Resolution of 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2- carboxylic acid with methyl (R)-2-phenylglycinate, reciprocal resolution and second order asymmetric transformation

Article abstract of DOI:10.1016/j.tetasy.2011.10.021

A novel, highly efficient method has been developed for the separation of the optical isomers of 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2- carboxylic acid with methyl (R)-2-phenylglycinate. The structural aspects of chiral discrimination have been discussed via comparison of the molecular structures and the packing energies of the diastereoisomeric salts determined by single crystal X-ray diffraction measurements. Reciprocal resolution and a new, highly efficient second order asymmetric transformation of racemic methyl 2-phenylglycinate with the pure enantiomer of the previously resolved atropisomeric carboxylic acid are also reported.

Full text of DOI:10.1016/j.tetasy.2011.10.021

Tetrahedron: Asymmetry 22 (2011) 1879–1884
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Tetrahedron: Asymmetry
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Resolution of 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic
acid with methyl (R)-2-phenylglycinate, reciprocal resolution and second order
asymmetric transformation
Ferenc Faigl a,b, , Béla Mátravölgyi b, Tamás Holczbauer c, Mátyás Czugler c, János Madarász d
⇑
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Budafoki út 8., Hungary
b Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, H-1111 Budapest, Budafoki út 8., Hungary
c Institute of Structural Chemistry, Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri út 59-67., Hungary
d
}
Department of General and Analytical Chemistry, Budapest University of Technology and Economics, 1111 Budapest, Muegyetem rkp. 3., Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 September 2011
Accepted 28 October 2011
A novel, highly efficient method has been developed for the separation of the optical isomers of 1-[2-car-
boxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid with methyl (R)-2-phenylglycinate. The
structural aspects of chiral discrimination have been discussed via comparison of the molecular struc-
tures and the packing energies of the diastereoisomeric salts determined by single crystal X-ray diffrac-
tion measurements. Reciprocal resolution and
a new, highly efficient second order asymmetric
transformation of racemic methyl 2-phenylglycinate with the pure enantiomer of the previously resolved
atropisomeric carboxylic acid are also reported.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
In order to find a more efficient resolution method for racemic
dicarboxylic acid 1, detailed experimental studies were carried out
1-Phenylpyrrole derivatives are known as important building
blocks for antibiotics,1,2 antiviral,3 and cytostatic4 compounds. Re-
cently, mineralcorticoid receptor antagonist effects of atropisomer-
ic 1-phenylpyrrole derivatives have been recognized.5 Optically
active 1-phenylpyrrole derivatives have also been used as chiral re-
agents, ligands, and organocatalysts.6 A useful intermediate of the
synthesis of atropisomeric 1-phenylpyrrole derivatives was pre-
pared several years ago in our laboratory. The pure enantiomers
of 1-[2-carboxy-6-(trifluoro-methyl)phenyl]-1H-pyrrole-2-carbox-
ylic acid 1 were prepared from the racemate via diastereoisomeric
salt formation which is one of the easiest methods for the separa-
and are reported herein.
2. Results and discussion
2.1. Highly selective method for the resolution of (R,S)-1
As a result of resolution trials, we have found that methyl (R)-2-
phenylglycinate (R)-3 was a much better resolving agent for 1 than
amine 2. Diastereoisomeric salt formation was accomplished in
ethanol and after 2 h of crystallization, the precipitated diastereo-
isomeric salt contained the (ꢁ)-(S)-1 enantiomer in excellent enan-
tiomeric purity (ee >96%). The optically active acid was liberated in
a dichloromethane/water mixture with aqueous sodium carbonate
followed by phase separation. Compound (S)-1 was isolated from
the aqueous solution by acidification with 15% hydrochloride acid
solution and filtration in good yield (Scheme 1).
