Chiral sulfinates studied by optical rotation, ECD and VCD: The absolute configuration of a cruciferous phytoalexin brassicanal C

Article abstract of DOI:10.1039/b813437e

The optical rotation, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) of chiral sulfinates have been studied experimentally, and analysed by density functional theory calculation, aiming at establishing a reliable and convenie

Full text of DOI:10.1039/b813437e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Chiral sulfinates studied by optical rotation, ECD and VCD: the absolute
configuration of a cruciferous phytoalexin brassicanal C
a
b
a
a
Tohru Taniguchi, Kenji Monde,* Koji Nakanishi and Nina Berova*
Received 4th August 2008, Accepted 9th September 2008
First published as an Advance Article on the web 16th October 2008
DOI: 10.1039/b813437e
The optical rotation, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) of
chiral sulfinates have been studied experimentally, and analysed by density functional theory
calculation, aiming at establishing a reliable and convenient methodology to determine their absolute
configuration. Through the study on a model chiral sulfinate with known absolute configuration,
(
R)-(+)-methyl p-toluenesulfinate ((R)-(+)-1), each technique was found to be reliable in assigning
chirality of sulfinates. We then applied these methods to a synthetically prepared cruciferous
phytoalexin, brassicanal C ((-)-2), and unambiguously determined its absolute configuration as S. The
advantages and disadvantages of each spectroscopy on sulfinates are also discussed.
Introduction
applicable to sulfinates without an internal reference. Therefore a
versatile methodology to determine sulfinic absolute configuration
is in demand in the realm of chiral sulfur compounds.
Chiral sulfinates have been extensively used as the primary
source for enantiopure sulfur compounds such as sulfoxides and
sulfinamides, which are of considerable importance as bioac-
tive compounds and synthetic intermediates (Scheme 1a). A
number of methods have been developed for the formation
of chiral sulfinates, including diastereoselective synthesis using
In our continuous stereochemical research on natural prod-
ucts, we have studied absolute configurations of several
sulfur-containing cruciferous phytoalexins by using chiroptical
1
8
techniques. Phytoalexins are antimicrobial secondary metabolites
produced de novo in response to various stresses such as pathogenic
invasion and UV light. Since the plant family cruciferae includes
a large number of dietary important crops (cabbage, turnip, rape-
seed, broccoli, cauliflower, mustard, wasabi, etc.), the constituent
2
chiral auxiliaries such as (S)-menthol (Andersen’s sulfinate) and
3
diacetone D-glucose, and enantioselective reactions using chiral
4
catalysts. In contrast, determination of absolute configuration of
sulfinates have relied on only a few approaches, including chemical
conversion to a known sulfoxide using organometallic reagents
and X-ray crystallography based on an internal reference. The
reliability of the former method is limited since the assumption
of the configurational inversion at the chiral sulfur atom was
9
phytoalexins are intimately related to human health. Stereochem-
5
ical studies of these phytoalexins are beneficial in understand-
ing the relationship between chirality and biological activities
6
8a,9a
8c,10
such as antimicrobial
and antitumor activities.
Moreover,
some natural cruciferous phytoalexins have been isolated with
7
found not to be valid in certain cases. Furthermore, conversion
8a,c,11
incomplete enantiomeric purities,
and therefore the analysis
to a known sulfoxide itself becomes demanding when the sulfinic
compound has a complicated structure or reactive functional
groups. The latter technique has no ambiguity, but it is not
of their chiral properties is also informative to elucidate their
complicated biosynthetic pathway. A cruciferous phytoalexin
brassicanal C (2, Scheme 1b) was first isolated from cabbage
8,9
(
Brassica oleracea var. capitata) inoculated with Pseudomonas
12
cichorii in 1991 as an optically active sulfinic natural product.
Pedras et al. recently isolated 2 fromcauliflower (Brassica oleraceae
var. botrytis) irradiated with UV light and confirmed its sulfinic
13
structure by synthesis of racemic (±)-2. However, the absolute
configuration of the naturally occurring (-)-2 has not yet been
assigned due to the lack of an effective method.
