Assignment of absolute configurations of permethrin and its synthon 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by electronic circular dichroism, optical rotation, and X-ray crystallography

Article abstract of DOI:10.1016/j.tetasy.2009.03.035

The availability of single stereoisomers of biologically/toxicologically relevant chiral compounds such as the pyrethroid-type insecticide permethrin (PM) and the reliable determination of their absolute configurations are of central importance for the de

Full text of DOI:10.1016/j.tetasy.2009.03.035

Tetrahedron: Asymmetry 20 (2009) 1027–1035
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Assignment of absolute configurations of permethrin and its synthon
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by electronic
circular dichroism, optical rotation, and X-ray crystallography
b,
b
a
Wolfgang Bicker a, , Karol Kacprzak , Marcin Kwit , Michael Lämmerhofer ,
*
*
Jacek Gawronski b, Wolfgang Lindner a
a Christian Doppler Laboratory for Molecular Recognition Materials, Department of Analytical Chemistry and Food Chemistry, University of Vienna, Waehringer Strasse 38,
A-1090 Vienna, Austria
b
´
Faculty of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, PL-60780 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The availability of single stereoisomers of biologically/toxicologically relevant chiral compounds such as
the pyrethroid-type insecticide permethrin (PM) and the reliable determination of their absolute config-
urations are of central importance for the detailed investigation and correct assignment of stereoselective
effects. In this context, single stereoisomers of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic
acid (DCCA), a precursor, metabolite, and environmental degradation product of PM, were isolated from a
mixture of all four stereoisomers in enantiomeric excesses of >99% via a two-step chromatographic pro-
cess combining a diastereoselective reversed-phase separation in the first step with a direct enantiomer
separation in the second step. Esterification of DCCA stereoisomers with 3-phenoxybenzyl alcohol
yielded PM. Electronic circular dichroism (ECD) spectra of DCCA and PM stereoisomers were measured
in non-polar (cyclohexane containing 5% v/v 1,2-dichloroethane) and non-protic polar (acetonitrile) sol-
vents. Cotton effects suitable to distinguish the four stereoisomers of each DCCA and PM were obtained.
Absolute configurations of DCCA were determined by confrontation of calculated (time-dependent den-
sity-functional theory using B3LYP hybrid functional) and experimental ECD and optical rotation (OR)
data. Fully convergent results between ECD and X-ray diffractometry (analysis of DCCA isomers co-crys-
Received 7 January 2009
Accepted 11 March 2009
Available online 7 May 2009
tallized with O-9-(2,6-diisopropylphenylcarbamoyl)quinine), which was employed as
a reference
method, were obtained. The importance of considering dimer formation of DCCA in solution for the com-
putational delineation of absolute configurations was demonstrated by (1R,3R)-cis-DCCA for which the
DG Boltzmann averaged calculated monomeric form delivered the opposite sign of OR compared to
the dimeric form and the value determined experimentally in dichloromethane. For (1S,3R)-trans-DCCA
both monomer and dimer delivered the identical sign of OR and this was in agreement with the exper-
imental measurement. In contrast to OR, the calculated ECD spectra of these two DCCA stereoisomers
were less sensitive toward intermolecular association.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
especially when suitable crystals are difficult to be obtained.3
The most straightforward and reliable approach to deduce infor-
X-ray crystallography is a standard approach for the direct
assignment of absolute configurations of chiral molecules but it
is limited to the solid state.1,2 Based on the substantial improve-
ments in computing capacity and quantum-mechanical calculation
methods, respectively, liquid state spectroscopic approaches such
as electronic circular dichroism (ECD) and optical rotation (OR)
have become increasingly popular alternatives to diffractometry
mation on absolute configurations from ECD or OR measurements
is the confrontation of experimental (configuration not known)
and theoretical (calculated for assumed configuration) data. This
concept has been successfully applied for both configurational
and conformational assignments for a variety of rigid as well as
flexible molecules.4–17 Although the detailed computational
parameters are rather case sensitive, time-dependent density-
functional theory (TDDFT) using B3LYP hybrid functional18 in con-
junction with enhanced basis sets (at least Aug-CC-pVDZ) is com-
monly used and provides a good compromise between accuracy
and computational costs.
* Corresponding authors. Tel.: +43 1 4277 52323; fax: +43 1 4277 9573 (W.B.);
tel.: +48 61 8291367; fax: +48 61 8658008 (K.K).
E-mail addresses: wolfgang.bicker@univie.ac.at (W. Bicker), karol.kacprzak@
gmail.com (K. Kacprzak).
A proper conformational analysis of the target molecule is,
however, a prerequisite for the reliability of this confrontation
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.035

1028
W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
approach. The utmost importance of this step lies in the fact that
even minor changes in molecule conformation can result in a change
of sign and/or magnitude of calculated ECD and OR data9,19–26 thus
bearing considerable risk for wrong assignments. This holds partic-
ularly true for conformationally labile compounds and therefore
the relative energies of the participating conformers should be
calculated with the highest available accuracy.27–29 In addition to
that, the potential occurrence of intermolecular associations has
to be considered as well when computing ECD and OR data.30
The alkene-substituted cyclopropane ring system is a structural
motif in many natural and synthetic compounds, including the nat-
ural pyrethrin-type insecticides and many of their synthetic pyre-
throid analogues.31 The non-substituted cyclopropane ring exhibits
high HOMO energy whereas the LUMO energy is low. It is therefore
Due to the lack of commercial sources for the set of single ster-
eoisomers of DCCA and PM, respectively, a two-step chromato-
graphic method was developed to obtain all four single DCCA
stereoisomers which were converted to the corresponding PM ster-
eoisomers via a simple esterification step. Experimental ECD and
OR data were used to determine absolute configurations via con-
frontation with calculated data. As independent method for verifi-
cation of the correct assignment of absolute configurations, X-ray
diffractometry data from single DCCA stereoisomers co-crystal-
lized with O-9-(2,6-diisopropylphenylcarbamoyl)quinine were
available from an earlier study.42
2. Results and discussion
an expectation that the cyclopropyl ring acts as both a good
p do-
2.1. Preparation of DCCA and PM stereoisomers
Previous work showed that cinchona-based chiral stationary
nor and a good
p
acceptor32 which in case of an alkene substituent
undergoes hyperconjugation to a degree between a saturated and
an unsaturated group. This has been demonstrated, for example,
for the optically active dictyopterenes A and B.33
phases exhibit stereorecognition capabilities for
a variety of
pyrethroic acids. This allows for their enantioselective but also dia-
stereoselective separation by high-performance liquid chromatog-
raphy (HPLC).43
Chiralpak QN-AX and Chiralpak QD-AX (Fig. 1), respectively, al-
lowed baseline separation of all four DCCA stereoisomers in polar-
organic mode under analytical conditions. However, at preparative
scale either loading capacity or stereoisomeric purity had to be sac-
rificed and thus a two-step chromatographic separation was cho-
sen to yield the individual stereoisomers of DCCA.