The (R)-1 isomer (ee >99%) was obtained by recrystallization of
(R > S)-1 (ee 80%), which was regenerated from the filtrate of the
salt formation reaction. The recrystallization was carried out in
ethyl acetate. The resolving agent could also be regenerated from
the organic phases of the diastereoisomeric salt decomposition
and the filtrate decomposition in good yield (85%).
tion of carboxylic acid enantiomers.7 (R)-
(S)- -naphthylethylamine, (S)- -hydroxymethylbenzylamine, and
a-Methylbenzylamine 2,
a
a
(R,R)-2-amino-1-phenyl-1,3-propanediol were tested for the sepa-
ration of the isomers of 1, and the best result was achieved with
(R)-a-methylbenzylamine. In this case the efficiency (‘S’) of the res-
olution (‘S’ = yield ꢀ ee ꢀ 0.01)8 of (R)-1 was about 0.28 (ee 95%,
yield 30%) and the single enantiomer of 1 could only be obtained
after recrystallization of the primary diastereoisomeric salt causing
a further decrease in the yield. The absolute configuration of the
carboxylic acid enantiomers was determined from the single crys-
tal X-ray diffraction measurements of the diastereoisomeric salts.7
The effect of the amount of resolving agent was also studied.
The results are collected in Table 1. We observed that better enan-
tiomer separation could be achieved with an equivalent amount of
resolving agent than with the half equivalent method. The
⇑
Corresponding author. Tel.: +36 1 463 3652; fax: +36 1 463 4648.
E-mail address: ffaigl@mail.bme.hu (F. Faigl).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.021

1880
F. Faigl et al. / Tetrahedron: Asymmetry 22 (2011) 1879–1884
COOCH3
COOH
COOH
N
ethanol
RT, 2h
+
H
H2N
(S)-1·(R)-3
F3C
(R,S)-1
(R)-3
COOH
COOH
N
a) aq. Na2CO3
b) 15% aq. HCl
ee >96%
(S)-1·(R)-3
yield 80%
F3C
(S)-1
Scheme 1. Resolution of racemic 1 with methyl (R)-2-phenylglycinate (R)-3.
Table 1
Resolution of 1 in case of different molar ratiosa
Resolving agent Molar ratio
Diastereoisomeric salt
Yieldb (%) de (config)c (%)
Efficiency (‘S’)
(R)-3
(R)-3
1:0.5
1:1
70 95 (S)
85 96 (S)
0.67
0.82
a
b
c
Crystallization was carried out for 2 h in ethanol.
Yields were calculated to the half of the racemate.
Configuration of 1 in the diastereoisomeric salt.
efficiency of the optimized resolution was high (‘S’ = 0.82), with it
being almost three times better than the previously reported
method.
2.2. Single-crystal X-ray diffraction, PXD and DSC studies
Previous X-ray studies proved the absolute configuration of the
(+)-(R)-1ꢂ(R)-27 salt.
We prepared single crystals from the new (S)-1ꢂ(R)-3 diastereo-
isomeric salt for X-ray studies by crystallization from methanol.
The structure of the (S)-1ꢂ(R)-3 salt is shown in the ORTEP-like dia-
gram9 in Figure 1. To compare the crystal structure of these two
diastereoisomeric salts, one has to invert the (+)-(R)-1ꢂ(R)-27 struc-
ture into the mirror image (S)-1-(S)-2 structure. Such a comparison
may shed some light on the details of the chiral discrimination pro-
cess during separation of the atropisomers of 1.
Unit cell data for these crystals can be seen in Table 2, and in-
clude the previously reported (R)-1ꢂ(R)-2 salt. From a comparison
of the two data series, the similarity of the two diastereoisomeric
salt crystals is apparent. It is noteworthy that the (S)-1ꢂ(R)-3 salt
has a larger density indicating a somewhat bigger thermodynamic
stability.
Figure 1. (S)-1ꢂ(R)-3 salt crystal structure with atomic numbering and 50%
probability anisotropic displacement ellipsoids for non-H atoms.9
The packing energies10,11 were calculated12 for the (S)-1ꢂ(R)-3
and (S)-1ꢂ(S)-2 salts as well using normalized hydrogen positions.