Recently, advances in density functional theory (DFT) calcula-
tion of optical activities, such as optical rotation, electronic circu-
lar dichroism (ECD) and vibrational circular dichroism (VCD),
have opened the way for nonempirical determination of absolute
Scheme
1
(a) The structure of a representative chiral sulfinate,
(
R)-(+)-methyl p-toluenesulfinate ((R)-(+)-1); (b) The structure of a sulfinic
cruciferous phytoalexin, (S)-(-)-brassicanal C ((S)-(-)-2).
14
configuration of a broad range of chiral molecules. Among them,
VCD spectroscopy is the most reliable and informative due to the
number of well-isolated signals and the higher accuracy of the
calculation of vibrational transitions; however, the requirement of
milligram-level sample and the rarity of VCD instruments have
restricted the accessibility of this technique. On the other hand,
optical rotation and ECD spectroscopies are more commonly
used owing to their higher sensitivity and accessibility, although
a
Department of Chemistry, Columbia University, New York, NY, 10027,
USA. E-mail: ndb1@columbia.edu; Fax: +1-212-932-1289; Tel: +1-212-
8
54-3934
b
Graduate School of Advanced Life Science, Frontier Research Center
for Post-Genome Science and Technology, Hokkaido University, N21W11,
Sapporo, 001-0021, Japan. E-mail: kmonde@glyco.sci.hokudai.ac.jp;
Fax: +81-11-706-9042; Tel: +81-11-706-9041
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assignments rely on a small number of signals. Although optical
rotation, ECD and VCD have recently been used for nonempirical
was confirmed to have >98%ee by chiral HPLC. The first-eluted
enantiomer of 1 was found to exhibit positive optical rotation ((+)-
15
◦
17
◦
determinations of chirality of sulfoxides and sulfinamides, their
application to sulfinates has been limited to a few empirical
1, [a]
D
+184 (c 0.2; EtOH); lit. [a]
D
+220 (c 3.23; EtOH)), while
the first-eluted enantiomer of 2 was identified as the levorotatory
2a,5a
7,16
◦
12
approaches based on optical rotatory dispersion
and ECD,
enantiomer ((-)-2, [a]
(c 1.04; MeOH)). Interestingly, brassicanal C isolated earlier was
levorotatory, but with a much smaller [a] value than the optically
pure (-)-2, indicating poor stereoselectivity in its biosynthesis, as
D
-231 (c 0.2; MeOH); lit. [a]
D
-13.3
while there is no nonempirical stereochemical study on them. In
the present study, we have conducted optical rotation, ECD and
VCD measurements of the sulfinates shown in Scheme 1 and
their theoretical calculation using DFT, aimed at establishing
a convenient and reliable method to assign sulfinic absolute
configurations. There is no previous DFT studies on optical
activities of sulfinates, and therefore we first applied these three
techniques to a sulfinic compound of known chirality, (R)-(+)-
D
8
a,c,11
observed in other cruciferous phytoalexins.
Conformational analysis of (R)-1 and (S)-2
Prior to the calculation of chiroptical properties of 1 and 2,
conformational searches were carried out to define their stable
conformers. The set of 18 initial conformations of (R)-1 was
17
methyl p-toluenesulfinate ((R)-(+)-1), in order to examine the
reliability of each method and to compare their possible scopes
and limitations to sulfinates. The results on 1 demonstrated that
each method can accurately assign the absolute configuration
of sulfinates. Lastly, we applied these techniques to the sulfinic
natural product (-)-2 and determined its absolute configuration
as S.
◦
generated by combination of incremental 60 rotation of the
◦
◦
◦
◦
◦
◦
dihedral angle C2C1S1O8 (-120 , -60 , 0 , 60 , 120 , 180 ) and
◦
◦
incremental 120 rotation of the dihedral angle C1S1O8C8 (-60 ,
0 , 180 ). For (S)-2, the 36 starting structures were created by
rotating the bond C3–C8 by 180 in addition to the rotation of
the C2–S2 bond (60 each) and the S2–O9 bond (120 each).
