Determination of the absolute configuration of 1,3,5-triphenyl-4,5- dihydropyrazole enantiomers by a combination of VCD, ECD measurements, and theoretical calculations

Article abstract of DOI:10.1016/j.tetasy.2011.06.003

The enantiomers of 1,3,5-triphenyl-4,5-dihydropyrazole (an intense blue fluorescent compound) have been separated for the first time and their absolute configuration was established by a combination of VCD and ECD measurements and theoretical calculations

Full text of DOI:10.1016/j.tetasy.2011.06.003

Tetrahedron: Asymmetry 22 (2011) 1120–1124
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Determination of the absolute configuration of
1,3,5-triphenyl-4,5-dihydropyrazole enantiomers by a combination of VCD,
ECD measurements, and theoretical calculations
Nicolas Vanthuyne a, Christian Roussel a, , Jean-Valère Naubron b, Nadine Jagerovic c, Paula Morales Lázaro c,
⇑
Ibon Alkorta c, José Elguero c
a ISM2, Chirosciences, Université Paul Cézanne, Case A62, Avenue Escadrille Normandie Niémen, F-13397 Marseille, France
b Spectropole, Université Aix-Marseille, Campus Scientifique de Saint Jérôme, Service 511, F-13397 Marseille, France
c Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiomers of 1,3,5-triphenyl-4,5-dihydropyrazole (an intense blue fluorescent compound) have
been separated for the first time and their absolute configuration was established by a combination of
VCD and ECD measurements and theoretical calculations. The enantiomers of 1,3,5-triphenyl-4,5
-dihydropyrazole which are highly fluorescent both in solution (CH2Cl2) and in the solid state may find
application in the very active field of enantioselective fluorosensors.
Received 5 May 2011
Accepted 1 June 2011
Available online 27 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Prasanna de Silva.7 In recent years, the enantioselective synthesis
of 2-pyrazolines has received much attention,8 due to the fact that
In 2001, some of us reported that 1,3,5-triphenyl-2-pyrazoline
(or 4,5-dihydropyrazole) 1 (Scheme 1) shows spontaneous resolu-
tion when crystallizing, being a conglomerate.1 To date, this remains
the only reported example of a conglomerate in 2-pyrazolines. 1,3-
Dimethyl-5-phenyl-2-pyrazoline 2 crystallizes enantiomerically
pure when included in chiral Toda’s host.2 We have also resolved
both enantiomers of 1,5-diphenyl-3-methyl-2-pyrazoline 3 using
chiral HPLC.3 Other authors have resolved other 2-pyrazolines via
crystallization with a chiral auxiliary or by chiral HPLC.4
some pharmaceutical compounds are chiral pyrazolines.9
We decided to use compound 1 (QUMZUT,10 Fig. 1) to test the
possibilities offered by VCD and ECD plus theoretical calculations
to assign the absolute configuration of the enantiomers of this
compound. We have successfully used this combination in previ-
ous work.11,12 In the case of 1 the lack of heavy atoms prevents
the use of Bijvoet’s anomalous dispersion method.13
2. Results and discussion
In the first step, HPLC screening of different chiral columns (see
Section 4) showed that Chiralcel OD-3 and Chiralpak AD-H
H3C
H3C
N
N
N
N
N
N
CH3
1
2
3
Scheme 1. Chiral 2-pyrazolines.
1,3,5-Triaryl-2-pyrazolines have important applications as
drugs5 and as optical devices,6 particularly those described by
⇑
Corresponding author. Tel.: +33 491 28 8257; fax: +33 491 28 9146.
E-mail address: christian.roussel@univ-cezanne.fr (C. Roussel).