Systematic studies on the spectroscopic effects of cyclopropane-
substituted alkenes have been published by Poulter.34 Large
bathochromic shifts of 8–15 nm for the
alkene chromophore due to hyperconjugation with the cyclopropyl
ring were observed. Other authors33,35–39 also suggested
p–
p* transition of the
p–
p*
transition as being a major contribution to electronic spectra of
alkene-substituted cyclopropanes including pyrethrins37 in the
short-wavelength region.
In the field of ECD spectroscopy, studies suggested that the
vinylcyclopropane motif is an inherently chiral chromophore, in
which rotation of charge takes place along the bond connecting
the three-membered ring with the double bond.40,41 Thereby, the
sign of the Cotton effect generated by this helically translated
charge is the same as the sign of the acute angle between bisectrix
and double bond.
H
S
silica
(3R)
(4S)
H
N
N (S)
H
O
8
9
X
O
H
In our ongoing work on the chemical42,43 and biological proper-
ties44 of pyrethroid stereoisomers and their (chiral) synthons and
phase I metabolites, respectively, we became interested in charac-
terizing the chiroptical properties of the pyrethroic acid 3-(2,2-
dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA)
1, ent-1, 2, ent-2 and permethrin (PM) 3, ent-3, 4, ent-4, particu-
larly aiming at determination of the absolute configurations of
their individual stereoisomers.
O
CH3
N
Figure 1. Structure of the chiral stationary phases based on O-9-(tert-butylcarba-
moyl)quinine (8S,9R) (trade name: Chiralpak QN-AX) and quinidine (8R,9S) (trade
name: Chiralpak QD-AX), respectively.
In a first step, diastereoselective separation of DCCA was
achieved on a conventional C18 reversed-phase (RP) type stationary
phase in preparative format injecting ca. 50 mg of the cis/trans-
mixture of DCCA per run (Fig. 2a) (Note: cis/trans nomenclature re-
fers to the spatial orientation of the C-3 dichlorovinyl substituent
relative to the C-1 carboxylic acid at the cyclopropane ring of
DCCA). The individual cis-DCCA and trans-DCCA diastereomers
were then successfully resolved into the single enantiomers on
Chiralpak QD-AX (Fig. 2b). Although higher mass loads would have
been tolerated by the employed 250 ꢀ 20 mm ID Chiralpak QD-AX
column, 50 mg of the racemate was injected per run, still yielding
baseline resolution, in order to end up with high enantiomeric ex-
cess (ee).
The overall yield of DCCA stereoisomers after the dual chro-
matographic process was in the range of 80%. According to analyt-
ical RP-HPLC-UV diastereomeric purity was always better than 99%
and no other chemical impurities were detected. Enantiomeric
purity as determined with an analytical Chiralpak QN-AX column
(showing reversed enantiomer elution order compared to the cor-
responding Chiralpak QD-AX column43), was between 99.2% and
99.9% ee for the various DCCA stereoisomers.
H3C CH3
H3C CH3
Cl
Cl
O
3
1
3
1
COOH
Cl
Cl
O
O
1 - cis-(1R,3R)-DCCA
ent - 1-cis-(1S,3S)-DCCA
2 - trans-(1R,3S)-DCCA
3 - cis-(1R,3R)-PM
ent-3 - cis-(1S,3S)-PM
4 - trans-(1R,3S)-PM
ent-2 - trans-(1S,3R)-DCCA
ent - 4-trans-(1S,3R)-PM
Cl
Cl
H3C
H3C
CH3
(1R)
CH3
(1S)
Cl
Cl
(3R)
(3R)
O
O
H
H
O
O
H
O
H
O
O
O
(1'R)
(1'S)
(3'R)
(3'R)
H3C
H3C
Cl
Cl
In a second step, stereoisomers of PM were synthesized from
the stereoisomerically pure DCCA building blocks. Thus, DCCA iso-
mers were reacted with oxalyl chloride to obtain the correspond-
CH
CH
3 Cl
3 Cl
5
6

W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
1029
1
2
a
trans-DCCA
800
600
400
200
0
10
20
10
10
20
cis-DCCA
ent-1
ent-1
ent-2
min
min
ent-2
5
10
15
20
Time,min
10
20
20
1
2
min
min
b
ent-1
ent-2
300
200
Figure 3. Enantiomeric purity of PM stereoisomers as determined by HPLC-UV
analysis on Chiralpak QN-AX after alkaline hydrolysis to the corresponding DCCA
stereoisomers. Diastereomeric purity of PM stereoisomers was independently
checked by RP-HPLC-UV. Chromatograms in gray color show the reference
separation of the DCCA stereoisomer mixture (cis/trans-ratio approximately
40:60). Chromatographic conditions are given in Section 4.
1
2
100
0
2.3. Assignment of absolute configurations of DCCA by ECD and
OR data
2.3.1. Experimental determination
10
20
30
40
DCCA and PM contain a number of distinctly different chro-
mophores. In case of DCCA these are the gem-disubstituted vinyl
motif, the cyclopropane ring, and the carboxylic group. Both the
carboxylic acid and the vinyl functionality are directly attached to
the cyclopropane ring allowing their mutual electronic interactions.
In the case of PM an additional aromatic moiety is present. Except
the cyclopropane ring itself, in the selected wavelength range of
185–300 nm all these chromophores exhibit UV and consequently
CD absorption in a similar spectral region which was thought to de-
liver complex UV and ECD spectra with overlapping transition
bands. The experimental findings are summarized in Table 1.
UV spectra of cis-DCCA and trans-DCCA showed a high degree of
similarity in the two selected solvent systems of contrasting polar-
ity (acetonitrile; cyclohexane + 5% v/v 1,2-dichloroethane) with an
absorption maximum around 215 nm. For PM the additional con-
tribution from the 3-phenoxybenzyl chromophore was evident.
Thereby, cis-PM enantiomers 3 and ent-3 gave slightly lower molar
absorption coefficients in short-wavelength region compared to
trans-PM enantiomers 4 and ent-4.