The total packing energy is ꢁ272.7 kJ/mol in the (S)-1ꢂ(R)-3 crystal,
while it is ꢁ250.8 kJ/mol in the (S)-1ꢂ(S)-2 case. The total packing
energy difference of 21.9 kJ/mol between the two crystal struc-
tures is partitioned the following way. The 1 molecules have a sim-
ilar interaction energies (ꢁ151.3 and ꢁ156.7 kJ/mol) in the two
crystal. However, the difference is larger between the two cationic
components 3 (ꢁ116.0 kJ/mol) and 2 (ꢁ99.5 kJ/mol), amounting to
approximately 2/3rd of the total energy difference between the
two salt pairs crystal structures. Thus the chemical change from
Table 2
Crystallographic cell data for (S)-1ꢂ(R)-3 and (R)-1ꢂ(R)-2 crystals
(S)-1ꢂ(R)-3
(R)-1ꢂ(R)-27
Formula
Molecular weight
C22H19F3N2O6
464.39
C21H19F3N2O4
420.38
Space group
a (Å)
b (Å)
P21
P21
11.9804(5)
7.8115(3)
12.9927(5)
118.25(2)
1071.1(1)
2
12.3977(12)
7.4905(14)
12.5196(14)
118.95(6)
1017.4(2)
2
c (Å)
b (°)
V (Å3)
Z
Dx (g cmꢁ3
)
1.440
1.372
a-methylbenzylamine 2 for the phenylglycine methyl ester 3 is re-

F. Faigl et al. / Tetrahedron: Asymmetry 22 (2011) 1879–1884
1881
flected in the respective packing energies of the crystals. It seems
that the resolution effectivity may be correlated to the packing en-
ergy differences, with the (S)-1ꢂ(R)-3 crystal structure being more
stable by ca. 22 kJ/mol than the (S)-1ꢂ(S)-2 one. A comparison of
the related molecular positions from a fit of 13 C and N atoms of
1 molecules of the two crystal structures also shows distinct
changes in the substituent alignments, although the salt H-bridges
are virtually identical in terms of geometry and energy aspects
(Fig. 2).
soluble one. Such a difference between the two diastereoisomeric
salts (S)-1ꢂ(R)-3 and (R)-1ꢂ(R)-3 clarify the observed high efficiency
of the new resolution method.
2.3. Effect of the duration of the crystallization on the efficiency
of the resolution
We observed that the enantiomeric excess of 1 in the crystalline
diastereoisomeric salt strongly depends on the duration of the
crystallization. Thus, practically pure (ꢁ)-(S)-1 (ee >96%) could be
isolated when the salt was filtered off after 2 h, while the ee de-
creased with increasing crystallization time and racemic 1 was iso-
lated from the salt after 2 weeks.
In order to determine the process of the decreasing enantio-
meric purity and the optimal duration of the crystallization a series
of experiments were carried out. We found that the enantiomeric
excess is very good and in fact increased slightly over a short per-
iod; however after 8 h the ee decreased dramatically. After 330 h,
the enantiomeric purity was only 4.7% (Fig. 4 and Table 3).
The observed phenomenon can be rationalized by taking into
consideration the stereochemical stability of the resolving agent
(R)-3. It is known from the literature that the esters of 2-phenylgly-
cine are stable in substantia but slow racemisation occurs in solu-
tion, in the presence of acids (e.g., tartaric acid).13 The rate of
racemisation dramatically increases if the amino group is con-
verted into a Schiff base (the addition of acetone or other oxo com-
pounds into the reaction mixture).13,14
Figure 2. The overlay fit10 of all C and N atoms of (S)-1 and the inverted (R)-1 from
the (S)-1ꢂ(R)-3 and from the inverted (R)-1ꢂ(R)-2 salt. The former salt pair is shown
with 30% displacement probabilities, while the latter is a stick model.9
Under the applied experimental conditions, racemisation of
compound 3 was observed without changing the stoichiometry
of the diastereoisomeric salt. A 1:1 mixture of (S)-1ꢂ(R)-3 and
Attempts to prepare single crystals from the more soluble (R)-
1ꢂ(R)-3 salt were unsuccessful, as amorphous solid material was
formed during the evaporation of the solvent under reduced pres-
sure. Differences between (S)-1ꢂ(R)-3 and (R)-1ꢂ(R)-3 diastereoiso-
meric salts were investigated by powder XRD and DSC methods.