Figure 1. The X-ray molecular structure of 1,3,5-triphenyl-2-pyrazoline 1.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.003

N. Vanthuyne et al. / Tetrahedron: Asymmetry 22 (2011) 1120–1124
1121
(a)
(b)
(c)
5.0
6.0
7.0
8.0
9.0
5.0
6.0
7.0
8.0
9.0 5.0
6.0
7.0
8.0
9.0
Minutes
Minutes
Minutes
Figure 2. Separation of the enantiomers of 1 on Chiralpak AD-H. (eluent 90:10 Hexane/2-PrOH, Flow rate 1 mL/min, 25 °C, UV 254 nm (black trace) and CD 220 nm (red
trace). (a) a reassembled mixture of enantiomers; (b) example of an enantiomerically pure crystal composed of the first eluted enantiomer; and (c) example of an
enantiomerically pure crystal composed of the second eluted enantiomer.
columns were suitable for separation of the enantiomers of 1 in a
90:10 Hexane/2-PrOH mixture of solvents (Fig. 2a). Chiralcel OD-
3 and Chiralpak AD-H columns were composed of cellulose and
amylose tris(3,5-dimethylphenyl)carbamate coated on silica,
respectively.
crystals, we suggest that isopropanol alone or in mixture with
CH2Cl2 gave a cleaner spontaneous resolution than ethanol.
In all the cases, the enantiopure crystals of 1 were too small to
attempt a preparative separation in an efficient way as we did for
the hydrobenzoine case which gave enantiopure crystals weighing
ca 14 mg each.15
In the second step, the individual crystals of 1 grown in differ-
ent solvents were submitted to liquid chromatography on Chir-
alpak AD-H. The objective was to verify if conglomerates were
obtained under different crystallization conditions. This method
has been already used to detect the formation of conglomerates
of pyrimidin-2(1H)-(thi)ones by Sakamoto et al.14 Some of us fur-
ther improved the method by using on line chiroptical detection
which allows a safer assignment in case of a possible drift of the
retention time or poor separation.15,16 Chromatography on chiral
support with chiroptical detection (Pol or ECD) is particularly
efficient in detecting the occurrence of a conglomerate when the
crystals are quite small; the only requirement is to obtain peaks
with an opposite sign and different retention depending on the
crystal picked. In the case of large crystals a small piece of the
picked crystal is submitted to chromatography and crystals of high
enantiomeric purity with the same retention and sign can be gath-
ered in the same flask. It is worth noting that chiral chromatogra-
phy immediately gives information on the enantiomeric purity of
the crystals while this type of information is not attainable without
considerable effort and time consumption by other classical meth-
ods such as polarimetry.
The chromatographic screening experiments yielded a lot of
information: the separation of the enantiomers on Chiralpak AD-
H is amenable to a semi-preparative scale. The first eluted enantio-
mer gave a (ꢀ) CD sign at 220 nm and a (+) CD sign at 254 nm in a
90:10 Hexane/2-PrOH mixture of solvent. Furthermore, detection
using a JASCO polarimeter on-line shows that the first eluted enan-
tiomer is the dextrogyre one (data not reported).
It is worth noting that Chiralcel OD-3 also provided very nice
separation of the enantiomers of 1. Since the same mobile phase
was used for Chiralpak AD-H and Chiralcel OD-3,17 CD detection
at 220 nm revealed that the two chiral stationary phases produced
the opposite order of elution (see Section 4.2).
The semi-preparative resolution of rac-1 was performed with
the same eluent as for analytical analysis on a (250 ꢁ 10 mm) Chir-
alpak AD-H column. Strictly speaking, we did not obtain rac-1 but a
reassembled mixture obtained by grinding a large crop of more or
less enantiomerically pure crystals of each configuration.
The semi-preparative separation afforded ca. 20 mg of each
enantiomer within 6 h. The first eluted enantiomer corresponded
to the (ꢀ)ECD220nm form according to CD detection in the mobile
phase. The specific rotation of the first and second eluted enantio-
mers was determined in CH2Cl2 at different wavelengths (Table 3,
Section 4), the first eluted enantiomer is dextrogyre, while the sec-
ond is levogyre. It is worth noting that the determination of the
specific rotation at 365 nm was not possible due to the intense
absorption about that wavelength which is associated with an in-
tense blue fluorescence18 (see Graphical abstract).