Time,min
Figure 2. Preparative separation of (a) DCCA diastereomers on a Purospher Star RP-
C18ec column and (b) cis-DCCA (red, solid line) and trans-DCCA (blue, dashed line)
enantiomers, respectively, on a Chiralpak QD-AX column (overlay of two separate
runs with the individual diastereomers). Chromatographic conditions are given in
Section 4.
ing acid chlorides. These intermediates were then esterified with
an excess of 3-phenoxybenzyl alcohol and were purified chromato-
graphically by preparative RP-HPLC. The PM stereoisomers were
obtained in 63–70% yield and the analytical control by RP-HPLC-
UV showed that diastereomeric impurities amounted to less than
0.1%. Absence of racemization at either of the two chiral centers
during synthesis was verified by quantitative hydrolysis of PM
stereoisomers in alkaline medium and subsequent diastereoselec-
tive and enantioselective chromatography of the DCCA stereoiso-
mers formed (Fig. 3).
In acetonitrile cis-DCCA enantiomer 1 showed a bisignate Cot-
2.2. Assignment of absolute configurations of DCCA by X-ray
crystallography
ton effect located at 213 nm (
De = +13.2) and at 187 nm
(D
e
= ꢁ10.6). In cyclohexane only long-wavelength Cotton effects
were observed due to the lower UV transparency of this solvent.
X-ray diffractometry of co-crystals of all four DCCA stereoiso-
mers with O-9-(2,6-diisopropylphenylcarbamoyl)quinine, a chiral
selector previously found to exhibit higher enantioselectivity to-
ward DCCA stereoisomers compared to O-9-(tert-butylcarba-
moyl)quinine,43 allowed the unequivocal assignment of absolute
configurations for DCCA. In addition to that, the data gave valuable
insight into the chiral recognition mechanism between this guest
molecule and the chiral selector host. Detailed results of this com-
prehensive study, which besides X-ray crystallography consisted
also of 1H NMR and thermodynamic experiments as well as com-
putational investigations, were subjects of a previous communica-
tion.42 In the present work the X-ray data served as reference
method for the determination of absolute configurations of DCCA
by ECD and OR (vide infra).
The first one appeared at 242 nm with a small positive amplitude
(D
e
= +0.5) while the second one had almost identical characteris-
tics to those observed in acetonitrile and was located at 213 nm
= +14.0). The opposite cis-DCCA enantiomer ent-1 showed sim-
(De
ilar locations of Cotton effects and these were in virtually perfect
mirror–image relationships to 1 with regard to signs and ampli-
tudes. This expected trend was also present for the second enantio-
meric pair of DCCA and the two PM enantiomer pairs (vide infra).
trans-DCCA enantiomers
2 and ent-2 delivered a weak
long-wavelength Cotton effect at ca. 240 nm and a broadened
short-wavelength transition at ca. 200 nm of lower amplitude in
acetonitrile. In cyclohexane, the long-wavelength Cotton effect
showed a hypsochromic shift by 7–9 nm and an almost fivefold
increase of the amplitude whereas the short-wavelength band

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W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
Table 1
tonitrile. In cyclohexane Cotton effects at 222 nm (
205 nm ( = +8.7) as well as a small long-wavelength transition at
263 nm (
= ꢁ0.2) were observed.
D
e
= ꢁ12.1) and
Experimental ECD and UV data for DCCA and PM stereoisomers
D
D
e
e
Compound
Acetonitrile
(nm) ECD,
Cyclohexanea
(nm) UV, e (nm)
This experimental series revealed that the enantiomeric forms
of 1–4 can be easily differentiated with the aid of ECD spectros-
copy. The esterification of DCCA with 3-phenoxybenzyl alcohol
does not change the principal ECD properties of the resulting PM
stereoisomers. Furthermore, the locations of major diagnostic Cot-
ton effects as well as their signs and, in most cases, their ampli-
tudes were not significantly influenced by the type of solvent
and this held true for both DCCA and PM.
ECD,
D
e
D
e
(nm)
ECD,
D
e
1
12,000 (214)
8100 (186)
+0.5 (242)
+13.2 (213)
+14.0 (213)
11,600 (213)
ꢁ10.6 (186)
ent-1
ꢁ0.5 (241)
ꢁ13.0 (213)
ꢁ14.2 (213)
+10.8 (187)
2
ꢁ0.8 (238)
12,500 (213)
ꢁ3.9 (231)
12,000 (215)
+6.6 (200)
+7.8 (205)
Due to the complex nature of the vinylcyclopropane chromo-
phore the origins of the observed transitions are not entirely clear.
Nevertheless, some general conclusions can be deduced. The
short-wavelength absorption in UV and ECD spectra presumably
ent-2
+0.8 (241)
ꢁ6.6 (201)
+4.0 (232)
ꢁ7.6 (206)
3
1900 (273)
48,800 (197)
52,000 (190)
ꢁ1.6 (230)
ꢁ1.9 (226)
+8.9 (209)
1800 (273)
15,000 (215)
38,700 (205)
originates from
p–
p* transition of the dichlorovinylcyclopropane
+10.7 (210)
chromophore, although many other transitions of lower intensity
may contribute to the absorption spectrum in this region as well.
On the other hand, the small long-wavelength Cotton effects in
the range of 230–240 nm, which were strongly affected by solvent
ꢁ4.1 (189)
ent-3
+1.4 (232)
+1.7 (225)
ꢁ8.6 (208)
ꢁ10.6 (210)
polarity, may be assigned to n–p
* transitions in chlorine atoms. The
+1.0 (188)
long-wavelength band observed for 4 and ent-4 in cyclohexane
at 263 nm originates from the 1Lb transition of the aromatic
chromophore.
With respect to OR measurements all four DCCA stereoisomers
gave specific OR values of about 40° at the sodium D line
(589.3 nm) in dichloromethane and they increased significantly
when going to shorter wavelengths (Table 2).
Due to the presence of two stereogenic centers in DCCA it is evi-
dent that the sign of OR is an insufficient stereochemical descriptor
to pinpoint the identity of the stereoisomers at least as long as no
information on the diastereomeric type (cis or trans) is available.
