Direct enantioseparation of 1-(2-hydroxyphenyl) ethylamines via diastereomeric salt formation: Chiral recognition mechanism based on the crystal structure

Article abstract of DOI:10.1039/c4ra00414k

In this study, the direct enantioseparation of unprotected 1-(2-hydroxyphenyl)ethylamines (1a and 1b) via diastereomeric salt formation is reported. After the one-pot synthesis of racemic 1, the screening of seven acidic chiral resolving agents showed tha

Full text of DOI:10.1039/c4ra00414k

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Direct enantioseparation of 1-(2-hydroxyphenyl)
ethylamines via diastereomeric salt formation:
chiral recognition mechanism based on the
crystal structure†
Cite this: RSC Adv., 2014, 4, 25609
*
*
Koichi Kodama, Naoki Hayashi, Mikidai Fujita and Takuji Hirose
In this study, the direct enantioseparation of unprotected 1-(2-hydroxyphenyl)ethylamines (1a and 1b) via
diastereomeric salt formation is reported. After the one-pot synthesis of racemic 1, the screening of
seven acidic chiral resolving agents showed that the extraction of (S)-naproxen (6) with dibenzoyl-L-
tartaric acid (5) afforded the corresponding 1 : 1 diastereomeric salts that were suitable for the resolution
of 1a and 1b. The optimization of the solvents resulted in high efficiencies for the resolution of 1a$6 in
aqueous alcohols, which was consistent with the fact that the incorporated water molecules in the less-
soluble diastereomeric salt reinforced its hydrogen-bonding network. For the efficient enantioseparation
of rac-1b with 5, the intramolecular CH/O hydrogen bond played an important role in the chiral
recognition.
Received 15th January 2014
Accepted 30th May 2014
DOI: 10.1039/c4ra00414k
www.rsc.org/advances
hydroxyphenyl)ethylamine (1a) has been used for the synthesis
of pharmaceutically important compounds.7 Moreover, the
Introduction
enantiopure 1-(2-hydroxyphenyl)alkylamines with bulky sub-
stituents on their phenyl groups have been successfully applied
as the chiral ligands for the asymmetric alkylation of alde-
hydes.8 One possible problem associated with the diastereo-
meric resolution of 1-phenylalkylamines with a hydroxy group
at the ortho position is the intramolecular hydrogen bond
between the acidic hydroxy and the basic amino groups,
resulting in the decreased basicity to prevent the diastereomeric
salt formation with an acidic chiral resolving agent.9
Several methods have been reported to obtain enantio-
enriched 1-(2-hydroxyphenyl)alkylamines. One successful
example is the stereoselective synthesis of the enantiomers
using 1-phenylethylamine or 1-phenyl-1,2-ethanediol as the
chiral auxiliary.10 Another example is the enantioseparation of
its precursor, 1-(2-methoxyphenyl)alkylamine via diastereo-
meric salt formation with enantiopure mandelic acid.11
However, the former method requires multi-step synthesis and
the latter method involves the Lewis acid-mediated depro-
tection of the phenol group, where acid-labile substituents
such as a tert-butyl group are not tolerable. Recently, acid-
catalyzed enantioselective transfer hydrogenation of ketimines
has been reported, even though it is not cost-effective for
industrial application.12 Therefore, we decided to develop a
direct enantioseparation method for 1-(2-hydroxyphenyl)eth-
ylamines 1a and 1b via diastereomeric salt formation. In
addition, the chiral recognition mechanisms were elucidated
from the X-ray crystallographic analysis of the less-soluble
diastereomeric salts.
Over the past two decades, various potent chiral catalysts have
been developed for asymmetric synthesis to meet the increasing
demand for enantiopure chiral compounds.1 On the other
hand, the enantioseparation of racemates into their enantio-
mers via classical diastereomeric salt formation is still a useful
method to synthesize enantiopure compounds on an industrial
scale.2 In addition to the classical method, new methodologies
such as Dutch resolution3 and solvent-induced chirality
switching4 have been recently reported. In any case, the key to
succeed in diastereomeric resolution is to nd a suitable
combination of chiral resolving agents that can afford a stable
acid–base diastereomeric salt.
