The determination of the absolute configuration of a chiral 2,3′-diindolylarylmethane by NMR spectroscopy

Article abstract of DOI:10.1002/mrc.4192

The University of Chinese Academy of Sciences, Beijing 100864, China We present the determination of the absolute configuration of a chiral 2,3′-diindolylarylmethane 1 by using the combination of NMR spectroscopic and circular dichroism techniques. The re

Full text of DOI:10.1002/mrc.4192

Rapid communication
Received: 10 October 2014
Revised: 31 October 2014
Accepted: 31 October 2014
Published online in Wiley Online Library: 22 January 2015
(wileyonlinelibrary.com) DOI 10.1002/mrc.4192
The determination of the absolute configuration
of a chiral 2,3′-diindolylarylmethane by
NMR spectroscopy
Shuai Qi,a,b Chuan-Qing Kanga and Fu-She Hana*
We present the determination of the absolute configuration of a chiral 2,3′-diindolylarylmethane 1 by using the combination of
NMR spectroscopic and circular dichroism techniques. The results would be useful for the future study of the effect of chirality
on the biological activity of 2,3′-diindolylarylmethanes. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: NMR; 1H; absolute configuration; 2,3′-diindolylarylmethane; Mosher’s model; α-methoxyphenylacetic acid (MPA); CD spectrum
configuration of the chiral compounds beforehand is of crucial im-
portance. Herein, we present the determination of the absolute
Introduction
Diindolylarylmethane compounds, originally found in cruciferous
vegetables, are an important class of leading compounds in the
search of new anticancer agents. They exhibit ample in vivo antican-
cer activities including growth inhibition, apoptosis, and
antiangiogenic activities.[1] Particularly, the diindolylarylmethane
analogues display high activity against a broad range of cancer cells
such as breast,[2] prostate,[3] colon,[4] pancreatic,[5] acute myeloge-
nous leukemia,[6] bladder,[7] and endometrial cancer cell lines.[8]
Furthermore, inhibition of a targeted cell line in a selective manner
might also be tuned by means of modifying the indole and/or aryl
rings appropriately. Despite of these impressive results, the antican-
cer activity of chiral diindolylarylmethanes remains not investi-
gated. However, numerous studies have demonstrated that the
configuration of chiral 2,3′-diindolylarylmethanes. The NMR
method based on chiral derivatizing reagents (CDAs)[13] and the cir-
cular dichroism (CD) spectroscopy,[14] which are well-established
methods for the assignment of the absolute stereochemistry of chi-
ral compounds, were employed in our study.
Results and discussion
Synthesis of the diastereomeric amides for NMR study
For a safe derivatization, we initially examined the optical stability
of chiral 2,3’-diindolylarylmethane 1 (Scheme 2) under a range of
acidic and basic conditions in considering that the methine proton
of the triarylmethanes (H-8 in structures 2 and 3 in Fig. 1) was rela-
tively acidic, which may cause racemization through the equilibra-
tion of deprotonation and protonation process. Our control
experiments showed that no racemization was observed by
treating the products with acidic silica gel, p-TsOH, Et3N, and pyri-
dine in CH2Cl2, NaOH in THF/H2O (v/v = 10 : 1), and NaH in THF at
room temperature, separately. These results indicate that the
diindolylarylmethanes exhibit pretty good resistance against a
range of acidic and basic conditions and provide useful information
for the option of appropriate conditions to derivatize with a chiral
reagent. In addition, these observations also preclude the suspicion
of racemization for future investigation into the effect of chirality on
the biological activity under the conditions similar to a physiologi-
cal environment because, in general, such environment displays a
weaker basicity or acidity than the those employed for control
experiments.
biological activity of
a molecule, including the hetero-
triarylmethanes,[9] is dramatically influenced by its chirality. It is thus
would be greatly interesting to investigate the anticancer property
of the related chiral compounds.