4
1500 (278)
1600 (272)
39,000 (203)
50,000 (189)
ꢁ0.2 (263)
ꢁ12.1 (222)
+8.7 (205)
1800 (273)
17,000 (230)
43,600 (202)
ꢁ10.5 (222)
+16.3 (197)
ent-4
+0.2 (262)
+12.4 (221)
ꢁ8.9 (205)
+8.8 (222)
ꢁ13.9 (195)
a
Containing 5% (v/v) 1,2-dichloroethane.
was bathochromically shifted by 5 nm accompanied by an increase
in the amplitude by ca. 20%.
cis-PM enantiomer 3 delivered two Cotton effects of opposite
2.3.2. Computational determination and confrontation with
experimental data
sign in acetonitrile, one positive at 210 nm (
D
e
= +10.7) and one
negative at 189 nm (
D
e
= ꢁ4.1). In cyclohexane, additional nega-
In order to correlate experimental ECD spectra and OR data with
absolute configurations extensive theoretical studies on structure–
chiroptical properties relationships were performed for DCCA. The
considerably higher structural complexity of PM did not allow us
to carry out ab initio calculations within a reasonable timeframe.
Absolute configurations of PM were, however, available as the syn-
thesis route employed for PM was carried out under preservation
of the absolute configurations of the single stereoisomer DCCA
synthons.
tive broad long-wavelength Cotton effects at ca. 230 nm were ob-
served for 3. This broad band showed at least two distinct
maxima at 226 and 230 nm with amplitudes of ꢁ1.9 and ꢁ1.6,
respectively. The major transition of 3 in cyclohexane, was similar
to that in acetonitrile, located at 209 nm and also showed compa-
rable amplitude (De = +8.9).
Opposed to the findings for 3, trans-PM enantiomer 4 gave Cot-
ton effects at 222 nm (
D
e
= ꢁ10.5) and 197 nm (De = +16.3) in ace-
Table 2
OR values calculated at the TDDFT/B3LYP/Aug-CC-pVDZ level for 1, 5, ent-2, and 6 and measured in dichloromethane for 1, ent-1, 2, and ent-2 (c = 1.5, T = 293 K)a
Compound
Conformer
Calculated specific OR (°)
Measured specific ORa (°)
589 nm
546 nm
436 nm
365 nm
589 nm
546 nm
436 nm
365 nm
1
A
B
ꢁ38
ꢁ23
ꢁ38
ꢁ47
ꢁ32
ꢁ47
ꢁ93
ꢁ58
ꢁ93
ꢁ181
ꢁ106
ꢁ181
+36
+45
+91
+177
D
G Boltzmann averaged
5
A–A
A–B
ꢁ36
+213
+74
ꢁ63
ꢁ126
+645
+213
ꢁ249
+1215
+395
+336
+113
D
G Boltzmann averaged
ent-1
2
ꢁ38
+40
ꢁ39
ꢁ47
+49
ꢁ47
ꢁ93
+91
ꢁ87
ꢁ181
+155
ꢁ149
ent-2
A
B
ꢁ38
+37
ꢁ32
ꢁ63
+63
ꢁ54
ꢁ121
+133
ꢁ103
ꢁ223
+290
ꢁ187
D
G Boltzmann averaged
6
A–A
A–B
B–B
+32
ꢁ121
+99
ꢁ8
+53
+109
ꢁ384
+342
ꢁ20
+231
ꢁ719
+716
ꢁ16
ꢁ198
+167
ꢁ13
D
G Boltzmann averaged
a
Measured OR values were not normalized to 100% ee.

W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
1031
Computational analyses included (i) conformational analysis,
(ii) geometry optimization of each low-energy conformer, (iii) cal-
culation of the rotational strength and OR for individual stable con-
Systematic conformational searches were performed taking
absolute configurations of (1R,3R) for 1 and (1S,3R) for ent-2,
respectively, as starting points (absolute configurations as derived
from an X-ray crystallography study, vide supra). Due to the pres-
ence of the cyclopropane motif, DCCA is a relatively rigid molecule.
Thus, its conformational dynamics are practically limited to the
rotation of the gem-dichlorovinyl and the carboxylic acid group.
Conformational analysis of monomeric 1 and ent-2 was carried
out at the B3LYP/6-31G(D)//MM level followed by construction of
the corresponding potential energy surface. Next, full structure
optimizations at the B3LYP/6-311++G(2D,2P) level of theory were
performed for the energy minima found on the potential energy
surface. The results obtained for monomeric forms were used as in-
put parameters in conformational analyses of dimers 5 and 6, for
which full structure optimizations at the B3LYP/6-311++G(2D,2P)
level were also carried out. The final stage involved frequency cal-
culations (B3LYP/6-311++G(2D,2P) level) for all optimized struc-
tures to confirm their stability. Percentage populations of
conformers with relative energies of 0–2 kcal molꢁ1 were calcu-
formers, and (iv) comparison between
DG Boltzmann averaged
calculated ECD spectra and calculated OR values with the experi-
mental data.
DCCA may exist either as monomeric or as dimeric species
whereby the equilibrium is likely to be strongly affected by the
polarity of solvent. Dimerization may dramatically change the chir-
optical properties of chiral molecules.30 Therefore the computa-
tional study was carried out for 1 and ent-2 as well as for
dimeric forms 5 and 6, which were derived from monomeric 1
and ent-2.
lated for
DG values using Boltzmann statistics (T = 298 K).
The structures of low-energy conformers of 1, ent-2, 5, and 6 are
depicted in Figure 4.
As expected, only a small number of low-energy conformers
were found. These conformers belong to two groups A and B which
differ only in the orientation of the carboxylic group (A H–C*–C@O
anti, B H–C*–C@O syn). For 1 a single conformer A was identified as
the dominant one as the second conformer B is over 2 kcal molꢁ1
higher in energy (Table 3). On the other hand, ent-2 can exist as
one major A (93% abundance) and one minor B (7% abundance)
conformer.
The calculated low-energy conformers of 1 and ent-2 were used
for construction of a set of possible dimers consisting of A–A, A–B,
or B–B combinations. Common structural feature of A-type con-
formers is the anti conformation of the carboxylic group and the
syn conformation of the vinyl substituent (defined correspondingly
by H–C*–C@O and H–C–C@C angles). In contrast, the syn conforma-
tions of both the vinyl and the carboxylic substituents were found
to be the less abundant B-type conformers. The corresponding val-
ues of acute angles between appropriate cyclopropane bisector and
C@O or olefinic bonds ranged from ꢁ4.5° to +35° (Table 3). These
structural features of monomeric species were consequently seen
in the corresponding dimeric counterparts as well.
Both anti and syn conformations of carboxylic and gem-dichlo-
rovinyl groups allowed for the interaction between degenerated
Figure 4. (a) Structures of individual conformers of monomeric 1 and ent-2 and
dimers 5 and 6 each calculated at the B3LYP/6-311++G(2D,2P) level. (b) Definition
of acute angle between the cyclopropane bisector and the olefinic double bond. The
transoid cyclopropane is drawn with bold lines, the cisoid with dashed lines.