1-Phenylethylamine is one of the most useful chiral auxilia-
ries and basic resolving agents because both of its enantiomers
are commercially available in a large quantity.5 The derivatives
of 1-phenylethylamine have been oen selected for the
systematic investigation of diastereomeric resolution because
of its simple structure.6 However, the enantioseparation of
1-phenylalkylamines with a hydroxy group at the ortho position
has been rarely investigated even though they are potent
chiral building blocks and chiral ligands. For example, 1-(2-
Department of Applied Chemistry, Graduate School of Science and Engineering,
Saitama University, 255, Shimo-Okubo, Sakura-ku, Saitama, 338-8570, Japan.
E-mail: kodama@mail.saitama-u.ac.jp; Fax: +81-48-858-9548
† Electronic supplementary information (ESI) available: TGA chart of the salt
(S)-1a$6 (Fig. S1) and copies of 1H NMR and 13C NMR spectra of the
compounds. CCDC 970253–970256. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ra00414k
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Results and discussion
Synthesis of racemic 1-(2-hydroxyphenyl)ethylamines (rac-1a
and rac-1b) and their diastereomeric resolution
The synthesis of rac-1a has already been reported, however, it
depended on multi-step synthesis or a detailed procedure was
missing and that of rac-1b has not been reported.13 Therefore we
opted for a one-pot synthetic route by the reductive amination
of the corresponding ketones (Scheme 1). To synthesize rac-1a,
commercially available 2-acetylphenol (2a) was derivatized to
the corresponding imine using methanolic ammonia solution,
followed by the reduction using sodium borohydride. The
reaction proceeded smoothly and afforded rac-1a in a moderate
yield. The same procedure was applied to 6-acetyl-2,4-di-tert-
butylphenol (2b), prepared according to the literature method,14
to afford rac-1b in a better yield. The structure of rac-1b was
further conrmed by the X-ray crystallographic analysis (Fig. 1).
Both the enantiomers were crystallized together and an intra-
molecular hydrogen bond was observed between the hydroxy
hydrogen and the nitrogen atoms, where the N/O distance was
Fig. 2 Acidic chiral resolving agents used in this study.
solution (Table 1, entries 4 and 7). The 1H NMR spectra showed
that both the crystals were 1 : 1 diastereomeric salts of 1a and
the resolving agent. In addition, 1a liberated from the precipi-
tated salt with 6 afforded (S)-1a with a resolution efficiency as
high as 0.55, whereas the diastereomeric salt with 9 resulted in
only rac-1a. It appears that the chiral resolving agents with a
large hydrophobic structure are suitable to afford the crystalline
salts with 1a probably due to its low molecular weight. When the
same screening experiment was applied to rac-1b, two other
chiral resolving agents afforded precipitates by the recrystalli-
zation from ethanol or 60% aqueous ethanol solution (Table 1,
entries 10 and 12). The diastereomeric salt with dibenzoyl-L-
tartaric acid (5) afforded enantio-enriched (R)-1b in a low effi-
ciency. On the other hand, the diastereomeric salt with L-pyro-
glutamic acid (7) showed a higher resolution efficiency. Notably,
enantio-enriched (S)-1b was obtained from the less-soluble
diastereomeric salts with 7, which was opposite to the case
when 5 was used. Because only one enantiomer of 5 and 7 is
available from the natural chiral source, it is advantageous that
both the enantiomers of 1b are accessible by changing the
ꢀ
˚
2.61 A and the O–H/N angle was 149 .
Though the basicity of these amines was expected to
decrease because of the abovementioned intramolecular
hydrogen bond, seven different acidic chiral resolving agents
(3–9), as shown in Fig. 2, were screened for the diastereomeric
resolution of 1a and 1b. The mixtures of equimolar amounts of
1 and each resolving agent were recrystallized once from
ethanol or aqueous ethanol. The precipitated diastereomeric
salts were partially liberated to determine the enantiopurity of
1, and the results are shown in Table 1.