So far, two protocols for the enantioselective synthesis of 3,3′-
diindolylarylmethanes have been developed via the Friedel–
Crafts-type reaction. The first one was reported in 2010 by You
and co-workers through the chiral phosphoric acid-catalyzed reac-
tion of (indol-3-yl aryl)methyl amines and N-methyl indole[10]
(Scheme 1a, 1). In a recent report,[11] Jiang and co-workers devel-
oped an improved method for accessing chiral 3,3′-hetero-
triarylmethanes through the chiral imidodiphosphoric acid-
catalyzed reaction of (indol-3-yl aryl)methyl silyl ethers with indoles
or pyrroles (Scheme 1a, 2). Very recently, we have achieved the
asymmetric synthesis of more challenging chiral 2,3′-
diindolylarylmethanes through a chiral Brønsted acid-catalyzed
reaction of indol-2-yl carbinols and indoles[12] (Scheme 1b).
Namely, by employing the chiral N-triflylphosphoramides derived
from the unsubstituted (R)-BINOL or (S)-BINOL as catalysts, both
enantiomers of 2,3′-diindolylarylmethanes could be obtained flexi-
bly in excellent yields of over 90% as well as high enantioselectivity
of up to 96% ee.
*
Correspondence to: Fushe Han, Changchun Institute of Applied Chemistry,
Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022,
China. E-mail: fshan@ciac.ac.cn
a Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625
Renmin Street, Changchun, Jilin, 130022, China
The successfully established protocols offer an opportunity for
the investigation of anticancer property of chiral diindolylary-
lmethanes. To this end, the assignment of the absolute
b The University of Chinese Academy of Sciences, Beijing 100864, China
Magn. Reson. Chem. 2015, 53, 181–187
Copyright © 2015 John Wiley & Sons, Ltd.

S. Qi, C.-Q. Kang and F.-S. Han
On the basis of these preliminary results, we chose
methoxyphenylacetic acid (MPA) as the suitable CDA because this
compound has been widely exemplified to be one of the most
powerful and readily available reagent in the determination of
absolute configuration of a rich range of chiral alcohols and
amines.[13] However, attempted condensation of (R)-MPA and (S)-
MPA with chiral 2,3′-diindolylarylmethane 1 (er= 91 : 9, synthesized
using the (R)-form of N-triflylphosphoramides[12]) according to the
procedure described by Trost (DCC, DMAP, Et3N)[15,16] was unsuc-
cessful (Scheme 2). The reaction did not proceed presumably be-
cause of the weak nucleophilicity of indole amine.[17] After some
trials, we found that by converting the MPA into its acyl
chloride[18,19] followed by in situ trapping the acyl chloride with
diindolylarylmethame 1 in the presence of NaH[20] could afford the
(R)-MPA and (S)-MPA amides 2 and 3, respectively in ca. 60% yield.
Scheme 1. Protocols for the enantioselective synthesis of 3,3′-
diindolylarylmethanes and 2,3′-diindolylarylmethanes.
Scheme 2. Preparation of the MPA derivatives 2 and 3.
Figure 1. 1H NMR spectra of (R)-MPA amide 2 (a) and (S)-MPA amide 3 (b) in CDCl3.
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The determination of the absolute configuration of novel chiral 2,3′-diindolylarylmethanes is presented
Figure 2. 1H–1H NOESY spectra of (R)-MPA amide 2 (a) and (S)-MPA amide 3 (b).
Assignment of the NMR spectra of MPA amides
6.92 ppm belong to H-2′ and H-12 of compound 2, respectively.
Similarly, as seen from Fig. 4b, the peaks at 6.95 and 6.92 ppm
can be assigned to H-2′ and H-12 of compound 3, respectively.
The 1H-NMR and 1H–1H NOESY spectra of 2 and 3 were shown in
Figs. 1 and 2 respectively. Most of the protons for 2 and 3 could
be easily assigned based on these spectra as labeled in Fig. 1a
and 1b, respectively. The chemical shift for proton H-8 (5.75ppm
for 2 and 5.72 ppm for 3) could be assigned by the use of a combi-
nation of 1H-NMR, 1H–1H NOESY, and 1H–13C HSQC spectra (Fig. 3).