Powder XRD studies of the salts have shown that (R)-1ꢂ(R)-3 is
amorphous having no peaks in the diffractogram, however the
powder XRD analysis curve of the (S)-1ꢂ(R)-3 salt suggests a crys-
talline solid (Fig. 3).
Figure 4. Effect of the duration of the crystallization on the ee of (S)-1 in the (S)-
1ꢂ(R)-3 salt.
Table 3
Change of the ee of (S)-1 in the diastereoisomeric salt (S)-1ꢂ(R)-3 during
crystallization
Timea (h)
eeb (%)
‘S’
0.25
1
4
96.6
97
0.82
0.81
0.82
0.82
0.77
0.49
0.40
0.25
0.32
0.23
0.14
0.05
97.6
97.8
91.5
45.3
38.5
22.3
24.6
18.8
12.1
4.7
8
15
30
40
68
75
115
161
330
Figure 3. The powder XRD spectrum of (S)-1ꢂ(R)-3 and (R)-1ꢂ(R)-3 salts.
The measured and the calculated powder XRD analysis curves
show a good agreement. From the DSC studies, similar results were
obtained. The less soluble (S)-1ꢂ(R)-3 salt melted at 191 °C, but it
decomposed before completion of the melting. The DSC analysis
curve of (R)-1ꢂ(R)-3 salt showed a small, wide endothermic peak
followed by a big exothermic peak at about 120 °C. This means that
this salt decomposed at a much lower temperature than the less
a
Independent experiments.
ee was determined by HPLC analysis using a chiral stationary phase (Chiralpak
b
AD–H).

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F. Faigl et al. / Tetrahedron: Asymmetry 22 (2011) 1879–1884
Table 4
(R)-1ꢂ(S)-3 salts was in the solid phase after a prolonged crystalli-
zation time. It should be mentioned that the transesterification of
compound 3 did not occur in the ethanolic solution within the
161 h reaction time.
Results of the reciprocal resolution and the second order asymmetric transformation
of (R,S)-3a
Entry Solvent
Yieldb (%) (S)-1ꢂ(R)-3 eec (%) (R)-3 Time (h) ‘S’
1e
2e
3
4
5
MeOH
MeOH
40d
63
95
95
96
86
82
92
83 2.5
99 360
0.33
0.62
0.48
0.86
0.86
0.82
0.78
0.87
2.4. Application of optically active 1 as a resolving agent
Tol/Ac 10/3
Tol/Ac 10/3
Tol/Ac 10/3
Tol/Ac 10/4
Tol/Ac 10/5
Tol/Ac 10/5
50
3
90 20
90 40
93 20
95 20
95 20
In reciprocal resolution the roles of substrate and resolving
agent are interchanged, that is resolution of a racemic mixture of
a compound used in the primary process as the resolving agent
is attempted with one of the enantiomers of the compound, which
had been originally subjected to resolution.
Reciprocal resolution of (R,S)-3 with (S)-1 was accomplished in
methanol. When the diastereoisomeric salt was filtered after 2.5 h
of crystallization, the enantiomeric excess was moderate and the
yield was poor. When increasing the duration of the crystallization
the diastereoisomeric salt contained more of the (R)-3 enantiomer.
Finally, after 360 h the salt crystallized in good yield and it con-
tained practically pure (R)-3 (ee 99%, Scheme 2).
6
7
8f
a
b
c
All reactions were carried out in 0.34 M solution at 40 °C.
Yield was calculated to the whole amount of the racemate.
ee was determined by HPLC analysis using a chiral stationary phase (Kromasil
5-AmyCoat).
d
Yield was calculated to the half of the racemate.
25 °C.