For rac-1a, most of the chiral resolving agents afforded a
trace amount or no crystalline material; however, (S)-naproxen
(6) and dehydroabietic acid (9) afforded the corresponding
crystalline diastereomeric salts from a 50% aqueous ethanol
1
resolving agent. The H NMR measurements showed that the
molar ratio of 1b and 5 in the precipitated diastereomeric salt
was 1 : 1, where 5 is a divalent carboxylic acid.
With the potential chiral resolving agents in hand, the
optimization of the crystallization solvents (MeOH, EtOH, 1-
PrOH, 2-PrOH, CH3CN, and their mixtures with H2O) for 1a$6,
1b$5, and 1b$7 was carried out and the results are summarized
in Table 2. When the recrystallization of 1a$6 was carried out
from pure alcohols, the resolution efficiencies decreased (Table
2, entries 2–4) whereas the low solubility of 1a$6 prevented its
recrystallization from water (Table 2, entry 1). On the other
hand, the recrystallization from aqueous alcohol solutions
afforded (S)-1a with better selectivities and high efficiency
(Table 2, entries 5–8). The result showed that the water in the
recrystallizing solvent mixture plays an important role in the
efficient resolution, while additional alcohol is necessary to
increase the solubility of the salt. The thermogravimetric
analysis (TGA) of the diastereomeric salt (S)-1a$6 prepared from
a 50% aqueous EtOH solution showed a gradual weight loss
from ꢁ100 ꢀC to 150 ꢀC before melting (Fig. S1†). It shows that
the salt was hydrated even though the amount of incorporated
water was difficult to be determined because of the successive
decomposition of the salt. On the other hand, the resolution of
Scheme 1 Synthesis of racemic 1-(2-hydroxyphenyl)ethylamines 1a
and 1b.
Fig. 1 Crystal structure of rac-1b. The dotted line shows a hydrogen
bond between an amino nitrogen atom and a hydroxy hydrogen atom. rac-1b using 5 or 7 from aqueous alcohols resulted in only low
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Table 1 Enantioseparation of racemic 1-(2-hydroxyphenyl)ethylamines 1a and 1b with acidic chiral resolving agents
1a
1b
Resolving
Entry agent
Resolving
Entry agent
Solvent (L molꢂ1
)
Yielda (%) eeb (%) Eff.c
Solvent (L molꢂ1
)
Yielda (%) eeb (%) Eff.c
1
2
3
4
5
6
7
3
4
5
6
7
8
9
50% EtOH (1.0)
50% EtOH (0.8)
50% EtOH (1.0)
50% EtOH (12.0)
50% EtOH (2.0)
—
Trace
Not crystallized
Not crystallized
—
—
—
—
8
9
10
3
4
5
6
7
8
9
EtOH (3.3)
EtOH (3.3)
60% EtOH (8.3)
EtOH (7.0)
EtOH (8.0)
EtOH (3.3)
EtOH (3.3)
Not crystallized
—
—
0.09
—
0.25
—
Trace
52
—
17(R)
97
57(S)
0.55 11
Not crystallized
Not crystallized
Not crystallized
82
—
—
0
12
13
14
83
30(S)
Not crystallized
Not crystallized
50% EtOH (28.0)
rac
—
a
b
Yield is based on the half amount of the salt. ee is determined by HPLC analysis. c Eff. ¼ yield ꢃ ee.
Table 2 Enantioseparation of 1-(2-hydroxyphenyl)ethylamines 1a and
1b recrystallized from various solvents
Resolving
agent
Entry
1
Solvent (L molꢂ1
)
Yielda (%) eeb (%) Eff.c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
6
6
6
6
6
6
6
6
5
5
5
5
7
7
7
H2O (60.0)
EtOH (5.0)
1-PrOH (8.0)
2-PrOH (8.0)
50% MeOH (30.0) 62
50% EtOH (12.0) 97
50% 1-PrOH (6.0) 59
50% 2-PrOH (6.0) 72
EtOH (2.7)
60% MeOH (17)
60% EtOH (8.3)
CH3CN (18)
EtOH (8.0)
50% EtOH (3.3)
Not dissolved
—
88
7(R)
0.06
0.32
0.13
0.51
0.55
0.38
0.35
—
0.08
0.09
0.29
0.25
0.01
0.29
Scheme 2 Preparation of an enantiopure (S)-1a.