The crystals of 1 could be obtained via recrystallization in vari-
ous solvents. Six crystals were selected from a recrystallization in
2-PrOH/CH2Cl2 (1:1) and four crystals were selected from recrys-
tallization in EtOH/CH2Cl2 (1:1) or 2-PrOH, respectively. Each se-
lected crystals was solubilized in ethanol and analyzed on a
Chiralpak AD-H column with CD detection at 220 nm. Amongst
the 14 crystals which were analyzed, 5 were enantiomerically
pure: 3 corresponded to the first eluted enantiomer (Rt = 6.01–
The experimental IR spectra of the enantiomers (red line in
Fig. 3a) and VCD spectra for the first eluted (red line in Fig. 3b)
and second eluted enantiomer (green line in Fig. 3b) were recorded
in CD2Cl2 and compared to the spectra calculated for (R)-1 (blue
line in Figs. 3a and 3b). As expected, the IR absorptions are identi-
cal and VCD spectra are mirror images. Conformational studies
6.11 min) (Fig. 2b) and
2 to the second eluted (Rt = 7.90–
8.09 min) (Fig. 2c). These results are in accordance with X-ray data
which gave a P21 space group for 1.
The nine remaining crystals were contaminated by the other
enantiomer (up to 20%). From that screening on a limited set of

1122
N. Vanthuyne et al. / Tetrahedron: Asymmetry 22 (2011) 1120–1124
Table 1
Frequencies and descriptions of the bands selected in Figs. 3a and 3b
ꢀ
ꢀ
Bands mcalc
mexp:
Description
(cmꢀ1
)
(cmꢀ1
)
1
2
3
4
5
6
1593
1598
—
1577
1562
—
Stretching C@Carom.
1583
1577
1567
1557
1492
Stretching C@Carom. and C@N
Stretching C@Carom. with bending Carom.–Csp3⁄–H
Stretching C@Carom.
Stretching C@Carom. and C@N
Stretching Carom.–N and Carom.–Csp2 with bending
C–Harom.
1502
7
1485
1495
Stretching Carom.–N and Carom.–Csp2 with bending
C–Harom.
8
9
10
1448
1442
1374
1455
1448
1392
Bending H–Csp3–H, Carom.–Csp3⁄–H and C–Harom.
Bending H–Csp3–H, Carom.–Csp3⁄–H and C–Harom.
Breathing of the five-membered heterocycle and
bending C–Harom.
11
12
13
14
1346
1322
1306
1291
1350
1334
1324
1302
Bending Carom.–Csp3⁄–H and C–Harom.
Rocking C–Harom., H–Csp3–H and Carom.–Csp3⁄–H
Rocking C–Harom., H–Csp3–H and Carom.–Csp3⁄–H
Deformations of the five-membered heterocycle
and of two phenyl groups
Deformations of the five-membered heterocycle
and of two phenyl groups
Deformations of the five-membered heterocycle
and of one phenyl group
Deformations of the five-membered heterocycle
and of two phenyl groups
Deformations of the five-membered heterocycle
and of two phenyl groups
Figure 3a. IR absorption spectra of 1 calculated for the (R)-enantiomer (in blue) and
measured in CD2Cl2 (in red). A scaling factor of 0.97 has been applied on the
frequencies of the calculated spectrum. The blue bars correspond to the calculated
dipole strengths.
15
16
17
18
19
20
1282
1271
1260
1233
1116
1066
—
1283
1268
1240
1125
1069
Stretching N–N with twist of H–Csp3–H, Carom.
–
Csp3⁄–H and bending C–Harom.
Stretching N–N with bending C–Harom.
showed that there was one conformation for (R)-1 which has a
geometry close to the one determined by X-ray diffraction analysis.
The geometry optimizations, vibrational frequencies, IR absorption
and VCD intensities were calculated with Density Functional The-
ory (DFT) using B3LYP combined with TZVP basis set. A very good
agreement was observed between the experimental and calculated
spectra (Figs. 3a and 3b). The VCD spectrum of the first eluted
enantiomer (red line in Fig. 3b) matches the calculated one for
(R)-1 (blue line in Fig. 3b). Among all the bands attributed on the
spectra, bands 1, 2, 6, 7, 8, 10, 11, 12, 13, 14, 15, 18, and 20 must
be highlighted due to their particularly good correspondence. The
normal modes corresponding to those bands are described in
Table 1.