Walsh orbitals of the cyclopropane ring and
p-electrons of these
Table 3
Relative energies (DG) and populations as well as torsion (a, c) and dihedral (b, d) angles for low-energy conformers of 1, ent-2, 5, and 6 calculated at the B3LYP/6-311++G(2D,2P)
level
Compound
Conformer
D
G (kcal molꢁ1
)
Population (%)
Angle (°)
aa
bb
cc
dd
1
A
B
0.00
2.48
100
—
174.7
ꢁ6.7
ꢁ3.4
9.1
3.8
5.6
0.8
5.6
ent-2
A
B
0.00
1.47
93
7
ꢁ167.7
10.0
35.1
2.9
3.9
2.5
ꢁ0.6
4.8
3.3, 0.3
16.3
5
6
A–Ae
A–B
0.00
0.14
56
44
174.1
174.6, ꢁ6.2
ꢁ4.5
8.6
7.3, 4.0
ꢁ3.4, 5.0
A–Ae
A–B
0.00
0.51
1.75
68
28
4
ꢁ168.4
9.3
32.0, 9.7
32.2
5.5
5.5, 4.6
5.7
0.2
0.8, 0.9
0.9
13.2, ꢁ168.1
19.4
B–Be
a
a
= H–C1–C@O.
b = acute angle between cyclopropane bisector and C@O bond.
= H–C3–C@C.
b
c
c
d
e
d = acute angle between bisector and C@C bond, for definition see Figure 4b.
C2 symmetry.

1032
W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
substituents.45–47 The hydrogen bond formation between the car-
bonyl oxygen and the hydrogen atoms of the olefinic (1(A)) or
one of the methyl ent-2(A) groups as well as a dipole–dipole inter-
action between the C@O and C*–H bonds can contribute further to
stabilization of the respective conformers. Surprisingly, the dipole–
dipole interaction between C@O and C*–H bonds does not seem to
play a crucial role in the case of the monomeric conformers of
DCCA. This is opposite to the dimers 5 and partially also 6 and
stands also in contrast to the results obtained for tartaric acid
and its derivatives.48 For example, 5(A–B) dimer is slightly less
abundant than 5(A–A), while the energy difference between the
conformers of 5 is negligible. The lengths of hydrogen bonds con-
necting two monomeric moieties ranged from 1.677 Å to 1.702 Å,
thus indicating strong bonding.
accordance with the data delivered by X-ray diffractometry (vide
supra).
The origin of the Cotton effect of DCCA occurring at ca. 220 nm
is the electronic transition involving mainly HOMO and LUMO
orbitals (
p–p
*), whereas transitions between HOMO and higher
antibonding orbitals are responsible for the second shorter wave-
length Cotton effect (Fig. 6).
The sign of the long-wavelength Cotton effect is, however, diffi-
cult to rationalize if only structural parameters of DCCA are consid-
Oscillator and rotatory strengths (TDDFT/B3LYP/6-311++G(2D,
2P) level) and OR values (TDDFT/B3LYP/Aug-CC-pVDZ level) were
calculated for thermally accessible conformers of 1, ent-2, 5, and
6. Figure 5 depicts overlays of calculated (1, 5, ent-2, and 6) and
measured (1, ent-2; both in acetonitrile) ECD spectra.
A reasonable overall agreement was found between the exper-
imental and computed signs of Cotton effects. For 1 a very good
reproduction was obtained with respect to both the positions of
the Cotton effects and their relative amplitudes. For ent-2 a less
than perfect agreement was found which, however, still allowed
unambiguous correlation of experimental and calculated short
and long-wavelength Cotton effects. Calculated ECD spectra for
the dimeric structures 5 and 6 were generally of higher amplitudes
while the sign of the Cotton effect around 220 nm was in all cases
positive and thus matched with experimental ECD data. Therefore
the confrontation of measured and calculated ECD data conve-
niently allowed the unequivocal assignment of absolute configura-
tions for DCCA stereoisomers and this assignment was fully in
Figure 6. Molecular orbitals involved in the electronic transitions of 1.
Figure 5. (a) Experimental (acetonitrile solution, solid lines, left column) and
lines, left column) and 5 (dash-dotted lines, left column). (b) Experimental (acetonitrile solution, solid lines, right column) and
D
G calculated Boltzmann averaged UV (upper panel) and ECD (lower panel) spectra of 1 (dashed
G Boltzmann averaged UV (upper panel) and
D
ECD (lower panel) spectra of ent-2 (dashed lines, right column) and 6 (dash-dotted lines, right column). Calculations were performed at the TDDFT/B3LYP/6-311++G(2D,2P)
level and spectra were wavelength corrected to match experimental long-wavelength kmax values.

W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
1033
ered (Fig. 4b). For example, the acute angle between the bisector of
the cyclopropane ring and the C@C bond of 1(A) is positive, and the
angle between the bisector and the C@O bond is negative while the
situation is completely different for ent-2(A). Yet, in both cases the
individual PM stereoisomers could also be successfully assigned.
Such unambiguous information on absolute configurations of bio-
logically/toxicologically relevant chiral compounds (PM being a
chiral pyrethroid-type pesticide, and DCCA being a mammalian
phase I metabolite and environmental degradation product of
PM) is central to the correct identification of stereoselectivity in
fate and effect profiles and thus forms the basis for valid risk
assessment.
calculated rotatory strength for the
p–
p* long-wavelength elec-
tronic transition is positive. Thus, the validity of the empirical rule
proposed by Snatzke41 needs further clarification.
Calculated OR values of DCCA stereoisomer ent-2 and its dimer
6 well reproduced the experimental data and thus confirmed the
assumed absolute configurations (Table 2). Regarding absolute
OR values, the calculation for ent-2 better reflected the experimen-
tal data. Possibly, the population of 6(A–B), which is responsible
for the net negative calculated ORs values for 6, was simply under-
estimated. However, a disagreement between calculated and
experimental OR data was found for monomeric enantiomer 1. This
may be due to the fact that in a non-polar environment (such as
dichloromethane) monomer 1 predominantly exists as dimer 5.