Finally, for the protons of H-10, H-12, H-14, and H-2′ whose chemical
shift is somewhat overlapped around 6.80–7.10 ppm could be un-
Assignment of the absolute configuration of
2,3′-diindolylarylmethane 1
To deduce the absolute configuration of 1 based on the informa-
tion offered by the 1H-NMR data, the chemical shift difference be-
tween the two diastereoisomers 2 and 3 is compared. The
chemical shifts for 2 (δR ppm), 3 (δS ppm), and the chemical shift dif-
ference between 2 and 3 (ΔδRS = δR À δS) are listed in Table 1. The
data showed that the ΔδRS values for H-4, H-8, H-18, H-2′, H-α, and
1
ambiguously confirmed by a further H–13C HMBC spectroscopic
analysis. As shown in Fig. 4a, from the correlation of 1H–13C HMBC,
we could clearly assign that the peaks that appear at 7.08 and
Magn. Reson. Chem. 2015, 53, 181–187
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S. Qi, C.-Q. Kang and F.-S. Han
Figure 3. Partial 1H–13C HSQC spectra of (R)-MPA amide 2 in CDCl3.
H-OMe are positive within a range of from +0.03 to +0.13, suggest-
ing that the chemical shifts of these protons are shifted toward up-
field in compound 3 as compared with those of compound 2. The
most remarkable effect was observed for H-18 and H-2′, whose ΔδRS
value was up to +0.12 and +0.13, respectively. On the other hand,
the protons H-15, H-16, and H-17 tend to shift somewhat downfield
in 3 (ΔδRS = À0.04, À0.02, and À0.02, respectively), indicating that
these protons were less shielded by the phenyl group in 3 than in 2.
diindolylarylmethanes 1 synthesized by using the (R)-form of N-
triflylphosphoramides as catalyst is R.
To further confirm the absolute configuration, we measured the
CD spectrum of 1 and compared the experimental CD spectra with
those of (R)-1 and (S)-1 obtained from quantum chemical calcula-
tions. This approach is also a well-established method for the deter-
mination of the absolute stereochemistry of a chiral molecule.[14] As
shown in Fig. 6, the experimental CD of chiral compound 1 is in
qualitative agreement with the calculated CD of (R)-1.
1
Based on the chemical shift difference of 2 and 3, the H–1H
NOESY correlation, and Mosher’s model[13] (i.e. the methoxy and
carbonyl groups in MPA and the central indole moiety are assumed
to situate approximately in the same plane, and the phenyl ring is
almost coplanar to the Cα–H bond), we could establish the opti-
mized conformation of compounds 2 and 3, which are in good
agreement with that obtained by the density functional theory
(DFT) calculations (E = À1731.1668 au for 2 and À1731.1672 au for
3) at B3LYP/6-31G**/PCM level. As shown in Fig. 5, the methoxy
group is syn-periplanar to the carbonyl group, and H-α and H-2′
are arranged approximately in the same side, which are the best ar-
rangement to effectively transmit aromatic shielding to the H-8, H-
2′, and the indole isopropyl and methyl groups. Consequently, a
strong NOE effect was observed between H-α and H-2′ (Fig. 2). In
addition, the H-15, H-16, and H-17 of isopropyl in (R)-MPA amide
2 are arranged in the same side with the phenyl group. This
explains why the protons are shielded somewhat more significantly
by the phenyl group in 2, and ultimately, exhibiting a larger upfield
shift (Fig. 5a, ΔδRS < 0 as seen in Table 1). Alternatively, in (S)-MPA
amide 3 (Fig. 5b), the protons H-4, H-8, H-18, and H-2′, particularly
the H-18 and H-2′, suffer from a stronger shielding effect by the
phenyl group of MPA moiety than those in compound 2 (ΔδRS > 0
as seen in Table 1). These observations matched well with the opti-
mized conformation of 3 wherein the mentioned protons and the
phenyl group in 3 are arranged in the same side. It should also be
mentioned that the H-α, and the protons in OMe of the MPA moiety
of compound 3 are slightly shifted upfield (ΔδRS = +0.04 and +0.05,
respectively). This is presumably because of the shielding effect of
3,5-dimethylphenyl group as seen from the optimized conforma-
tion. Thus, on the basis of the NMR analysis, we could tentatively
assign that the absolute configuration of the chiral 2,3′-
In conclusion, we have determined the absolute configuration of
a chiral 2,3′-diindolylarylmethane 1 by using the NMR method
based on the CDAs combined with the use of CD analytical method.