Figure 3b. VCD spectra of
1 calculated for the (R)-enantiomer (in blue) and
measured in CD2Cl2 for the first eluted (in red) and the second eluted (in green)
enantiomers. A scaling factor of 0.97 has been applied on the frequencies of the
calculated spectrum. The blue bars correspond to the calculated VCD rotary
strengths.
Following Polavarapu’s recommendation that more than one
chiroptical spectroscopic method should be applied for the abso-
lute configuration determination, the ECD spectra of the enantio-
mers were recorded in n-hexane.19
The bands at 220 and 254 nm (Fig. 4) were in perfect agreement
with the observed signals during chiral HPLC CD detection. The
first eluted enantiomer (red line in Fig. 4b) presents a negative sig-
nal at 220 nm and a positive one at 254 nm. The ECD and UV spec-
tra were calculated using time dependent density functional
theory (TDDFT) with CAM-B3LYP functional and 6-31++G(d,p) ba-
sis set (Figs. 4a and 4b). Considering that the calculations were car-
ried out in the gas phase and that the calculated results have not
been shifted, the agreement between calculated and experimental
spectra is satisfactory. Particularly, the large band above 300 nm
confirms the assignment of the (R)-configuration to the first eluted
enantiomer.
Figure 4a. UV spectra of
1 calculated for the (R)-enantiomer (in blue) and
measured in hexane for the first and second eluted enantiomers (in red). The blue
bars correspond to the calculated oscillator strengths.
3. Conclusion
Chromatography on chiral support associated with chiroptical
detection confirmed the X-ray observation that compound 1 af-
fords a conglomerate when crystallized in different solvents. The
absolute configuration of the enantiomers of 1,3,5-triphenyl-2-
pyrazoline 1 which were readily obtained by chromatography on
Chiralpak AD-H was established using vibrational and electronic

N. Vanthuyne et al. / Tetrahedron: Asymmetry 22 (2011) 1120–1124
1123
Table 2
Screening of chiral columns for the separation of 1 (flow-rate = 1 mL minꢀ1, UV
detection at 254 nm, eluent: Hexane/2-PrOH (90:10))
Column
tR1
k1
tR2
k2
a
Rs
Chiralpak AS-3
Lux-amylose-2
Whelk-O1 (S,S)
Ulmo (S,S)
Lux-cellulose-2
Lux-cellulose-4
Chiralpak AZ-H
Chiralcel OD-3
Chiralpak AD-H
5.55
5.17
4.02
4.21
4.42 (+)
4.44
5.42 (ꢀ)
6.26 (+)
6.04 (ꢀ)
0.81
0.69
0.31
0.38
0.44
0.45
0.81
1.09
1.01
1
1
1
1
1.13
1
1.21
1.97
1.65
0
0
0
0
<0.5
0
1.76
8.43
5.66
4.65 (ꢀ)
0.51
5.93 (+)
9.45 (ꢀ)
8.02 (+)
0.98
2.15
1.67
The associated sign corresponds to the sign of the CD trace at 220 nm.
4.3. Specific rotation of the enantiomers of 1
Figure 4b. ECD spectra of
1 calculated for the (R)-enantiomer (in blue) and
measured in hexane for the first eluted (in red) and the second eluted (in green)
enantiomers. The blue bars correspond to the calculated ECD rotary strengths.
The specific rotations were determined on a Perkin-Elmer MC-
241 in CH2Cl2 at 25 °C. They are reported in Table 3. It was not pos-
sible to determine the specific rotation at 365 nm, as the transmit-
ted energy was too low.
CD spectroscopy experiments in comparison with the calculated
spectra for the (R)-form. The first eluted enantiomer on a Chiralpak
AD-H column, which gives a (ꢀ) CD sign at 220 nm and a (+) spe-
cific rotation in CH2Cl2 presents the (R)-absolute configuration. The
first separation of the enantiomers of 1 and their intense blue fluo-
rescence, which was observed both in the solution and in the solid
state, paves the way for further studies in the field of enantioselec-
tive fluorescent sensors.7e,20
Table 3
Specific rotation in CH2Cl2
k
½
a 2D5
ꢂ
(c 0.5, CH2Cl2) for the first
½ ꢂ (c 0.3, CH2Cl2) for the second
a 2D5
(nm)
eluted enantiomer on Chiralpak
eluted enantiomer on Chiralpak
AD-H (R)-form
AD-H (S)-form
589
578
546
436
+425
+452
+569
ꢀ424
ꢀ451
4. Experimental
ꢀ567
4.1. Preparation of 1,3,5-triphenyl-2-pyrazoline 1
+1929
ꢀ1927
This compound was prepared in a crystalline form as previously
described.1 The samples were not stable on standing in CHCl3 and
they are highly fluorescent under UV lamp.
