, 1596, 1583, 1496, 1457, 1421, 1339,
1293, 1266, 1248, 1235, 1182, 1082, 1058, 972, 753, 703, 693,
531, 517; 1H NMR (400 MHz, DMSO) d 7.39–7.37 (d, J = 7.6 Hz,
2H), 7.32–7.22 (m, 4H), 7.18–7.15 (m, 1H), 6.97–6.93 (m, 3H),
4.58 (s, 1H), 4.04–4.02 (m, 1H), 3.96–3.89 (m, 2H), 3.00 (dd,
J = 12.8, 3.2 Hz, 1H), 2.79 (dd, J = 12.8, 8.8 Hz, 1H). 13C NMR
4.2. Preparation of resolving agents (S)-2, (S)-3, and (S)-4
Phenol (32 g, 0.34 mol) was added to the mixture of (S)-epichlo-
rohydrin (265 mL, 3.4 mol, 10 equiv) and K2CO3 (61 g, 0.44 mol,
1.3 equiv). The mixture was kept at 110 °C for 2–3 h followed by
filtration and concentrated under vacuum. The residue (50 g,
0.33 mol) was added dropwise into excess ammonia water
(2500 mL, 3.3 mol) for 24 h at room temperature. Next the mixture
was filtered and the solution was evaporated under vacuum. The
residue was recrystallized with ethyl acetate (2 ꢂ 80 mL) to give
the precipitate (S)-2 (39.7 g, 0.24 mol, yield: 72%).
(100 MHz, DMSO)
126.76, 126.63, 121.19, 114.93, 73.97, 70.00, 66.43, 42.39.
¼ þ27:0 (c 1.0, ethanol).
d 175.77, 158.78, 143.95, 129.96, 127.87,
(S)-2. Yield: 72%; mp: 102–110 °C; IR (KBr) cmꢁ1: 3375, 3074,
3063, 3008, 2965, 2936, 2841, 1593, 1509, 1465, 1450, 1346,
1331, 1295, 1258, 1231, 1188, 1125, 1054, 1025, 913, 860, 826,
778, 747; 1H NMR (400 MHz, CDCl3) d 7.33–7.28 (m, 2H), 7.01–
6.93 (m, 3H), 4.17-4.11 (m, 1H), 4.04–4.02 (m, 2H), 2.95 (dd,
J = 12.0, 4.0 Hz, 1H), 2.89 (dd, J = 12.4, 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 158.55, 129.53, 121.19, 114.57, 70.25, 68.77,
51.86. HRMS (ESI) calcd for C9H13NO2 [M+H]+: 168.1025, found
168.1031. The ee value of (S)-2 was determined by HPLC on Lux
½ ꢃ
a 2D3
4.4. Preparation of (S)-1 from the less soluble salt
The crystal (S)-1ꢀ(S)-2ꢀH2O (100 mg, 0.31 mmol) was dissolved
in H2O (5 mL) and diluted with HCl (1 M, 0.94 mL). The mixture
was extracted by ethyl acetate (3 ꢂ 5 mL) and dried over anhy-
drous Na2SO4. The solution was concentrated under reduced
pressure to give (S)-1 (45 mg, 0.30 mmol). The ee value of (S)-1
was determined by HPLC on Lux Cellulose-1 (4.6 mm ꢂ 250 mm
Cellulose-1 (4.6 mm ꢂ 250 mm I.D., 3
lm, Phenomenex) (hexane/
ethanol = 50:50 with 0.2% diethylamine, 0.8 mL/min), UV 224 nm,
I.D.,
3 lm, Phenomenex) (hexane/ethanol = 90:10 with 0.15%
t(R)-2 = 6.10 min, t(S)-2 = 11.67 min. ½a D24
¼ ꢁ10:5 (c 1.0, ethanol).
ꢃ
trifluoroacetic acid, 0.8 mL/min), UV 210 nm, t(S)-1 = 9.67 min,
t(R)-1 = 12.19 min.
(S)-3 was prepared using the same method as (S)-2. (S)-3.
Yield:76%; mp: 36–46 °C; IR (KBr) cmꢁ1:3322, 3104, 3068, 3038,
2970, 2944, 2926, 2865, 2804, 1598, 1586, 1496, 1480, 1449,
1437, 1351, 1304, 1247, 1173, 1148, 1127, 1082, 1035, 969, 927,
910, 826, 813, 761, 690; 1H NMR (400 MHz, CDCl3) d 7.33–7.28
(m, 2H), 7.00–6.93 (m, 3H), 4.14–4.09 (m, 1H), 4.02–4.01 (m, 2H),
2.85 (dd, J = 12.0, 4.0 Hz, 1H), 2.79 (dd, J = 12.0, 7.2 Hz, 1H), 2.51
(s, 3H). 13C NMR (100 MHz, CDCl3) d 158.64, 129.50, 121.07,
114.54, 70.37, 68.11, 53.90, 36.41. HRMS (ESI) calcd for
Acknowledgments
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (81172937), New Teachers’
Fund for Doctor Stations, Ministry of Education (20114101
120013), China Postdoctoral Science Foundation (20100480857),
and Special Financial Grant from the China Postdoctoral Science
Foundation (201104402). We are indebted to Mr. Bing Zhao for
the NMR and Mr. Jie Wu for the X-ray diffraction by a single crystal.
C
10H15NO2 [M+H]+: 182.1181, found 182.1180. The ee value of
(S)-3 was determined by HPLC on Lux Cellulose-1 (4.6 mm ꢂ
250 mm I.D., 3 m, Phenomenex) (hexane/ethanol = 50:50 with
l
0.2% diethylamine, 0.8 mL/min), UV 224 nm, t(R)-3 = 5.11 min,
t(S)-3 = 6.49 min. ½a D25
¼ ꢁ16:0 (c 1.0, ethanol).