94
124
34(S)
10(S)
84(S)
57(S)
65(S)
49(S)
overall efficiency was as high as 0.60, and it was shown that this
resolution method is potentially applicable to a larger-scale
production of an enantiopure 1a.
9
Not crystallized
10
11
12
13
14
15
20
52
33
83
26
42(R)
17(R)
88(R)
30(S)
2(S)
Crystallographic analyses of the less-soluble diastereomeric
salts 1a$6, 1b$7, and 1b$5
To elucidate the chiral recognition mechanism of 1a and 1b,
X-ray crystallographic analyses of the three less-soluble salts
1a$6, 1b$7, and 1b$5 were carried out. The structure of (S)-1a$6
is shown in Fig. 3, where the absolute conguration of 1a was
determined to be (S)-isomer by the comparison with that of 6. As
suggested from the TGA result, the diastereomeric salt was
90% CH3CN (13.3) 83
35(S)
a
b
Yield is based on the half amount of the salt. ee is determined by
HPLC analysis. c Eff. ¼ yield ꢃ ee.
efficiency (Table 2, entries 10, 11, and 14). The recrystallization hydrated and the composition ratio was (S)-1a : 6 : H2O ¼
of the diastereomeric salts from CH3CN or 90% CH3CN resulted 2 : 2 : 1. They constructed a one-dimensional (1D) columnar
in moderate efficiencies and the enantiomeric excess (ee) of hydrogen-bonding network along the b axis, which is an oen
(R)-1b resolved using 5 reached up to 88% ee, whereas 1b$7 observed motif in primary ammonium-carboxylate salts.16 The
afforded the antipode (S)-1b in only 35% ee (Table 2, entries 12 water molecules were positioned at the center of the columnar
and 15).15 The introduction of bulky tert-butyl groups on the structure to connect (S)-1a and 6 along the columnar axis by the
aromatic ring of 1a drastically changed the matched combina- hydrogen bonds (Fig. 3a). The participation of water to reinforce
tion with chiral resolving agents to afford the corresponding the 1D network stabilized (S)-1a$6 salt, resulting in the high
crystalline diastereomeric salts and more functionalized acids resolution efficiency in aqueous alcohols as stated above. One of
have been favored for 1b.
the ammonium hydrogen atoms of (S)-1a formed a bifurcated
With the optimized condition in hand, we applied it to a hydrogen bond and shared by the intramolecular hydroxy
˚
resolution of rac-1a to prepare an enantiopure 1a (Scheme 2). oxygen atom (the N/O distance was 2.72 A) to x the aromatic
The diastereomeric salt of rac-1a (0.99 g) and 6 (1.68 g) was group of (S)-1a. The high enantioselectivity can be explained by
recrystallized from a 50% aqueous EtOH solution to afford (S)- the favorable CH/p interaction between the CH of the methyl
1a$6 (1.09 g, 79% yield, 91% ee). The resolution efficiency was group of (S)-1a and the naphthalene ring of 6 (the C/p-plane
˚
improved up to 0.72 probably because of the decreased opera- distance was 3.48 A, as indicated by the arrows in Fig. 3b), which
tional loss. Another recrystallization of the diastereomeric salts xed the position of the methyl group of (S)-1a.17 Notably, the
from the same solvent successfully afforded the salts (0.83 g, salt of 1a and (R)-2-phenylpropionic acid did not crystallize
60% yield, >99% ee) in a diastereomerically pure form. The under the same conditions, indicating that not only the
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Fig. 4 Crystal structure of 1b$7 viewed from the b axis. The dotted
lines show hydrogen bonds. Two hydroxy oxygen atoms of (RS)-1b are
shown at site B due to rotational disorder of the phenyl group.