4.4. IR, VCD and UV, ECD measurements
4.2. Enantioseparation
Infrared (IR) and vibrational circular dichroism (VCD) spectra
were recorded on a Bruker PMA 50 accessory coupled to a Vertex
70 Fourier transform infrared spectrometer. A photoelastic modula-
tor (Hinds PEM 90) set at 1/4 wave retardation was used to modulate
at 50 kHz the handedness of the circular polarized light. Demodula-
tion was performed by a lock-in amplifier (SR830 DSP). An optical
low-pass filter (<1800 cmꢀ1) before the photoelastic modulator
was used to enhance the signal/noise ratio. A transmission cell
The analytical chiral HPLC experiments were performed on a
unit composed of a Merck D-7000 system manager, Merck-La-
chrom L-7100 pump, Merck-Lachrom L-7360 oven, Merck-La-
chrom L-7400 UV-detector, and on-line Jasco OR-1590
polarimeter. Hexane and isopropanol, HPLC grade, were degassed
and filtered on a 0.45 lm membrane before use. Semi-preparative
separations were performed on a Knauer unit with pump, UV
detector and a software to collect the different fractions.
The columns (250 ꢁ 4.6 mm) used for the analytical separation
of 1 were: Chiralpak AD-H, Chiralcel OD-3, Chiralpak AS-3 and
Chiralpak AZ-H from Chiral Technologies Europe (Illkirch, France),
Lux-Amylose-2, Lux-Cellulose-2 and Lux-Cellulose-4 from Phe-
nomenex, Le Pecq (France), Whelk-O1 (S,S) and Ulmo (S,S) are from
Regis Technologies, Morton Grove (USA).
A Chiralpak AD-H column (250 ꢁ 10 mm) from Chiral Technol-
ogies Europe (Illkirch, France) was used for semi-preparative sepa-
ration (flow-rate = 5 mL minꢀ1, UV detection at 254 nm, eluent:
Hexane/2-PrOH (90:10)).
equipped with sealed CaF2 windows of 200 lm of optical pathlength
was used. Solutions with a concentration of 0.18 mol Lꢀ1 were pre-
pared by dilution of solid samples in CD2Cl2. The VCD spectra of each
pure enantiomer were measured and the baseline of the spectra was
correctedby taking the half difference of the spectra of the two enan-
tiomers. For the individual spectra of the enantiomers, approxi-
mately 12,000 scans were averaged at 4 cmꢀ1 resolution
(corresponding to 3 h measurement time). For IR absorption spectra,
the cell filled with CD2Cl2 served as a reference.
UV and ECD spectra were measured on a JASCO J-815 spectrom-
eter equipped with a JASCO Peltier cell holder PTC-423 to maintain
the temperature at 20.0 0.2 °C. A cell of 1 mm of optical path-
Retention times Rt in minutes, retention factors ki = (Rti ꢀ Rt0)/
Rt0 are given. Rt0 was determined by injection of tri-t-butylben-
zene. The CD detector was set at 220 or 254 nm. The analyses were
performed at 25 °C, with 1 mL minꢀ1 as flow-rate, detections by UV
at 254 nm and CD. The sign given by the on-line JASCO CD-1595
detector is the CD sign of the product in the solvent used for the
chromatographic separation at the selected wavelength. The
screening of the chiral columns is reported in Table 2.
length was used. Solutions with
a concentration of 7.5 mg/
100 mL were prepared by dilution of solid samples in n-hexane
(HPLC grade). The CD spectrometer was purged with nitrogen be-
fore recording each spectrum, which was baseline subtracted.
The baseline was always measured for the same solvent and in
the same cell as the samples.
The spectra are presented without smoothing and further data
processing.