ꢃ
References
(S)-4 was prepared using the same method as (S)-2. (S)-4. Yield:
87%; mp: 83–87 °C; IR (KBr) cmꢁ1: 3315, 3051, 2969, 2925, 2868,
2837, 1598, 1584, 1491, 1447, 1380, 1333, 1296, 1241, 1173,
1147, 1109, 1085, 1034, 1018, 894, 846, 813, 761, 697; 1H NMR
(400 MHz, CDCl3) d 7.33–7.28 (m, 2H), 7.00–6.93 (m, 3H), 4.12–
4.06 (m, 1H), 4.00 (d, J = 5.2 Hz, 2H), 2.90 (dd, J = 12.0, 4.0 Hz,
1H), 2.82–2.69 (m, 3H), 2.48 (s, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) d 158.69, 129.48, 121.03, 114.57, 70.48,
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Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry 2006, 17, 1541–1543.
5. (a) Sun, Y.; Wan, X.; Wang, J.; Meng, Q.; Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett.
2005, 7, 5425–5427; (b) Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu,
W. Y.; Li, Y. M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128,
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2350.
68.33, 51.66, 44.12, 15.35. HRMS (ESI) calcd for
C11H17NO2
[M+H]+: 196.1338, found 196.1335. The ee value of (S)-4 was
determined by HPLC on Lux Cellulose-1 (4.6 mm ꢂ 250 mm I.D.,
3 lm, Phenomenex) (hexane/ethanol = 50:50 with 0.2% diethyl-
amine, 0.8 mL/min), UV 224 nm, t(R)-4 = 4.45 min, t(S)-4 = 6.86 min.
½ ꢃ
a 1D9
¼ ꢁ13:0 (c 1.0, ethanol).
4.3. Preparation of the less soluble salt
6. (a) Kaul, P.; Banerjee, A.; Banerjee, U. C. Biomacromolecules 2006, 7, 1536–1541;
(b) Mateo, C.; Chmura, A.; Rustler, S.; Rantwijk van, F.; Stolzb, A.; Sheldon, R. A.
Tetrahedron: Asymmetry 2006, 17, 320–323; (c) Langen van, L. M.; Rantwijk van,
F.; Sheldon, R. A. Org. Proc. Res. 2003, 7, 828–831; (d) Wang, P. Y.; Chen, T. L.;
Tsai, S. W.; Kroutil, W. Biotechnol. Bioeng. 2007 Sep, 1(98), 30–38; (e) Ju, X.; Yu,
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Wang, P. Y.; Chen, T. L.; Tsai, S. W. Enzyme Microbiol. Technol. 2006, 30, 930–
935.
The traditional resolution procedure is as follows (Table 2, entry
2): to a 5 mL flask were added rac-1 (152 mg, 1 mmol), (S)-2
(167 mg, 1 mmol), and water (1 mL). The solution was then kept
at 70 °C for 0.5 h. Next, the solution was gradually cooled to
25 °C and kept for 12 h. The precipitate was filtered off and washed
with cooled water (0.3 mL) to afford (S)-1ꢀ(S)-2ꢀH2O (183 mg,
0.54 mmol, yield 109%, 65% de, E 71%).
7. (a) Mckenzie, A. J. Chem. Soc., Trans. 1899, 75, 964–973; (b) Baar, M. R.; Cerrone-
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Middlesex, C.S.Y. US4259521, 1981.; (d) Ingersoll, A. W.; Babcock, S. H.;
The Pope and Peachey resolution procedure is as follows (Ta-
ble 5, entry 3): to a 5 mL flask were added rac-1 (152 mg, 1 mmol),

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US4322548, 1982.
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Florida, 1994; (c) Wilen, S. H.; Davidson, R.; Spector, R.; Stelfanou, H. Chern.
Cornrnun. 1969, 603; (d) Ogawa, R.; Fujino, T.; Hirayama, N.; Sakai, K.
Tetrahedron: Asymmetry 2008, 19, 2458–2461.
13. Crystal data for (S)-1ꢀ(S)-2ꢀH2O have been deposited at the Cambridge
Crystallographic Data Centre (deposition no. CCDC-862962). Copies of these
data can be obtained free of charge at www.ccdc.cam.ac.uk/data_request/cif.
14. (a) Kinbara, K.; Sakai, K.; Hashimoto, Y.; Nohira, H.; Saigo, K. J Chem. Soc., Perkin
Trans. 2 1996, 2615–2622; (b) He, Q.; Peng, Y. F.; Rohani, S. Chirality 2010, 22,
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707–716; (d) Kobayashi, Y.; Kinbara, K.; Sato, M.; Saigo, K. Chirality 2005, 17,
108–112.
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Wiley: New York, 1981; (b) Kozma, D. Optical Resolutions via Diastereomeric Salt
Formation; CRC Press, 2002; (c) Nohira, H.; Sakai, K. Optical Resolution by
Means of Crystallization. In Enantiomer Separation: Fundamental and Practical
Method, January; Toda, F., Ed.; Kluwer Academic Publishers: Netherlands, 2005;
pp 165–191.
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3668.
10. Zhang, J.-Y.; Liu, H.-M.; Xu, H.-W.; Shan, L.-H. Tetrahedron: Asymmetry 2008, 19,
512–517.
11. Zhang, J.-Y.; Liu, H.-M.; Wang, X.-J.; Wang, P.; Zheng, J.-X. Chirality 2009, 21,
745–750.