Each geometry was optimized by using the DFT/B3LYP/6–
◦
◦
6
◦
◦
◦
Results and discussion
3
1G(d) level of theory, where some of the initial conformations
were converged to the same conformer. Further optimization
at the DFT/B3LYP/6–311+G(2df,2p) level of theory led to the
three and four stable conformers for 1 and 2, respectively, within
2 kcal/mol from the most stable one (Fig. 1 and 2). In the stable
Preparation of (R)-(+)-1 and (-)-2
Racemic (±)-1 was prepared by following a reported method
using p-tolyldisulfide and NBS with an excess amount of
18
=
methanol. Racemic (±)-2 was prepared by using a procedure
conformations of 1, the S1 O1 bond and the phenyl ring are
◦
1
3
similar to the synthesis reported by Pedras et al. as shown
in Scheme 2. Reaction of indoline-2-thione and the Vilsmeier
reagent prepared from phosphoryl chloride and DMF afforded
almost coplanar (the tilt angle is less than 3 , data not shown),
19
where the conformers are stabilized by p conjugation. On the other
hand, the S2
=
O2 bond of 2 directs toward the neighboring N1–H1
1
9
3
-(N,N-dimethylamino)methyleneindoline-2-thione (85%). The
group to avoid the steric repulsion with the C8 aldehyde group,
and probably to obtain an extra stabilization from intermolecular
hydrogen bonding between O2 and H1. Table 1 and 2 show a
few representative dihedral angles, the relative energies and the
dimethylamino compound was then transformed to the aldehyde
compound by treatment with aqueous hydrochloric acid. The
resulting crude compound was oxidized by I
2
in methanol solution,
yielding (±)-2 (15% in 2 steps). The NMR data was identical to
12
that previously reported.
Fig. 1 B3LYP/6–311+G(2df,2p) optimized structures for three stable
conformers of (R)-1.
3
Scheme 2 Synthesis of (±)-2. Reagents and conditions: (a) POCl , DMF,
◦
reflux, 85%; (b) HCl aq, EtOH, rt; (c) NBS, MeOH, pyridine, 0 C, 15%
in 2 steps.
The enantiomers of 1 and 2 were separated by using chiral
ꢀ
R
HPLC on a CHIRALCEL OD column (1 cm f ¥ 25 cm) at
hexane : EtOAc = 99:1 and 80:20, respectively. The elution time
and the separation factors a are as follows (t
0
= 3.4 min was
used to calculate a): For 1, t(+) = 15.6 min, t(-) = 16.5 min,
a = 1.07; For 2, t(-) = 16.8 min, t(+) = 20.0 min, a = 1.24.
Both enantiomers of 1 were purified by repeating chiral HPLC of
partially enantioenriched fractions. Each enantiomer of 1 and 2
Fig. 2 B3LYP/6–311+G(2df,2p) optimized structures for four stable
conformers of (S)-2.
4
400 | Org. Biomol. Chem., 2008, 6, 4399–4405
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a
b
Table 1 Three stable conformers of (R)-1 optimized without considering a solvent effect, and their calculated [a]
D
and observed [a] of (+)-1
D
a
Dihedral angles
a
b
DE (kcal/mol)
Boltzmann population
C2C1S1O8
C1S1O8C8
calcd [a]
D
◦
◦
◦
◦
◦
(
(
(
R)-1a
R)-1b
R)-1c
0.000
0.784
0.790
65.4%
17.4%
17.2%
65.52
65.66
+364.6
+352.7
+347.5
◦
◦
-112.49
-174.80
◦
◦
70.81
-174.75
◦
averaged [a]
D
+360
◦
CHCl
MeCN
EtOH
3
+185
+177
+184
◦
observed [a]
D
(c = 0.2 [g/(100mL)])
◦
a
b
Optimized at the DFT/B3LYP/6–311+G(2df,2p), Calculated at the TDDFT/B3LYP/aug-cc-pVDZ.