1124
N. Vanthuyne et al. / Tetrahedron: Asymmetry 22 (2011) 1120–1124
5. (a) Bilgin, A. A.; Palaska, E.; Sunal, R.; Gumusel, B. Pharmazie 1994, 49, 67–69;
4.5. DFT calculations
(b) Palaska, E.; Erol, D.; Demirdamar, R. Eur. J. Med. Chem. 1996, 31, 43–47; (c)
Manna, F.; Chimenti, F.; Bolasco, A.; Bizzarri, B.; Befani, O.; Pietrangeli, P.;
Mondovi, B.; Turini, P. J. Enzyme Inhib. 1998, 13, 207–216; (d) Chimenti, F.;
Bolasco, A.; Manna, F.; Secci, D.; Chimenti, P.; Befani, O.; Turini, P.; Giovannini,
V.; Mondovi, B.; Cirilli, R.; La Torre, F. J. Med. Chem. 2004, 47, 2071–2074; (e)
Fioravanti, R.; Bolasco, A.; Manna, F.; Rossi, F.; Orallo, F.; Ortuso, F.; Alcaro, S.;
Cirilli, R. Eur. J. Med. Chem. 2010, 45, 6135–6138.
Calculations were performed on the (R)-enantiomer of 1 start-
ing from the X-ray structure available in the CSD database (QUM-
ZUT).10 The geometry optimizations, vibrational frequencies, IR
absorption and VCD intensities were calculated with Density Func-
tional Theory (DFT) using B3LYP functionals combined with TZVP
basis set.21,22 Frequencies were scaled by a factor of 0.97. IR
absorption and VCD spectra were constructed from calculated di-
pole and rotational strengths assuming lorentzian band shape with
a half-width at half maximum of 6 cmꢀ1. Based on the B3LYP/TZVP
optimized geometry (Fig. 5), the ECD and UV spectra were calcu-
lated using time dependent density functional theory (TDDFT)23
with CAM-B3LYP functional and 6-31++G(d,p) basis set.24 Calcula-
tions were performed for vertical 1A singlet excitation using 50
states. For a comparison between the theoretical results and the
experimental values, the calculated UV and ECD spectra have been
modeled with lorentzian functions, using a half-width of 0.21 eV.
All calculations were performed using Gaussian09 Revision A02.25
6. (a) Rivett, D. E.; Rosevear, J.; Wilshire, J. F. K. Aust. J. Chem. 1983, 36, 1649–1658;
(b) Doroshenko, A. O.; Skripkina, V. T.; Shershukov, V. M.; Ponomaryov, O. A. J.
Fluoresc. 1997, 7, 131–138; (c) Zhang, H.; Chen, H.; Li, Y.; Jiang, Q.; Xie, M.
Polym. Bull. 2006, 57, 121–128; (d) Brik, M. G.; Kuznik, W.; Gondek, E.; Kityk, I.
V.; Uchacz, T.; Szlachcic, P.; Jarosz, B.; Plucinski, K. J. Chem. Phys. 2010, 370,
194–200.
7. (a) de Costa, M. D. P.; Prasanna de Silva, A.; Pathirana, S. T. Can. J. Chem. 1987,
65, 1416–1419; (b) Prasanna de Silva, A.; de Silva, S. A.; Dissanayake, A. S.;
Sundanayake, K. R. A. S. J. Chem. Soc. Chem. Commun. 1989, 1054–1056; (c)
Prasanna de Silva, A.; Gunaratne, H. Q. N. J. Chem. Soc.,Chem. Commun. 1990,
186–188; (d) Prasanna de Silva, A.; Gunaratne, H. Q. N.; McCoy, C. P. Nature
1993, 364, 42–44; (e) Prasanna de Silva, A.; Gunaratne, H. Q. N.; Gunnlaugsson,
T.; Huxley, A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997,
97, 1515–1566; (f) Prasanna de Silva, A.; Dixon, I. M.; Gunaratne, H. Q. N.;
Gunnlaugsson, T.; Maxwell, P. R. S. J. Am. Chem. Soc. 1999, 121, 1393–1394.