hand, two enantiomers of 1b existed in a disordered manner at
site B, and they were not distinguished. The low enantiose-
lectivity for (S)-1b in the resolution experiment with 7 probably
reected the sum of the selectivity at these two sites. The ster-
eoselective incorporation of (S)-1b at site A could be attributed
to the xation of the hydrogen atom on the stereogenic center
of (S)-1b as well as the ammonium and phenyl groups. The
carboxylate oxygen atom of 7 that forms hydrogen bonds with
the ammonium nitrogen and hydroxy oxygen atoms of (S)-1b is
also close to the hydrogen atom of (S)-1b. The CH/O distance
Fig. 3 Crystal structure of (S)-1a$6$0.5H2O. (a) Side view of the
columnar structure. Water oxygen atoms are represented with red
balls. (b) Top view of the columnar structures. Hydrogen atoms are
omitted for clarity. The dotted lines and arrows show hydrogen bonds
and CH/p interactions, respectively.
structure of 2-arylpropionic acid, but also the rigid and long
naphthyl group of 6 contribute to the efficient packing of the
molecules.
˚
was as short as 2.52 A, which is shorter than the sum of the van
˚
˚
der Waals radii of hydrogen and oxygen atoms [2.80 A ¼ 1.20 A
Platelet ne crystals were obtained during the resolution of
rac-1b with 7, and the crystal structure was determined. As in
the case of (S)-1a$6 salt, 1D columnar hydrogen-bonding
networks were constructed from 1b and 7 along the b axis,
whereas no solvent molecules were incorporated. Interestingly,
additional hydrogen bonds of the amide group of 7 connected
the neighboring columns to form two-dimensional (2D) sheet-
like networks (Fig. 4). The efficient van der Waals packing of the
resultant sheets contributed to the high stability of the diaste-
reomeric salt. In contrast to (S)-1a$6, the hydroxy group of 1b
interacted only with the carboxylate oxygen atom of 7 instead of
involving in the intramolecular hydrogen bond. Two crystallo-
graphically independent molecules of 1b with slightly different
orientations were observed in the asymmetric unit, positioned
at sites A and B, respectively. The stereoselective salt formation
occurred at site A, and only (S)-1b was positioned. On the other
(hydrogen) + 1.60 A (oxygen)].18 This intermolecular CH/O type
˚
hydrogen bond appears to be important for the chiral recogni-
tion of (S)-1b.
Finally, a single crystal of 1b$5 was prepared from a CH3CN
solution of the equimolar mixture of rac-1b and 5, which
afforded high enantioselectivity for (R)-1b (Table 2, entry 12).
The crystal consisted of 5 and (R)-1b in a ratio of 1 : 1, which was
1
in accordance with the H NMR result of the precipitated salt
(Fig. 5). The molecules arranged to construct a 1D hydrogen-
bonding network along the b axis, which was reinforced by the
intermolecular hydrogen bond between the ionized and neutral
carboxyl groups of 5. Such a motif has been also reported in
other salts of substituted 1-phenylethylamines and 5.19
Furthermore, the hydroxy hydrogen atom of (R)-1b interacted
with the ester carbonyl group of 5. The high enantioselectivity
for (R)-1b could be explained by the intramolecular CH/O type
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CH/O interaction as well as the hydrogen bond between the
ester group of 5 involving the hydroxy group of (R)-1b contrib-
uted to the efficient chiral recognition for (R)-1b$5. Although
their chiral recognition mechanisms were found to be not
consistent and dependent on their molecular structures, the
hydroxy group played an important role for efficient chiral
recognition in each less-soluble diastereomeric salt. These
insights may help to nd the suitable conditions in the enan-
tioseparation and enable to easily synthesize various enantio-
pure 1-(2-hydroxyphenyl)alkylamines, which can be applied for
chiral building blocks and ligands. Further investigation for the
strategic enantioseparation of other chiral 1-(2-hydroxyphenyl)
alkylamines are now in progress.