10 mol % water was added.
e
f
1 and methyl 2-phenylglycinate 3 are good resolving agents for
each other. Within this pair of compounds, the stereochemical sta-
bility of 3 determines the applicable duration of the crystallization
of the diastereoisomeric salts, and it can be used to govern the out-
come of the resolution processes.
Higher than 50% yield of the diastereoisomeric salt (in this case
the yield was calculated with regards to the whole amount of the
racemate) was due to a second order asymmetric transformation
of 3. In order to improve the yield of the diastereoisomeric salt
(S)-1ꢂ(R)-3, further studies were carried out by changing the sol-
vent. We found that the yield of the desired salt was at its highest
when toluene was used as a solvent; the addition of acetone accel-
erated the racemisation of methyl (S)-2-phenylglycinate resulting
in better enantiomeric excesses in the crystallized diastereoiso-
meric salt. When 30% of acetone was used, the enantiomeric purity
of (R)-3 was higher, however the yield decreased. The addition of
10% of water resulted in 92% yield and the ee of (R)-3 in the salt
was as high as it was in the absence of water (‘S’ = 0.87). The results
of the reciprocal resolution and the second order asymmetric
transformation are summarized in Table 4.
From the experimental data we concluded that optically active
1 can be used as an efficient resolving agent for the separation of
methyl 2-phenylglycinate enantiomers and the second order
asymmetric transformation could be achieved by prolonged reac-
tion time or by the addition of acetone into the reaction mixture.
The atropisomeric dicarboxylic acid was stereochemically stable
under the conditions of the second order asymmetric transforma-
tion (40 °C, 40 h) and it was regenerated in good yield. The optimal
conditions of such a transformation were a toluene–acetone–water
solvent mixture, 20 h and 40 °C. Under these conditions we ob-
tained (R)-3 from the crystalline diastereoisomeric salt in 92% yield
and >95% enantiomeric excess. The mechanism of this second or-
der asymmetric transformation with an equivalent amount of opti-
cally active 1 related to the racemate of methyl 2-phenylglycinate
is shown in Scheme 3.
Thus, one should separate the crystalline diastereoisomeric salt
from the reaction mixture of (R,S)-1 and (R)-3 within 2–3 h in order
to obtain the (S)-1ꢂ(R)-3 diastereoisomeric salt in high de. In this
case, the efficiency of the resolution is excellent (‘S’ = 0.87), much
better then that of the previously published method, where (S)-
or (R)-2 was used as resolving agent (‘S’ = 0.28). A comparison of
the X-ray crystal structures and the packing energies of the two
diastereoisomeric salts (S)-1ꢂ(R)-3 and (S)-1ꢂ(S)-2 showed a very
similar H-bridge system in the salts and larger packing energy dif-
ference between the cationic species of the salts. Furthermore, the
diastereoisomeric pair, that is (R)-1ꢂ(S)-2 of (S)-1ꢂ(S)-2 could easily
be isolated in crystalline form while the diastereoisomeric pair,
that is (R)-1ꢂ(R)-3 of (S)-1ꢂ(R)-3 remained amorphous under the
conditions investigated, showing a bigger difference between the
latter mentioned pairs of diastereoisomeric salts. All of the above
mentioned differences may explain the much higher efficiency of
the resolution accomplished with (R)-3 compared to the previously
described one (with (S)-2).
On the other hand, the reciprocal resolution and, as a more use-
ful method, second order asymmetric transformation of (R,S)-3
with a pure enantiomer of 1, could be accomplished when a pro-
longed crystallization time was used and/or the racemisation of
the enantiomers of 3 was accelerated with an additive (acetone),
in toluene solution. Practically pure (R)-3 (ee >95%) could also be
isolated from the diastereoisomeric salt in high yield (92%, calcu-
lated to the whole amount of racemic 3) when the reaction mixture
contained 10% of water.
All of the aforementioned results demonstrate that optically ac-
tive atropisomeric dicarboxylic acid 1 can be prepared easily and,
in addition to its application as a chiral precursor of other atropiso-
meric 1-phenylpyrrole derivatives,6 it can also be used as an excel-
lent resolving agent.