a
b
Table 2 Four stable conformers of (S)-2 optimized without considering a solvent effect, and their calculated [a]
D
and observed [a] of (-)-2
D
a
Dihedral angles
a
b
DE (kcal/mol)
Boltzmann population
O8C8C3C2
C3C2S2O9
C2S2O9C9
calcd [a]
D
◦
◦
◦
◦
(
(
(
(
S)-2a
S)-2b
S)-2c
S)-2d
0.000
0.644
0.956
1.247
60.3%
20.3%
12.0%
7.4%
179.08
0.67
179.40
0.48
-68.53
-61.57
-500.1
◦
◦
◦
◦
-76.04
-146.24
-264.6
◦
◦
◦
◦
◦
◦
◦
-76.13
-74.54
-173.19
-368.1
-589.4
◦
-61.39
◦
averaged [a]
D
-443
◦
observed [a]
D
(c = 0.2 [g/(100mL)], MeOH)
-231
a
b
Optimized at the DFT/B3LYP/6–311+G(2df,2p), Calculated at the TDDFT/B3LYP/aug-cc-pVDZ.
Boltzmann populations of these conformers. Theoretical optical
rotation, ECD and VCD of (R)-1 and (S)-2 were calculated for
each stable conformer, and then these data were averaged based
on their Boltzmann population to obtain the final spectra.
the calculated value of (R)-1 is accurately predicted to have the
positive sign, demonstrating the reliability of the assignment based
on optical rotation.
The ECD and UV spectra of (+)-1 were recorded in acetonitrile
as shown in Fig. 3. The observed ECD spectrum exhibits the first
positive Cotton effect at 249 nm and the negative band at 215 nm.
The theoretical ECD spectrum of (R)-1 was calculated using the
TDDFT/B3LYP/aug-cc-pVDZ level, where all three conformers
show closely compatible first positive Cotton bands at the longer
wavelength region, while different patterns are seen in the shorter
wavelength region: (R)-1a has a slightly positive signal, but (R)-1b
and (R)-1c have negative bands. The averaged theoretical spectrum
therefore exhibits a first positive band and then a weak negative
band as shown in Fig. 3. Although the comparison between
the observed ECD spectrum and the predicted one finds slight
differences in the wavelength of the positive band and the relative
intensities of the negative band, the overall spectral pattern in
the experimental data is well reproduced in the theoretical one,
thus supporting the previously assigned R-configuration. The
similarity seen between the observed and calculated UV spectra
supports the reliability of the calculations. Furthermore, a better
agreement of ECD curves has been achieved by considering the
influence of the solvent on the stability of these conformers. The
energy calculations of the three conformers in acetonitrile solvent
conducted at the 6–311+G(2df,2p) basis set using the polarizable
continuum model found an increase in the Boltzmann populations
of (R)-1b and (R)-1c (Table 3). Consequently, the ECD spectrum
based on the populations in acetonitrile (Fig. 3b), which exhibit
a clearer negative band in the region of 245–205 nm, provides
Chiroptical Spectra of (R)-(+)-1
The [a]
D
of (+)-1 was measured in chloroform, acetonitrile and
◦
ethanol, resulting in almost same values around +180 (Table 1).
Although optical rotatory power is known to be influenced by
20
solvents, seemingly such an effect on the optical rotation of (+)-1
is negligible. As is the case for (+)-1, chiral sulfinates have been
21
reported to exhibit large [a] values. Therefore, this series of
D
compounds represents a favorable case where, according to recent
studies, absolute configuration can be assigned by time-dependent
1
4,22
DFT calculation of optical rotation at the sodium-D line.