4. Experimental
4.1. Chemicals
A cis/trans-DCCA stereoisomer mixture consisting of about 40%
cis-DCCA and about 60% trans-DCCA was kindly provided by Agro-
Chemie (Budapest, Hungary). Both oxalyl chloride and 3-phen-
oxybenzyl alcohol were supplied from Fluka (Buchs, Switzerland)
in purum grade. Acetic acid (AcOH), dichloromethane (DCM)
(both Fluka), N,N-dimethylformamide (Aldrich, Vienna, Austria),
formic acid (Riedel de Haën, Seelze, Germany), 1-heptane (Fisher
Scientific, Loughborough, UK), hydrochloric acid (Merck, Darms-
tadt, Germany), potassium hydroxide, tert-butyl methyl ether
(TBME) (both Riedel de Haën), phosphoric acid (Merck), pyridine
(Aldrich), sodium sulfate (Fluka), and triethyl amine (TEA) (Fluka)
were of analytical grade. Acetonitrile (ACN), methanol (MeOH)
(both Fisher Scientific), and water (Sigma–Aldrich) were of HPLC
grade. For UV and ECD measurements acetonitrile, cyclohexane,
and 1,2-dichloroethane of spectroscopic grade (all Aldrich) were
used.
D
G Boltzmann averaged ORs of 5 calculated for the gas phase,
are in accordance with the experimental data thus supporting this
hypothesis.
3. Conclusions
The present approach to prepare PM stereoisomers in high ee
via the DCCA intermediate can be extended to other pyrethroids
as also cypermethrin and cyfluthrin contain the DCCA moiety. Fur-
ther, the cinchona-type chiral stationary phases employed are
capable of resolving stereoisomers of chrysanthemic acid and fen-
valeric acid as well,43 both of which are also pyrethroid synthons.
This gives access to individual isomers of other pyrethroids by the
same methodology. The individual PM stereoisomers prepared
within this work were required for toxicological studies directed
at the elucidation of stereoselectivity in the biological behavior
of this widely used chiral insecticide.44
The chiroptical approach employed to determine absolute con-
figurations via measured and calculated ECD and OR data was suit-
able for the stereochemical assignment of DCCA. Prerequisites are,
however, a thorough conformational analysis and the consider-
ation of (solvent-dependent) inter-molecular association which
may influence the results considerably. The reliability of this con-
frontation approach was proven by reference data from X-ray
crystallography.
Knowledge on the absolute configurations of DCCA allowed der-
ivation of elution orders of DCCA stereoisomers on the employed
Chiralpak QN-AX and Chiralpak QD-AX columns, thereby providing
a chromatographic reference method for other studies. Under the
conditions employed in Figure 3, the elution order on Chiralpak
QN-AX was (1R,3R)-cis-DCCA < (1R,3S)-trans-DCCA < (1S,3S)-cis-
DCCA < (1S,3R)-trans-DCCA. It is worth noting that the order of
elution may be altered for the diastereomers upon a change of
the elution conditions such as organic modifier type and content,
pH or temperature. In particular the (1R,3S)-trans-DCCA and
(1S,3S)-cis-DCCA isomers (middle peak pair) tend to co-elute under
specific conditions or may even reverse their order of elution. In
contrast, the enantiomer elution order was never found to be re-
versed under the elution conditions tested previously (polar organ-
ic and hydroorganic conditions with either methanol or
acetonitrile as polar solvent and organic modifier, respectively).43
On the other hand, the enantiomer elution order can conveniently
be reversed by a switch to the corresponding Chiralpak QD-AX col-
umn, viz. (1S,3S)-cis-DCCA < (1R,3R)-cis-DCCA and (1S,3R)-trans-
DCCA < (1R,3S)-trans-DCCA.43
4.2. Instrumentation
Analytical HPLC runs were carried out on a HP1090 system from
Agilent (Waldbronn, Germany) equipped with a diode array detec-
tor. Liquid chromatography in preparative scale was performed on
a HPLC system from Bischoff Chromatography (Leonberg, Ger-
many) (pump module: HPD pump multitherm 200 XL, UV-detec-
tor: Lambda 1010). 1H NMR spectra were acquired on a Bruker
DRX spectrometer with an operating frequency of 400 MHz (Bru-
ker Optics, Vienna, Austria). For mass spectrometric measurements
an API 365 triple–quadrupole system (Applied Biosystems, Thorn-
hill, Canada) interfaced with a pneumatically assisted electrospray
ionization source was used. OR values were determined with a
polarimeter model 341 from Perkin Elmer (Vienna, Austria). UV
and ECD spectra were recorded using a J-700 spectropolarimeter
from Jasco Inc. (Easton, MD).
4.3. Preparation of DCCA stereoisomers
4.3.1. Diastereoselective preparative liquid chromatography of
cis/trans-DCCA
A 50 mg mLꢁ1 solution (1.0 mL) of cis/trans-DCCA in ACN/water/
MeOH (50:50:0.1; v/v/v) was injected onto a 150 ꢀ 16 mm ID
10 lm Purospher Star RP-C18ec column (Merck, Darmstadt, Ger-
many; packed by Austrian Research Centers, Seibersdorf, Austria)
which was kept at 25 °C. Elution was carried out in isocratic mode
at 10 mL minꢁ1 with ACN/water/phosphoric acid (40:60:0.1; v/v/v)
(detection wavelength 240 nm). After injection of total 2.5 g cis/
trans-DCCA the combined fractions of each diastereomer
(ktrans = 8.9; kcis = 12.0) were concentrated at 35 °C under reduced
pressure to remove ACN. The residual aqueous phases were ex-
tracted with 2 ꢀ 50 mL TBME. After drying the organic phase with
sodium sulfate cis- and trans-DCCA were isolated by evaporation of
the volatile fraction followed by drying at 10 mbar for 24 h at
ambient temperature.
Since the PM stereoisomers were obtained from DCCA stereo-
isomers by chemical transformation with preservation of the con-
figurations, the absolute configurations of the synthesized

1034
W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
4.3.2. Enantioselective preparative liquid chromatography of
cis- and trans-DCCA
cis- and trans-DCCA (each 0.55 g), respectively, prepared as re-
ported above, was dissolved at a concentration of 100 mg mLꢁ1
in ACN containing 20 mM AcOH and 2.5 mM TEA. This solution
DCM); (1S,3S)-cis-PM ent-3: 70% yield; >99.95% diast. purity,
20
20
20
20
99.6% ee,
½
a
ꢂ
¼ ꢁ22:5,
½
a
ꢂ
¼ ꢁ10:4,
½
a
ꢂ
¼ ꢁ4:6,
½
a
ꢂ
¼
365
436
546
589
ꢁ3:7 (c 1.5, DCM); (1R,3S)-trans-PM 4: 63% yield; 99.94% diast.