3. Conclusion
On the basis of our experimental results, we conclude that 1-[2-
carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid
NH2
COOCH3
COOH
N
methanol
(S)-1·(R)-3
RT, 360h
+
F3C
COOH
de 99%
yield 63%
(RS)-3
(S)-1
Scheme 2. Reciprocal resolution of racemic 3 with an equivalent amount of (S)-1.

F. Faigl et al. / Tetrahedron: Asymmetry 22 (2011) 1879–1884
1883
COOCH3
-
N
COOCH3
COOCH3
H
N
N
H+
H
(S)-4
(R)-4
COOCH3
N
- acetone
+ acetone
COOCH3
COOCH3
H2N
H
H2N
H
(S)-3
(R)-3
1 eq. (S)-1
in toluene-acetone-water
solvent mixture
(S)-1·(S)-3 salt
(S)-1·(R)-3 salt
in solution
solid phase
COOCH3
(S)-1·(S)-3
COOH
N
H
+H3N
F3C
COO-
de up to 95%
(S)-1·(R)-3
yield = 92%
Scheme 3. Second order asymmetric transformation of methyl 2-phenylglycinate 3.
filter, X’celerator detector, and ‘zero background’ single crystal
silicon sample holder in the range of 2h = 2–42°. Differential
scanning calorimetry (DSC) measurements were performed using
a DSC 2920 device (TA Instruments Inc., USA). The samples
(1–8 mg) were measured in sealed Al-pans at a heating rate of
10 K/min.
4. Experimental
4.1. General
All commercial starting materials were purchased from Sigma–
Aldrich and Merk-Schuchardt and were used without further
purification.
Routine 1H NMR spectra were recorded in DMSO-d6 solution on
a BRUKER AV 300 spectrometer. Proton chemical shifts are re-
ported in ppm relative to the solvent (dDMSO = 2.50 ppm). IR spectra
were recorded on an appliance type PERKIN ELMER 1600 with a
Fourier Transformer. Data are given in cmꢁ1. The specific rotations
of the optically active samples were determined on a PERKIN EL-
MER 245 MC polarimeter using a sodium lamp (589 nm).
4.2. Resolution of dicarboxylic acid 1; a typical example
Racemic dicarboxylic acid 1 (0.5 g, 1.67 mmol) was dissolved in
ethanol (5 mL) and methyl (R)-2-phenylglycinate (0.276 g,
1.67 mmol) was added to it. The clear solution of the mixture
was stirred at room temperature and after a short time it was
seeded with the crystals of the (S)-1ꢂ(R)-3 salt. The diastereoiso-
meric salt was filtered off after 2 h crystallization. The crystals
were washed with cold ethanol and dried to yield 0.33 g of a white
solid (85%).
Powder X-ray diffraction patterns were recorded with
PANalytical X’pert Pro MPD (PANalytical Bv., The Netherlands)
multipurpose X-ray diffractometer using Cu-K radiation, Ni
a
a

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F. Faigl et al. / Tetrahedron: Asymmetry 22 (2011) 1879–1884
The salt was suspended in water (1 mL) and a saturated sodium
UV detector 222 nm, 20 °C, retention time for (S)-3: 18.4 min., for
(R)-3: 22.0 min.
carbonate solution (5 mL) was poured into it. The resolving agent
was extracted with dichloromethane (3 ꢀ 5.0 mL), then the aque-
ous solution was acidified with hydrochloric acid solution until
pH 1. After half an hour of stirring at 5 °C, the precipitate was fil-
tered off, washed with ice water and dried. Thus optically active
4.5. Crystal structure determination
A selected single crystal (0.4 ꢀ 0.3 ꢀ 0.2 mm) of (S)-1ꢂ(R)-3 was
1 was obtained (0.20 g, 80%, ee 96%), ½a D25
ꢃ
¼ ꢁ43:1 (c 1.0, EtOH).
mounted on a Rigaku R-AXIS RAPID diffractometer (graphite
The optically active dicarboxylic acid samples 1 were quantita-
tively converted into their bismethyl esters before HPLC analysis.