Experimental
Materials and general methods
All commercially available reagents (1a, 3–9) were used as
received. 1H and 13C NMR spectra were recorded on Bruker
AVANCE 300 or 500 spectrometer. IR spectra were measured on
a JASCO FT/IR-460 spectrometer by the KBr method at room
temperature. Melting points were recorded on a MEL-TEMP
apparatus and reported uncorrected. TG-DTA analysis was
performed on a SII EXSTAR 6000 system at a heating rate of
10 ꢀC minꢂ1 under a nitrogen atmosphere. Enantiomeric
excesses were determined by HPLC analyses with a Daicel OD-3
or OJ-3 column with detection at 254 nm.
Fig. 5 Crystal structure of (R)-1b$5 viewed from the b axis. The dotted
lines show hydrogen bonds.
Synthesis and characterization
interaction; the hydrogen atom on the stereogenic center of (R)-
1b was directed toward the hydroxy group within the molecule.
rac-1-(2-Hydroxyphenyl)ethylamine (rac-1a). 2a (3.01 g, 22.1
mmol) was dissolved in an ice-cooled NH3/MeOH solution (180
mL) and the solution was stirred at room temperature over-
night. The solvent was removed under reduced pressure and the
residue was dissolved in MeOH (180 mL). NaBH4 (4.16 g, 0.11
mol) was added portionwise to the mixture at 0 ꢀC and stirred at
room temperature overnight. Aer the reaction mixture was
acidied by addition of 1 N HCl aq., MeOH was removed under
reduced pressure. The aqueous phase was washed with CHCl3
(40 mL ꢃ 6) and basied by addition of NaHCO3 until the pH
˚
The CH/O distance was 2.23 A, which is much shorter than
their sum of the van der Waals radii. This result indicates that
the phenol moiety plays a crucial role in the xation of not only
the aromatic group on the stereogenic center, but also the
hydrogen atom on the stereogenic center, resulting in the effi-
cient chiral recognition.
Conclusions
In this study, we have carried out the direct enantioseparation became 8–9. The resulting mixture was extracted with EtOAc
of unprotected 1-(2-hydroxyphenyl)ethylamines 1a and 1b via (40 mL ꢃ 6) and the organic phase was dried over anhydrous
diastereomeric salt formation. Rac-1a could be efficiently Na2SO4. The solvent was removed under reduced pressure and
resolved with (S)-naproxen (6) by the recrystallization from an the residue was puried by silica gel column chromatography
aqueous alcohol solution, whereas bulkier rac-1b was separated (CHCl3 to CHCl3–EtOAc ¼ 1 : 1). Further recrystallization from
with more functionalized chiral resolving agent, L-pyroglutamic hexane–EtOAc ¼ 500 : 1 (18 mL) gave rac-1a (1.97 g, 14.4 mmol,
acid (7) or dibenzoyl-L-tartaric acid (5). The X-ray crystallo- 65%) as a white solid. Mp: 85–88 ꢀC. 1H NMR (300 MHz, CDCl3):
graphic analysis of the less-soluble diastereomeric salt showed d 7.17–7.12 (m, 1H), 6.98–6.95 (m, 1H), 6.85–6.75 (m, 2H), 4.33
that the incorporated water molecule reinforced the 1D (q, J ¼ 6.6 Hz, 1H), 1.48 (d, J ¼ 6.6 Hz, 3H). 13C NMR (125 MHz,
hydrogen-bonding network of the crystal of (S)-1a$6 salt. The CDCl3): d 157.6, 128.5, 128.1, 127.2, 119.0, 117.2, 51.7, 23.9. IR
high enantioselectivity was attributed to the CH/p interaction (KBr): nmax 3344, 2979, 2488, 1594, 1455, 1353, 1291, 1039, 894,
between (S)-1a and the large p-plane of 6. Although the enan- 746, 606, 563, 523 cmꢂ1
tioselectivity of (S)-1b obtained by the resolution with 7 was not
rac-1-(2-Hydroxy-3,5-di-tert-butylphenyl)ethylamine
.