8. (a) Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710–10711; (b)
Yanagita, H.; Kanemasa, S. Heterocycles 2007, 71, 699–709; (c) Müller, S.; List, B.
Angew. Chem., Int. Ed. 2009, 48, 9975–9978; (d) Mahé, O.; Dez, I.; Levacher, V.;
Brière, J.-F. Angew. Chem., Int. Ed. 2010, 49, 7072–7075.
9. (a) Calvet, C.; Cuberes, R.; Pérez-Maseda, C.; Frigola, J. Electrophoresis 2002, 23,
1702–1708; (b) Pérez-Maseda, C.; Calvet, C.; Cuberes, R.; Frigola, J.
Electrophoresis 2003, 24, 1416–1421; (c) Alcón, M.; Pericás, M.; Cuberes, M.
R.; Frigola, J. U.S. Patent 6,958,403, 2005; (d) Gökhan-Kelekci, N.; Yabanoglu, S.;
Küpeli, E.; Salgin, U.; Özgen, Ö.; Ucar, G.; Yesilada, E.; Kendi, E.; Yesilada, A.;
Bilgin, A. A. Bioorg. Med. Chem. 2007, 15, 5775–5786.
10. Cambridge Structural Database Allen, F. H. Acta Crystallogr., Sect. B 2002, 58,
380; Allen, F. H.; Motherwell, W. D. S. Acta Crystallogr., Sect. B 2002, 58, 407.
CSD version 5.32, updated Nov. 2010. http://www.ccdc.cam.ac.uk.
11. Vachon, J.; Harthong, S.; Dubessy, B.; Dutasta, J.-P.; Vanthuyne, N.; Roussel, C.;
Naubron, J.-V. Tetrahedron: Asymmetry 2010, 21, 1534–1541.
12. Graus, S.; Tejedror, R. M.; Uriel, S.; Serrano, J. L.; Alkorta, I.; Elguero, J. J. Am.
Chem. Soc. 2010, 132, 7862–7863.
13. In some cases, it is possible to determine the absolute configuration of
molecules lacking heavy atoms using Friedel pairs, this is the case for
acetomycin Cano, F. H.; Foces-Foces, C.; Elguero, J. Acta Crystallogr., Sect. C
1988, 44, 919–921.
14. Sakamoto, M.; Utsumi, N.; Ando, M.; Saeki, M.; Mino, T.; Fujita, T.; Katoh, A.;
Nishio, T.; Kashima, C. Angew. Chem., Int. Ed. 2003, 42, 4360–4363.
15. Roussel, C.; Vanthuyne, N.; Jobert, J.-L.; Loas, A. I.; Tanase, A. E.; Gherase, D.
Chirality 2007, 19, 497–502.
16. Uncuta, C.; Bartha, E.; Gherase, D.; Loas, I. A.; Teodorescu, F.; Varga, R. A.;
Vanthuyne, N.; Roussel, C.; Berg, U. J. Mol. Struct. 2011, 989, 20–30.
17. Roussel, C.; Vanthuyne, N.; Serradeil-Albalat, M.; Vallejos, J.-C. J. Chromatogr., A
2003, 995, 79–85.
18. (a) Rivett, D. E.; Rosevear, J.; Wilshire, J. F. K. Aust. J. Chem. 1979, 32, 1601–
1612; (b) Yamamoto, H.; Sano, Y.; Shirota, Y.; Seki, H.; Mikawa, H. Bull. Chem.
Soc. Jpn. 1979, 52, 1533–1534; (c) Wiley, R. H.; Jarboe, C. H.; Hayes, F. N.;
Hansbury, E.; Nielsen, J. T.; Callahan, P. X.; Sellars, M. C. J. Org. Chem. 1958, 23,
732–738.
Figure 5. B3LYP/TZVP optimized structure of 1.
Acknowledgments
This work was supported by the Ministerio de Ciencia e Innova-
ción (Project No. CTQ2009-13129-C02-02), the Comunidad Autóno-
ma de Madrid (Project MADRISOLAR, ref. S-0505/PPQ/0225) and by
the computing facilities of the Centre Régional de Compétences en
Modélisation Moléculaire de Marseille (CRCMM). The Spanish
authors thank the CTI (CSIC) for allocation of computer time.