As
◦
Stephens et al. pointed out, molecules with [a]
D
< 100 should be
treated with caution since calculations may predict [a] values of
D
22
incorrect sign. The calculation of the optical rotation of (R)-1 was
carried out at the TDDFT/B3LYP/aug-cc-pVDZ level, leading
to almost same values for the three conformers irrespective of
the rotations of the C1–S1 bond and the S1–O8 bond (Table 1).
◦
However, the averaged theoretical [a]
D
value of (R)-1 (+360 ) is
◦
twice larger than the observed ones (ca. +180 ). This discrepancy
could be due to errors in the functional or the basis set, or due
to vibrational effects, which are not taken into account in these
calculations. Interestingly, twice larger predicted optical rotations
have also been seen for a chiral sulfoxide compound in a previous
15g
report and for (-)-2 in this study (vide infra). Most importantly,
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Fig. 4 Comparison of VCD and IR spectra of observed (+)-1 in
CDCl
3
(0.2 M) and the calculated (R)-1 using the DFT/B3LYP/
6
–311+G(2df,2p).
S1=O1 stretching and C7 methyl deformation, respectively. The
agreement seen between experimental and theoretical VCD bands
leads to the R assignment. This study represents the first example
of the application of VCD spectroscopy to a sulfinate, and provides
unambiguous determination of its absolute configuration. It is
Fig. 3 (a) The calculated ECD spectra at the TDDFT/B3LYP/
aug-cc-pVDZ for (R)-1 in vacuo. (b) The averaged calculated ECD
spectrum based on the Boltzmann populations in acetonitrile solution
as shown in Table 3. (c) The observed ECD of (+)-1. (d) The observed
and averaged calculated UV spectra. The UV spectrum calculated in
acetonitrile is omitted since it is indistinguishable from that calculated in
vacuo. ECD and UV of (+)-1 (acetonitrile, 0.3 mM) lext (De): 199 (+2.8),
=
noteworthy that characteristic VCD signals arising from S O
stretch have been observed in previous studies of sulfoxides and
15b–j
sulfinamides.
The stretching of sulfinic S=O, which occurs at
the chiral center itself, can be considered to give rise to strong
VCD absorption that can be the most informative in the analysis
of absolute configuration of sulfinates.
In the study of (+)-1, each chiroptical technique reliably
predicted the R configuration in accordance with the previous
2
12 (-10.8), 249 (+15.1); lmax (e): 196 (40100), 225 (10400), 249 (5700).
17
Table 3 Relative energies and Boltzmann populations of three stable
assignment by Mikolajczyk and Drabowicz. This is the first
example of nonempirical determination of sulfinic absolute config-
uration. Supported by the finding that optical rotation, ECD and
VCD techniques can accurately assign sulfinic chirality, we then
applied these methods to the natural product (-)-2 to determine
its absolute configuration.
a
conformers of (R)-1 calculated by using PCM in acetonitrile
a
DE (kcal/mol)
Boltzmann population
(
(
(
R)-1a
R)-1b
R)-1c
0.000
0.315
0.319
46.1%
27.0%
26.9%
a
Calculated using the DFT/B3LYP/6-311+G(2df,2p).
Determination of absolute configuration of (-)-2
Calculations of optical activities were carried out for the four
stable conformers of (S)-2 (Fig. 2) without consideration of the
solvent effects. Compound 2 is rather hydrophilic due to the C8
carbonyl and N1 amino groups, and hence it has limited solubility
in apolar solvents. Although aprotic solvents are commonly used
for comparison of observed data and theoretical calculation, the
a closer similarity with the experimental, thus confirming the R
configuration.
The VCD and IR spectra of (+)-1 were measured as a CDCl
3
solution, and compared with the theoretical ones calculated
for (R)-1 at the DFT/B3LYP/6–311+G(2df,2p) level of theory
(
Fig. 4). The observed IR spectrum shows good agreement with the
experimental [a] and ECD measured in methanol and acetoni-
D
calculated in their frequencies and relative intensities, including the
trile, respectively, showed good agreement with the calculated data
intense IR absorption band due to S1=O1 stretching vibration at
as discussed below.