Namely, the absolute configuration of the product obtained by
using the (R)-form and (S)-form of catalyst is R and S, respectively.
As mentioned, the 2,3′-diindolylarylmethanes are novel indole de-
rivatives and are anticipated to be interest candidates as new anti-
cancer agents. However, the biological properties of neither the
racemic nor the chiral 2,3′-diindolylarylmethanes have been stud-
ied. As such, the method for flexibly accessing both R and S enan-
tiomers of chiral 2,3′-diindolylarylmethanes established in our
previous study[12] together with the results for the determination
of the absolute configuration presented herein would pave the
way for a thorough investigation of the anticancer properties of
2,3′-diindolylarylmethane derivatives. On the basis of the results in
this work, a further study toward the establishment of a general
method for the assignment of the absolute configuration of a range
of 2,3′-diindolylarylmethanes by using the NMR technique is
underway.
Experimental
Preparation of MPA amides
To a solution of (R)-α-MPA or (S)-α-MPA (49.8mg, 0.3mmol) in dried
CH2Cl2 (3 ml) was added oxalyl chloride (26 μl, 0.3 mmol) and N,N-
Dimethylformamide (DMF) (31μl, 0.4mmol) at 0 °C. The reactants
were mixed with a magnetic stir bar in an ice bath for 1 h to obtain
the corresponding methoxyphenylacetyl chloride.
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The determination of the absolute configuration of novel chiral 2,3′-diindolylarylmethanes is presented
Figure 4. Partial 1H–13C HMBC spectra of (R)-MPA amide 2 (a) and (S)-MPA amide 3 (b) in CDCl3.
To a solution of the chiral 2,3′-diindolylarylmethane 1 (81 mg,
0.2mmol) in dried THF (2ml) was added NaH (16 mg, 0.4mmol,
60% in mineral oil) at 0 °C. The slurry thus formed was gradually
warmed to room temperature over a 30 min period. The mixture
was then cooled to 0 °C, and the previously prepared
methoxyphenylacetyl chloride was added dropwise. The mixture
was stirred at 0 °C for 4 h. The reaction mixture was poured to ice
water and extracted with ethyl ether three times. The organic layer
was combined, washed with water, and dried over anhydrous
MgSO4. The solvent was removed under vacuum, and residue
was purified by chromatography in silica gel to give the desired
compound (66.5 mg, 0.12mmol, 60%).
PL6 software with a 5 mm smart probe equipped with a z-gradient
coil. The 1D 1H NMR spectra were measured with a spectral width of
10kHz on a data size of 32 K with pulse length of 13.0 μs. The 13C
NMR spectra were measured with a spectral width of 32.5kHz on
a data size of 128 K with pulse length of 7.5μs. The acquisition times
1
were 5 s in H NMR spectra and 3 s in 13C NMR spectra. Chemical
shifts were recorded relative to internal standard TMS (δ 0.0 ppm)
for 1H NMR and the central peak of CDCl3 (δ 77.0 ppm) for 13C NMR.