19. Polavarapu, P. Chirality 2008, 20, 664–672.
20. (a) Wolf, C.; Liu, S.; Reinhardt, B. C. J. Chem. Soc., Chem. Commun. 2006, 4242–
4244; (b) Mei, X.; Martin, R. M.; Wolf, C. J. Org. Chem. 2006, 71, 2854–2861.
21. (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100; (b) Becke, A. D. J. Chem. Phys.
1993, 98, 5648–5652; (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789.
22. Hariharan, P. A.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222.
23. (a) Furche, F.; Rappoport, D. Density Functional Methods for Excited States:
Equilibrium Structure and Electronic Spectra, Chapter III. In Computational
Photochemistry; Olivucci, M., Ed.; Theoretical and Computational Chemistry;
Elsevier: Amsterdam, 2005; Vol. 16, (b) Bauernschmitt, R.; Ahlrichs, R. Chem.
Phys. Lett. 1996, 256, 454–464.
24. Yanai, T.; Tew, D.; Handy, N. Chem. Phys. Lett. 2004, 393, 51–57.
25. Gaussian 09, Revision A.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A.
F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand,
J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc.,
Wallingford CT, 2009.
References
1. Foces-Foces, C.; Jagerovic, N.; Elguero, J. Z. Kristallogr. 2001, 216, 240–244.
2. Toda, F.; Tanaka, K.; Infantes, L.; Foces-Foces, C.; Claramunt, R. M.; Elguero, J. J.
Chem. Soc., Chem. Commun. 1995, 1453–1454.
3. Elguero, J.; Claramunt, R. M.; Shindo, Y.; Mukai, M.; Roussel, C.; Chemlal, A.;
Djafri, A. Chem. Scripta 1987, 27, 283–288.
4. (a) Mukai, M.; Miura, T.; Nanbu, M.; Yoneda, T.; Shindo, Y. Can. J. Chem. 1979,
57, 360–366; (b) Cirilli, R.; Ferretti, R.; Gallinella, B.; Turchetto, L.; Bolasco, A.;
Secci, D.; Chimenti, P.; Pierini, M.; Fares, V.; Befani, O.; La Torre, F. Chirality
2004, 16, 625–636; (c) Reddy, P.; Bell, S. C; Reddy, R. M. V. World Patent
2,004,093,829; (d) Lange, J. H. M.; Coolen, H. K. A. C.; van Stuivenberg, H. H.;
Dijksman, J. A. R.; Herremans, A. H. J.; Ronken, E.; Keizer, H. G.; Tipker, K.;
McCreary, A. C.; Veerman, W.; Wals, H. C.; Stork, B.; Verveer, P. C.; den Hartog,
A. P.; de Jong, N. M. J.; Adolfs, T. J. P.; Hoogendoorn, J.; Kruse, C. G. J. Med. Chem.
2004, 47, 627–643; (e) Sibi, M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc.
2005, 127, 8276–8277; (f) Sibi, M. P.; Stanley, L. M.; Soeta, T. Adv. Synth. Catal.
2006, 348, 2371–2375; (g) Donohue, S. R.; Pike, V. W.; Finnema, S. J.; Truong, P.;
Andersson, J.; Gulyás, B.; Halldin, C. J. Med. Chem. 2008, 51, 5608–5616; (h)
Bergman, J. M.; Coleman, P. J.; Fraley, M. E.; Garbaccio, R. M.; Hartman, G. D.; Li,
C.; Neilson, L. A.; Olson, C. M.; Tasber, E. S. U.S. Patent application
20,080,287,414.; (i) Coleman, P. J.; Mercer, S. P.; Roecker, A. J. U.S. Patent
application 20,080,045,492.; (j) Cirilli, R.; Simonelli, A.; Ferretti, R.; Bolasco, A.;
Chimenti, P.; Secci, D.; Maccioni, E.; La Torre, F. J. Chromatogr., A 2006, 1101,
198–203; (k) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128,
2174–2175; (l) Cirilli, R.; Alcaro, S.; Fioravanti, R.; Secci, D.; Fiore, S.; La Torre,
F.; Ortuso, F. J. Chromatogr., A 2009, 1216, 4673–4678.