First, the observed [a] value in methanol was compared with
the calculated shown in Table 2. The TDDFT/B3LYP/aug-cc-
pVDZ calculation predicted various optical rotations for each
conformer, but all exhibit negative values with large intensities
-
1
around 1125 cm . Similarly, both the experimental and theoretical
D
-
1
VCD spectra are almost featureless above 1200 cm , while they
show a characteristic positive couplet, i.e., a positive band at ca.
1
-1
1
125 cm- and a negative band at ca. 1160 cm originating from
4
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regardless of the rotations of the C3–C8 bond and the S2–O9
◦
bond. The averaged theoretical [a]
D
of (S)-2 (-443 ) is about twice
◦
larger than the experimental one (-231 ), as observed in the case of
1. Both results show large negative values, thus clearly suggesting
the absolute configuration of (-)-2 be S. It is noteworthy that the
predicted magnitude of the rotation of 2 is greater than that of 1,
as observed experimentally.
To verify the predicted S-configuration, ECD spectroscopy was
then applied to 2 (Fig. 5). Both the experimental ECD spectrum
obtained in acetonitrile and the averaged theoretical spectrum
using the TDDFT/B3LYP/aug-cc-pVDZ level show a negative
broad band at around 320 nm and a sharp intense peak at
around 215 nm. Although the observed small negative couplet
at around 250 nm becomes flat in the calculated data because
they are compensated by each other (data not shown), the overall
agreement between the two spectra unambiguously leads to the
assignment as S.
Finally, the assignment of the S-configuration is further con-
firmed by VCD spectroscopy (Fig. 6). The IR and VCD measure-
ments were conducted for CDCl
0.05 M) due to the hydrophilicity of 2. As a result, the observed
spectrum shows a relatively low S/N ratio especially in the region
above 1500 cm , and therefore this region was omitted to avoid
any misinterpretation. The theoretical IR and VCD spectra were
calculated at the DFT/B3LYP/6–311+G(2df,2p) level and then
compared with the experimental ones. The observed IR spectrum
shows moderate agreement with the predicted; however, the former
exhibits somewhat broader bands than the latter. Considering the
molecular property of 2, the band broadness may indicate that part
3
but at a lower concentration
(
Fig. 6 Comparison of VCD and IR spectra of observed (-)-2 in
CDCl3 (0.05 M) and the calculated (S)-2 using the DFT/B3LYP/
-
1
6
–311+G(2df,2p). Some of the putative band assignments are shown by
dotted lines.
hydrogen bonding between the C8 carbonyl of one molecule and
the N1 amino group of another. Nevertheless, the experimental
VCD feature reasonably agrees with the theoretical as shown in
Fig. 6, where several putative assignments of each observed band
of the molecule has intermolecular interactions in CDCl such as
3
Fig. 5 (a) The calculated ECD spectra at the TDDFT/B3LYP/aug-cc-pVDZ for (S)-2 in vacuo. (b) The observed ECD of (-)-2. (c) The observed and
averaged calculated UV spectra. ECD and UV of (-)-2 (acetonitrile, 0.3 mM). lext (De): 212 (+15.3), 242 (+5.7), 260 (-6.3), 321 (-6.3); lmax (e): 196
(
24000), 215 (23800), 245 (14200), 305 (9800).
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are depicted. Specifically, the negative feature in the S=O stretching
The combined extract was washed with brine, then dried over
-
1
region (ca. 1110 cm ) is significant in both the observed and
calculated spectra. These VCD results suggest the S-configuration
of (-)-2 in consistency with the conclusions deduced from optical
rotation and ECD.
Na
2
SO , filtered and concentrated. The residue was subjected
4
to silica-gel column chromatography (hexane:EtOAc = 30:70
to 0:100) to afford 3-(N,N-Dimethylamino)methyleneindoline-2-
19
thione (356 mg, 85%).