(rac-
so high because of the partially disordered structure of 1b, the 1b). 2b (5.57 g, 22.4 mmol) was dissolved in an ice-cooled NH3/
intermolecular CH/O interaction between the hydrogen atom MeOH solution (150 mL) and the gaseous NH3 was introduced
of 1b and the carboxylate group of 7 was responsible for the to the solution for 2.5 h. Aer the solution was stirred at room
chiral recognition. On the other hand, the intramolecular temperature for 4 days, the solvent was removed under reduced
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pressure and the residue was dissolved in MeOH (150 mL).
NaBH4 (4.24 g, 112 mmol) was added portionwise to the solu-
tion at 0 ꢀC and stirred at room temperature for 5 days. Aer the
reaction mixture was acidied by addition of HCl aq., MeOH
was removed under reduced pressure and the aqueous phase
was extracted with CHCl3. The organic phase was washed with
sat. NaHCO3 aq. and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the residue was
puried by silica gel column chromatography (hexane–EtOAc ¼
10 : 1). Further recrystallization from hexane afforded rac-1b
(4.74 g, 19.0 mmol, 85%) as a colorless needle crystal. Mp: 104–
Single crystal X-ray analyses
X-ray crystallographic data were collected on a Bruker Smart
APEX II diffractometer with graphite monochromated Mo-Ka
radiation. The structures were solved by a direct method using
SIR 97 (ref. 20) and rened by SHELXL-97 or SHELXL-2013
programs.21 Crystal data for rac-1b: C16H27NO, M ¼ 249.39,
˚
monoclinic, a ¼ 15.4268(18), b ¼ 9.5663(11), c ¼ 11.1965(13) A,
3
ꢀ
˚
b ¼ 105.9770(10) , V ¼ 1588.5(3) A , T ¼ 150 K, space group P21/
c, Z ¼ 4, 2789 reections measured, 2366 independent reec-
tions (Rint ¼ 0.1447). The nal R1 was 0.0755 (I > 2s(I)) and
wR(F2) was 0.2066 (I > 2s(I)). Crystal data for (S)-1a$6$0.5H2O:
1
ꢀ
106 C. H NMR (300 MHz, CDCl3): d 7.22–7.21 (m, 1H), 6.85–
6.84 (m, 1H), 4.31 (q, J ¼ 6.6 Hz, 1H), 1.49 (d, J ¼ 6.6 Hz, 3H),
1.43 (s, 9H), 1.29 (s, 9H). 13C NMR (125 MHz, CDCl3): d 154.2,
140.2, 136.5, 127.2, 122.7, 122.0, 52.5, 35.0, 34.2, 31.7, 29.7, 23.7.
IR (KBr): nmax 3371, 3300, 2954, 2871, 1601, 1587, 1479, 1440,
C
22H26NO4.5, M ¼ 376.44, monoclinic, a ¼ 23.818(8), b ¼
3
ꢀ
˚
˚
5.5862(18), c ¼ 15.671(5) A, b ¼ 113.803(4) , V ¼ 1907.8(11) A ,
T ¼ 150 K, space group C2, Z ¼ 4, 2980 reections measured,
2690 independent reections (Rint ¼ 0.0979). The nal R1 was
0.0590 (I > 2s(I)) and wR(F2) was 0.1577 (I > 2s(I)). Crystal data
1361, 1252, 1232, 1053, 880, 820 cmꢂ1
.