20 20 20
purity, 99.3% ee,
½aꢂ
¼ ꢁ45:3,
½aꢂ
¼ ꢁ20:5,
½a
ꢂ
¼ ꢁ9:6,
365
436
546
20
589
½aꢂ
¼ ꢁ8:0 (c 1.5, DCM); (1S,3R)-trans-PM ent-4: 69% yield;
20 20
365
(0.5 mL) was injected onto a 250 ꢀ 20 mm ID 10
l
m Chiralpak
>99.95% diast. purity, 99.8% ee, ½
a
ꢂ
¼ þ46:7, ½
a
ꢂ
¼ þ21:3,
436
20
546
20
589
QD-AX column (Chiral Technologies Europe, Illkirch, France) which
was kept at 25 °C. Isocratic elution was performed at 20 mL minꢁ1
with 20 mM AcOH and 2.5 mM TEA in ACN (detection wavelength
½aꢂ
¼ þ10:3, ½
aꢂ
¼ þ8:4 (c 1.5, DCM).
240 nm).
k
A
crude product of each enantiomer (cis-DCCA:
4.5. Chromatographic purity assessment
(1S,3S) = 8.1, k(1R,3R) = 10.0; trans-DCCA: k(1S,3R) = 9.0, k(1R,3S) = 11.1)
was obtained after evaporation of the volatile fraction. Treatment
with 30 mL of 1% aqueous phosphoric acid, extraction with
2 ꢀ 25 mL 1-heptane, and evaporation of the latter phase afforded
the individual DCCA stereoisomers as white crystals, which were
finally dried at 10 mbar for 24 h at ambient temperature.
Each of the four stereoisomers of DCCA and PM were checked
chromatographically for chemical and diastereomer purity with a
150 ꢀ 4.6 mm ID 10
lm Purospher Star RP18ec (Merck) column.
For DCCA isocratic elution was performed at 25 °C and
1.0 mL minꢁ1 with ACN/water/phosphoric acid (40:60:0.1; v/v/v),
while PM was analyzed with ACN/water/phosphoric acid
(80:20:0.1; v/v/v) under otherwise identical conditions. Then
cis-DCCA: 1H NMR (400 MHz, CDCl3): 6.21 (d, 1H), 2.10 (t, 1H),
1.85 (d, 1H), 1.28 (s, 3H), 1.27 (s, 3H) ppm; ESI-MS: 207.0 [MꢁH]ꢁ;
trans-DCCA: 1H NMR (400 MHz, CDCl3): 5.62 (d, 1H), 2.27 (dd, 1H),
10 l
L of a 2 mg mLꢁ1 solution of DCCA and a 4 mg mLꢁ1 solution
1.62 (d, 1H), 1.33 (s, 3H), 1.21 (s, 3H) ppm; ESI-MS: 207.0 [MꢁH]ꢁ;
of PM, respectively, were injected and peak monitoring was carried
out at 230 nm.
20
365
(1R,3R)-cis-DCCA 1: 99.1% diast. purity, 99.8% ee, ½
aꢂ
¼ þ176:6,
20
436
20
546
20
589
½
aꢂ
¼ þ90:7,
½aꢂ
¼ þ45:3,
½a
ꢂ
¼ þ36:5 (c 1.5, DCM);
Determination of ee of DCCA stereoisomers was performed by
stereoselective liquid chromatography with a 150 ꢀ 4 mm ID
20
365
(1S,3S)-cis-DCCA ent-1: 99.1% diast. purity, 99.2% ee, ½
aꢂ
¼
20
436
20
546
20
589
ꢁ181:3,
½
aꢂ
¼ ꢁ93:1,
½a
ꢂ
¼ ꢁ46:6,
½aꢂ
¼ ꢁ38:0 (c 1.5,
5 lm Chiralpak QN-AX (Chiral Technologies Europe) column. The
DCM); (1R,3S)-trans-DCCA 2: >99.95% diast. purity, 99.2% ee,
flow rate was adjusted to 0.8 mL minꢁ1 and stereoselective
separation was carried out with ACN/MeOH/AcOH (95:5:0.1;
20
365
20
436
20
546
20
589
½aꢂ
¼ þ154:7, ½
a
ꢂ
¼ þ90:6, ½
a
ꢂ
¼ þ49:2, ½
aꢂ
¼ þ40:3 (c
1.5, DCM); (1S,3R)-trans-DCCA ent-2: >99.95% diast. purity,
v/v/v) at 25 °C (detection wavelength: 230 nm). Then, 10 lL of a
20
365
20
436
20
546
20
589
99.8% ee, ½
aꢂ
¼ ꢁ148:7, ½
aꢂ
¼ ꢁ86:9, ½
aꢂ
¼ ꢁ47:0, ½
aꢂ
¼
2 mg mLꢁ1 solution of the individual DCCA stereoisomers was
injected.
ꢁ38:8 (c 1.5, DCM).
To confirm the absence of racemization in the course of esteri-
4.4. Preparation of PM stereoisomers
fication, 2 mg of each PM stereoisomer was dissolved in 200
lL
ACN. Aqueous potassium hydroxide solution (500 L 2 M) was
l
At first, 150 mg (0.72 mmol) of the respective chromatographi-
cally purified DCCA stereoisomer was dissolved in 5 mL DCM. After
added and quantitative hydrolysis was yielded by incubating the
reaction mixture at 40 °C for 24 h. Afterwards, the ACN was re-
moved with a gentle stream of nitrogen and DCCA was obtained
addition of 150
lL oxalyl chloride (2.16 mmol) the reaction
mixture was stirred at 25 °C for 2 h under nitrogen. Then 10
lL
by extraction of the acidified aqueous phase (addition of 100
lL
N,N-dimethylformamide was added and stirring was continued
for further 14 h. The volatile fraction was then carefully removed
by evaporation and dried for 1 h at 40 °C and 10 mbar. The remain-
ing oil was dissolved in 8 mL DCM followed by the addition
concentrated hydrochloric acid) with 500 L TBME. After removal
l
of the volatile fraction with a gentle stream of nitrogen the residual
DCCA was analyzed by stereoselective HPLC under the above
specified conditions for DCCA ee determination using Chiralpak
QN-AX.
of 250 lL 3-phenoxybenzyl alcohol (1.43 mmol) and 65 lL
(0.80 mmol) pyridine. The mixture was stirred at ambient temper-
ature and anhydrous conditions for 6 h. After evaporation the
residual product was treated with 2 ꢀ 5 mL TBME and the precip-
itated pyridine chloride salt was removed by filtration. The volatile
fraction was evaporated and the residual oil was dissolved in
7.5 mL ACN/water/phosphoric acid (80:20:0.1; v/v/v). Chromato-
graphic purification was carried out by injecting 1.5 mL fractions
onto the preparative Purospher Star RP-C18ec column (vide supra)
and isocratic elution at 10 mL minꢁ1 with ACN/water/phosphoric
acid (80:20:0.1; v/v/v) (detection wavelength 230 nm). The organic
modifier of the collected and combined PM peak fraction was evap-
orated and the oily layer of the remaining aqueous phase was ex-
tracted with 2 ꢀ 25 mL TBME. After drying with sodium sulfate and
evaporation each PM stereoisomer was obtained as colorless oil.