A solution of 50 mg (0.24 mmol) of the above dimethylamino
compound in 8 mL of EtOH was added to 10 mL of 0.5 M HCl
aq and stirred for 2 h at rt. The reaction mixture was poured
into water and extracted with EtOAc. The combined extract
Conclusions
We have applied the theoretical calculation of optical rotation,
ECD and VCD spectroscopies to chiral sulfinates for the first time.
Comparison of each observed and calculated data of chiral model
sulfinate 1 accurately predicted (+)-1 as R in accordance with the
previous assignment. Furthermore, the cruciferous phytoalexin
was washed with water, brine, then dried over Na
2
SO , filtered
4
and concentrated. Without further purification, the crude 2-
sulfanylindole-3-carboxaldehyde was dissolved in 3 mL of MeOH
and 200 mL of pyridine, and then NBS (85 mg, 0.48 mmol)
◦
was portionwisely added to the solution at 0 C. After stirring
(
-)-2 has been unambiguously assigned as S. Determination of
for 1 h, the mixture was diluted with CHCl
water and brine. The organic layer was dried over Na
3
and washed with
SO , filtered
chirality of sulfinates by chiroptical spectroscopies is a reliable
and convenient alternative to conventional methods that require
derivatization or crystallization.
2
4
and concentrated. The residue was subjected to silica-gel column
chromatography (hexane:EtOAc = 85:15 to 80:20) to afford (±)-2
Using only a single method could lead to satisfactory assign-
ments for the sulfinates studied here; however, each method has
its own advantages and disadvantages in terms of their sensitivity,
reliability, restriction of measurement conditions, etc. We have
shown that the absolute configurations of sulfinates, which typ-
1
(
7 mg, 15% in 2 steps). Brassicanal C ((±)-2): H NMR (400 MHz,
CDCl
3
): d 10.34 (1H, s), 9.83 (1H, br s), 8.28 (1H, d, J = 7.8 Hz),
7.55 (1H, d, J = 8.2 Hz), 7.45 (1H, ddd, J = 1.2, 7.6, 7.6 Hz), 7.40
(
1H, ddd, J = 1.2, 7.5, 7.5 Hz), 3.69 (3H, s); HRMS (FAB) m/z
+
for C10
H
10NO
3
S (M ), calcd 224.0381, found 224.0384.
ically exhibit large [a] values, can conveniently be determined
D
by calculations of optical rotation. However, caution must be
taken for this approach in order to avoid erroneous assignments
Measurement of optical activities
in case the calculated and experimental [a]
D
fall into “the zone of
indeterminacy” reported in ref 22. In such cases optical rotations
Optical rotations were measured on a Perkin-Elmer 343 polarime-
ter at the sodium-D line using a 1-cm optical cell. ECD spectra
were recorded on a JASCO J-810 spectrometer with a 1-mm quartz
cell. IR and VCD spectra were obtained on a Bomem/BioTools
Chiralir spectrometer equipped with a second elastic modulator
23
at several wavelengths (i.e. optical rotatory dispersion) or other
methods such as ECD and VCD must be examined. On the other
hand, ECD and VCD spectroscopies can be more effective tools
when the compound has other chiral moieties. In particular, VCD
spectroscopy is advantageous for this purpose because of a large
using a 72-mm BaF cell. Data were corrected by solvent data
2
24
number of well-isolated vibrational transitions including the
obtained at the same experimental conditions. In each technique,
the pairs of enantiomers showed results with the opposite sign.
S=O stretching vibration that strongly reflects sulfinic chirality.
The assignment by these methods becomes more reliable by
25
considering solvent effects, as exemplified in the ECD study
of 1. If properly used, each method alone could assign absolute
configuration with satisfactory accuracy, and furthermore the
use of more than one technique will lead to further reliable
conclusions.