All 2D spectra were measured with Bruker standard TopSpin 3.2
PL6 program noesygpphpp for 1H–1H NOESY, hsqcedetgpsp.3 for
1H–13C HSQC, and shmbcctetgpl2nd for 1H–13C HMBC. The 1H–1H
NOESY spectra were obtained with a spectral width of 6000Hz in
a 2048 × 128 data matrix with four scans per t1 increment. The
1H–13C HSQC spectra were collected with 2048 × 256 data points
in a spectral width of 6000 Hz for F2 (1H) and 100 000 Hz for F1
NMR experiments
1
All NMR experiments were performed on a Bruker AVANCE HD
500 MHz spectrometer in CDCl3 at 298 K using Bruker TopSpin 3.2
(13C). The H–13C HMBC spectra were collected with 2048 × 256
data points in a spectral width of 6000 Hz for F2 (1H) and
Magn. Reson. Chem. 2015, 53, 181–187
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S. Qi, C.-Q. Kang and F.-S. Han
Table 1. 1H NMR data and ΔδRS values (in ppm) for (R)-MPA and (S)-
MPA amides of 2 and 3 in CDCl3
Proton
signal
1H chemical shifts, δ (ppm)
ΔδRS (ppm)
δR À δS
2
3
H-4
7.54
7.46
5.75
6.77
6.92
4.53
1.15
1.33
1.85
2.26
5.21
3.47
7.08
8.53
7.51
7.46
5.72
6.77
6.92
4.57
1.17
1.35
1.73
2.26
5.17
3.42
6.95
8.54
+0.03
0.00
H-7
H-8
+0.03
0.00
H-10, H-14
H-12
0.00
H-15
À0.04
À0.02
À0.02
+0.12
0.00
H-16
H-17
H-18
H-19, H-20
H-α
H-OMe
H-2′
Figure 6. The experimental and simulated electronic circular dichroism
spectra of 1 at B3LYP/6-31G**/PCM (methanol) level.
+0.04
+0.05
+0.13
À0.01
H-7′
(S0) was optimized using DFT together with the D3 version of
Grimme’s dispersion (D3) with Becke–Johnson damping (BJ).[22]
The used functional and basis set is B3LYP and 6-31G**, respec-
tively. The frequency analysis was also performed at the same level
to check the stationary nature of optimized geometry. In addition,
the optimized geometry of compounds (R)-1 and (S)-1 in methanol
solvent were obtained using the same theoretical level mentioned
in the preceding texts.
Then, based on the S0 geometry, linear response time-
dependent DFT (TDDFT) calculations with B3LYP functional and
6-31G** basis set were performed to obtain the excitation energy
and rotatory strengths of compounds (R)-1 and (S)-1, which can
be convoluted into electronic circular dichroism (ECD) spectrum
in multiwfn 3.3.5[23] using Gaussian model. The solvation effect
of methanol solvent, in which experimental data of ECD spec-
trum were measured, was considered during the optimization
and TDDFT calculations by means of the polarizable continuum
model (PCM).
37 500 Hz for F1 (13C). The data were processed using QSINE for
weighting in both dimensions before Fourier transformation.
Measurement of CD spectrum of 1
The CD spectra were recorded on a Bio-Logic MOS-450 spectropo-
larimeter using a quartz cell of 1-cm optical path length. The scan-
ning speed was 150 nm minÀ1 with a response time of 0.1s and
over a wavelength range of 220–400 nm. The concentration of
chiral 2,3′-diindolylarylmethane 1 was 1 × 10À4 M in methanol,
and the CD spectra was representative of three averaged scans
taken at 25 °C.
Computational details
All calculations were performed in Gaussian 09 program
package.[21] The geometry of compounds 2 and 3 at ground state
Figure 5. The optimized geometry of compounds 2 and 3 at B3LYP/6-31G**/PCM level.
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The determination of the absolute configuration of novel chiral 2,3′-diindolylarylmethanes is presented
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Financial support from NSFC (21272225) is acknowledged. The au-
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Bin Li and Prof. Zhong-Min Su at Institute of Functional Material
Chemistry, Faculty of Chemistry, Northeast Normal University.
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