Drying at 10 mbar for 24 h at ambient temperature afforded cis-
PM enantiomers as white crystals whereas trans-PM enantiomers
remained oily. PM stereoisomers were stored at ꢁ20 °C until fur-
ther use.
4.6. X-ray crystallography
All four single DCCA stereoisomers were co-crystallized with
O-9-(2,6-diisopropylphenylcarbamoyl)quinine in chloroform/1-
heptane. Detailed experimental information on the diffractometric
analysis is given in an earlier communication.42 Crystallographic
data (excluding structure factors) for the structures have been
deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Numbers CCDC 665833–665836. Cop-
ies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.7. UV and ECD spectroscopy
All measurements were carried out at an optical pathlength of
1 mm and concentration values of ca. 9 ꢀ 10ꢁ4 M (DCCA) and ca.
3 ꢀ 10ꢁ4 M (PM), respectively. Spectral conditions were as follows:
bandwidth 0.5 nm, scan speed 100 nm minꢁ1, response time 1 s.
Acetonitrile (kmin = 185 nm) and cyclohexane containing 5% (v/v)
1,2-dichloroethane (kmin = 200 nm) were employed as solvents.
All spectra were corrected using the respective blank solvents.
Absorption and ECD spectra were simultaneously reprocessed
using the methodology of Arvinte.49
cis-PM: 1H NMR (400 MHz, CDCl3): 7.38–6.93 (m, 9H), 6.26 (d,
1H), 5.08 (s, 2H), 2.03 (t, 1H), 1.89 (d, 1H), 1.24 (s, 3H), 1.23 (s,
3H) ppm; ESI-MS: 391.1 [M+H]+; trans-PM: 1H NMR (400 MHz,
CDCl3): 7.38–6.94 (m, 9H), 5.60 (d, 1H), 5.10 (s, 2H), 2.26 (dd,
1H), 1.65 (d, 1H), 1.27 (s, 3H), 1.18 (s, 3H) ppm; ESI-MS: 391.1
[M+H]+; (1R,3R)-cis-PM 3: 65% yield; >99.95% diast. purity, 99.7%
20
365
20
436
20
546
20
589
ee, ½
aꢂ
¼ þ19:7, ½
aꢂ
¼ þ8:5, ½
a
ꢂ
¼ þ3:7, ½
a
ꢂ
¼ þ2:6 (c 1.5,

W. Bicker et al. / Tetrahedron: Asymmetry 20 (2009) 1027–1035
12. Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524–2539.
1035
4.8. Computational details
13. Ruud, K.; Stephens, P. J.; Devlin, F. J.; Taylor, P. R.; Cheeseman, J. R.; Frisch, M. J.
Chem. Phys. Lett. 2003, 373, 606–614.
Initial conformational analyses of 1 and ent-2 were performed
by MM3 force field (CaChe Conflex software, Fujitsu Ltd, Tokyo, Ja-
pan. Fifty four conformations for 1 and 63 conformations for ent-2
were obtained, which were optimized using B3LYP hybrid func-
tional and a 6-31g(d) basis set (GAUSSIAN 0350). The conformers with
relative energies between 0 and 5 kcal molꢁ1 were refined using
the same hybrid functional and the enhanced basis set 6-
311++G(2D,2P). Finally, for these structures frequency calculations
were carried out at the B3LYP/6-311++G(2D,2P) level of theory to
establish their stability. For conformers having the relative energy
ranging from 0 to 2 kcal molꢁ1 percentage populations were calcu-
14. Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J.; Bortolini, O.; Besse, P.
Chirality 2003, 15, S57–S64.
15. Autschbach, J.; Ziegler, T.; van Gisbergen, S. J. A.; Baerends, E. J. J. Chem. Phys.
2002, 116, 6930–6940.
16. Grimme, S. Chem. Phys. Lett. 2001, 339, 380–388.
17. Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J. J. Phys. Chem. A 2001,
105, 5356–5371.
18. Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157–167.
19. Kwit, M.; Sharma, N. D.; Boyd, D. R.; Gawronski, J. Chirality 2008, 20, 609–620.
20. Kwit, M.; Sharma, N. D.; Boyd, D. R.; Gawronski, J. Chem. Eur. J. 2007, 13, 5812–
5821.
21. Kundrat, M. D.; Autschbach, J. J. Phys. Chem. A 2006, 110, 4115–4123.
22. Kundrat, M. D.; Autschbach, J. J. Phys. Chem. A 2006, 110, 12908–12917.
23. Pecul, M. Chem. Phys. Lett. 2006, 418, 1–10.
24. Pecul, M.; Ruud, K.; Rizzo, A.; Helgaker, T. J. Phys. Chem. A 2004, 108, 4269–
4276.
lated on the basis of
DE and DG values, using Boltzmann statistics
and T = 298 K. Due to their similarity only
DG values were taken
25. Wiberg, K. B.; Vaccaro, P. H.; Cheeseman, J. R. J. Am. Chem. Soc. 2003, 125, 1888–
1896.
into further considerations.
26. Specht, K. M.; Nam, J.; Ho, D. M.; Berova, N.; Kondru, R. K.; Beratan, D. N.; Wipf,
P., ; Pascal, R. A., Jr.; Kahne, D. J. Am. Chem. Soc. 2001, 123, 8961–8966.
27. Stephens, P. J.; McCann, D. M.; Devlin, F. J.; Smith, A. B., III J. Nat. Prod. 2006, 69,
1055–1064.
Excited-state calculations of 1 and ent-2 using TDDFT (GAUSSIAN
0350) were based on the ground state geometries of single mole-
cules. Calculations of oscillator and rotatory strengths were per-
formed at the B3LYP/6-311++G(2D,2P) level of theory. Rotatory
strengths were calculated using both length and velocity represen-
tations. Due to minor differences between the length and velocity
of calculated values of rotatory strengths only velocity representa-
tions were taken into account. ECD spectra were simulated by
overlapping Gaussian functions for each transition according to
the procedure described previously.12 Specific OR values at 365,
436, 546, and 589 nm were calculated at the B3LYP/Aug-CC-pVDZ
level of theory.
ˇ
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