Calculations
Geometry optimizations and optical activity calculations were
2
6
performed with Gaussian 03. The 18 and 36 initial geometries
of (R)-1 and (S)-2, respectively, were first optimized by using
DFT/B3LYP/6–31G(d) level of theory, and then resultant stable
conformers within 5 kcal/mol from the most stable one were
further optimized at the DFT/B3LYP/6–311+G(2df,2p) level.
The conformers within 2 kcal/mol from the most stable one
were taken into account for optical rotation, ECD and VCD
calculations. For the ECD study of (+)-1, the energy calcula-
tions of the three conformers of (R)-1 were conducted at the
DFT/B3LYP/6–311+G(2df,2p) level using PCM in acetonitrile
(e = 36.64) as implemented in Gaussian 03. Theoretical optical
rotations were calculated using the DFT/B3LYP/aug-cc-pVDZ
level at the 589.3 nm. Computation of ECD and UV spectra
were carried out using the DFT/B3LYP/6–311+G(2df,2p) level of
theory. The ECD spectra were simulated from the first 40 singlet →
singlet electronic transitions using Gaussian band shapes and
0.30 eV standard deviation. IR and VCD spectra were calculated
at the DFT/B3LYP/6–311+G(2df,2p) level, and simulated with
Experimental section
Preparation of (R)-(+)-1 and (-)-2
1
H (400 MHz) NMR spectra were recorded on a Bruker Avance
spectrometer. FAB MS was performed on a JEOL HX110
spectrometer. Enantioseparation of (±)-1 and (±)-2 was conducted
ꢀ
R
on a CHIRALCEL OD column (1 cm f ¥ 25 cm) using a
Shimadzu LC-6A liquid chromatograph instrument equipped with
a Shimadzu SPD-6AV UV-Vis spectrometric detector.
Preparation of (±)-2 used a procedure similar to that reported by
13
Pedras et al. Phosphoryl chloride (400 mL) was added dropwisely
to DMF (2 mL) with stirring at rt under N . After 2 h, a solution
2
19
of indoline-2-thione (300 mg, 2.01 mmol) in DMF (1.5 mL)
was added dropwisely to the mixture. The reaction mixture was
stirred for 4 h at rt, then poured into 2 mL of wet ice, then
-
1
added to 10 mL of sat NaHCO
3
aq, and stirred overnight.
Lorentzian lineshapes of 8 cm width. The calculated frequencies
n were scaled with the equation of (1.04 ¥ 10 )n + 9.894n. Final
-
5
2
The mixture was poured into water and extracted with EtOAc.
4
404 | Org. Biomol. Chem., 2008, 6, 4399–4405
This journal is © The Royal Society of Chemistry 2008

View Article Online
data were obtained based on the Boltzmann population average
of each data.
68, 9821–9822. For application of DFT calculation see; (b) Y. Wang,
G. Raabe, C. Repges and J. Fleischhauer, Int. J. Quantum Chem.,
2
003, 93, 265–270; (c) A. Aamouche, F. J. Devlin, P. J. Stephens, J.
Drabowicz, B. Bujnicki and M. Mikolajczyk, Chem. Eur. J., 2000,
6, 4479–4486; (d) J. Drabowicz, B. Dudzinski, M. Mikolajczyk, F.
Wang, A. Dehlavi, J. Goring, M. Park, C. J. Rizzo, P. L. Polavarapu,
P. Biscarini, M. W. Wieczorek and W. R. Majzner, J. Org. Chem.,
Acknowledgements
The authors are grateful to Prof. Shin-Ichiro Nishimura, Dr.
Takahiro Maeda, Mr. Masakazu Hachisu, Mr. Atsufumi Naka-
hashi and Mr. Masafumi Yoshida for the support for enantiosep-
aration and VCD measurements. T. T. acknowledges the Japan
Society of the Promotion of Science Postdoctoral Fellowship for
Research Abroad.
2
001, 66, 1122–1129; (e) P. J. Stephens, A. Adamouche, F. J. Devlin,
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This journal is © The Royal Society of Chemistry 2008
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