for 1b$7: C21H34N2O4, M ¼ 378.50, monoclinic, a ¼ 16.749(4),
3
ꢀ
˚
˚
b ¼ 8.124(2), c ¼ 17.552(4) A, b ¼ 116.504(3) , V ¼ 2137.2(9) A ,
T ¼ 150 K, space group P21, Z ¼ 4, 5394 reections measured,
4024 independent reections (Rint ¼ 0.1078). The nal R1 was
0.0814 (I > 2s(I)) and wR(F2) was 0.2084 (I > 2s(I)). Crystal data
for (R)-1b$5: C34H41NO9, M ¼ 607.68, monoclinic, a ¼ 29.287(5),
General procedure for the diastereomeric resolution of rac-1
An equimolar amounts of 1 and each resolving agent (0.5 mmol
for 1a and 0.3 mmol for 1b) were dissolved in methanol. Aer
concentration, the diastereomeric salts were recrystallized from
an appropriate solvent and the precipitated salt was collected by
ltration and dried under reduced pressure. The yield was
calculated based on a half amount of rac-1 initially used. (S)-
ꢀ
˚
b ¼ 7.6383(12), c ¼ 18.538(4) A, b ¼ 126.490(4) , V ¼ 3333.9(10)
3
˚
A , T ¼ 150 K, space group C2, Z ¼ 4, 5298 reections measured,
4235 independent reections (Rint ¼ 0.1093). The nal R1 was
0.0495 (I > 2s(I)) and wR(F2) was 0.1021 (I > 2s(I)).†
1
1a$6. H NMR (300 MHz, CDCl3–CD3OD): d 7.72–7.69 (m, 3H),
7.46–7.43 (m, 1H), 7.17–7.11 (m, 3H), 7.02–6.99 (m, 1H), 6.83–
6.77 (m, 2H), 4.32 (q, J ¼ 6.9 Hz, 1H), 3.92 (s, 3H), 3.82 (q, J ¼ 7.2
Hz, 1H), 1.56 (d, J ¼ 7.2 Hz, 3H), 1.49 (d, J ¼ 6.9 Hz, 3H). 1b$5.
1H NMR (300 MHz, CDCl3–CD3OD): d 8.13 (d, J ¼ 8.1 Hz, 4H),
7.61–7.56 (m, 2H), 7.48–7.43 (m, 4H), 7.26 (s, 1H), 6.99 (s. 1H),
5.96 (s, 2H), 4.53–4.47 (m, 1H), 1.52 (d, J ¼ 6.3 Hz, 3H), 1.39 (s,
Notes and references
1 (a) H. Pellissier, Recent Developments in Asymmetric
Organocatalysis, Royal Society of Chemistry, Cambridge,
2010; (b) Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley,
Weinheim, Germany, 3rd edn, 2010.
1
9H), 1.28 (s, 9H). 1b$7. H NMR (300 MHz, CDCl3–CD3OD): d
7.28 (d, J ¼ 2.4 Hz, 1H), 7.05 (d, J ¼ 2.4 Hz, 1H), 4.56 (q, J ¼ 6.9
Hz, 1H), 4.18–4.13 (m, 1H), 2.54–2.30 (m, 3H), 2.22–2.11 (m,
1H), 1.74 (d, J ¼ 6.9 Hz, 3H), 1.43 (s, 9H), 1.30 (s, 9H).
To determine the enantiomeric excess of resolved 1a, a small
amount of the salt was added in 1 N HCl aq. and washed with
CHCl3, and the solution was basied by addition of NaHCO3.
The aqueous phase was extracted with EtOAc and dried over
anhydrous Na2SO4. Aer removal of the solvent, 1a was
obtained as a solid. Resolved 1a was quantitatively derivatized
to its acetamide in the presence of acetic anhydride, of which
the enantiomeric excess was determined by a HPLC analysis
(Daicel ChiralPak OD-3, hexane–2-propanol ¼ 9 : 1, 1.0 mL
minꢂ1, tr(R) ¼ 13.4 min; tr(S) ¼ 15.3 min).
2 (a) J. Jacques, A. Collet and S. H. Wilen, Enantiomers,
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Malabar, Florida, 1994; (b) D. Kozma, Optical Resolutions
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´
´
´
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T. R. Vries, Q. B. Broxterman, R. F. P. Grimbergen,
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EtOAc due to the low solubility of 1b in an aqueous phase. The
extract was washed with sat. NaHCO3 aq., water and dried over
anhydrous Na2SO4. Aer removal of the solvent, 1b was
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literature.10b
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