HPLC measurements were carried out on Chiralpak AD–H column
monochromator Cu-K radiation, k = 1.54187 Å). Data collection
a
was performed at room temperatures (T = 295 2 K). Crystal data
for (S)-1ꢂ(R)-3: C22H19F3N2O6, Fwt.: 464.39, colorless, chunk, mono-
clinic, space group P21, a = 11.9804(5) Å, b = 7.8115(3) Å, c =
12.9927(5) Å, b = 118.252(2)°, V = 1071.07(7) Å3, Z = 2, Dx =
1.440 g/cm3. Initial structure model was obtained by SHELXS-97,
completed by successive difference Fourier syntheses and refined
to convergence by SHELXL-97.15 Anisotropic full-matrix least-
squares refinement on F2 for all non-hydrogen atoms yielded
R1 = 0.0356 and wR2 = 0.0982 for 1332 [I >2s(I)] and R1 = 0.0375
and wR2 = 0.1002 for all (3395) intensity data, (number of param-
eters = 302, goodness-of-fit = 1.070, extinction coefficient =
0.0052(7), absolute structure parameter x = 0.05(15)).
(5
l
m, 250 ꢀ 4.6 mm), eluent hexane/2-propanol = 98/2, 0.8 mL/
min, UV detector 256 nm, 20 °C, retention time for (S)-1 ester:
9.8 min, for (R)-1 ester: 11.3 min.
4.2.1. 1-[2-Carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-
carboxylic acid methyl 2-phenylglycinate salt (after 161 h
crystallization)
IR (KBr, cmꢁ1): 3481, 3122, 2854, 2635, 2502, 2080, 1994, 1750,
1676, 1529, 1433, 1316, 1252, 1131. 1H NMR (DMSO-d6, 300 MHz)
dH (ppm): 7.94 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 7.8 Hz), 7.41–7.35
(5H, m), 6.81 (1H, s), 6.74 (1H, dd, J = 2.1, 3.3 Hz), 6.19 (1H, t,
J = 3.2 Hz), 4.89 (1H, s), 3.65 (3H, s). Anal. Calcd for C22H19F3N2O6
(464.39): C, 56.90; H, 4.12; N, 6.03. Found: C, 56.86; H, 3.90; N,
6.13.
CCDC 844299 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
4.3. Enantiomeric enrichment of the dicarboxylic acid 1 from
the filtrate of the resolution; a typical example
Acknowledgements
This work is connected to the scientific program of the ‘Devel-
opment of quality-oriented and harmonized R+D+I strategy and
functional model at BME’ project. This project is supported by
the New Hungary Development Plan (Project ID: TÁMOP-4.2.1/B-
09/1/KMR-2010-0002). A part of the project was sponsored by
the Hungarian Scientific Research Fund (OTKA, Project No.:
048362). Costs of the SXRD studies were in part defrayed by OTKA
K-75869.
An enantiomeric mixture of (R > S)-1 was isolated from the fil-
trate of the diastereoisomeric salt formation reaction. The solvent
was evaporated, and the residue was worked up in an analogous
way to the work-up procedure of the crystalline diastereoisomeric
salt (see Section 4.2). Pure (R)-1 isomer was obtained by recrystal-
lization of (R > S)-1 (0.25 g, 0.84 mmol, ee 80%) from ethyl acetate
(1 mL). The crystalline product was 0.185 g (74%, ee >99%).
4.4. Second order asymmetric transformation of methyl 2-
phenylglycinate 3; a typical example
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}
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ꢃ
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The filtrate of the diastereoisomeric salt formation was concen-
trated under reduced pressure and then was added to an aqueous
solution of the salt decomposition. It was then acidified with
hydrochloric acid until pH 1. After half an hour of stirring at 5 °C,
the precipitate was filtered off, washed with ice water and dried.
Thus optically active 1 was recovered (0.45 g, 90%, ee >99%).
The HPLC measurements of optically active amino ester sam-
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lm,
250 ꢀ 4.6 mm), eluent hexane/2-propanol = 90/10, 0.5 mL/min,