Chiral discrimination of natural isoflavanones using (R)- and (S)-BINOL as the NMR chiral solvating agents

Article abstract of DOI:10.1016/j.tetasy.2016.09.002

Commercially available chiral solvating agents (R)- and (S)-BINOL were applied to the enantiodifferentiation of natural isoflavanones via¹H NMR spectroscopy. The absolute configurations of the enantiomers of isoflavanones including sativanone 1, 3'-O-methylviolanone 2, and homoferreirin 3 were assigned by comparing the corresponding δ^Rand δ^Svalues. This approach provided a simple and general means to tentatively assign the enantiomeric purity and absolute configuration of isoflavanones.

Full text of DOI:10.1016/j.tetasy.2016.09.002

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
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Chiral discrimination of natural isoflavanones using (R)- and
(S)-BINOL as the NMR chiral solvating agents
a,
Jingyu Yi a, Guoxin Du a,y, Yaxi Yang b, Yuanchao Li b, Yiming Li a, , Fujiang Guo
⇑
⇑
a School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Commercially available chiral solvating agents (R)- and (S)-BINOL were applied to the enantiodifferenti-
ation of natural isoflavanones via 1H NMR spectroscopy. The absolute configurations of the enantiomers
of isoflavanones including sativanone 1, 30-O-methylviolanone 2, and homoferreirin 3 were assigned by
comparing the corresponding dR and dS values. This approach provided a simple and general means to
tentatively assign the enantiomeric purity and absolute configuration of isoflavanones.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 July 2016
Accepted 6 September 2016
Available online xxxx
1. Introduction
1
O
8
5
7
2
*
2'
5'
Isoflavonoids, which are based on a 3-phenylchromene skele-
ton, form a distinctive subclass of flavonoids.1 Isoflavonoids mainly
occur in the subfamily Papilionoideae of the Leguminosae.2 Isofla-
vonoids and their derivatives play a role as phytoalexins in plants,
helping the plant fight microbial disease.3 There are several bene-
ficial properties to human health associated with the isoflavonoids,
including a reduction in osteoporosis and cardiovascular disease.
Moreover, dietary isoflavonoids can act as phytoestrogens in ani-
mals to exert estrogenic effects because of the similarity in struc-
ture3 and reduce the incidence of some distinct cancer forms that
are hormone-dependent, such as breast, prostate, and lung cancer.4
There have been more than 1600 naturally occurring isoflavo-
noids reported, which can be divided into 11 major subclasses
including isoflavones, pterocarpanoids, rotenoids, isoflavanones,
isoflavans, as well as less common ones such as coumestans, 3-
arylcoumarins, isoflavonoid oligomers, coumaronochromones, iso-
flav-3-enes, etc.4,5 Among them, isoflavanones are considerably
rare, with a rather limited taxonomic distribution. The chemical
characteristic of isoflavanones, which is based on the 2,3-dihy-
dro-2-phenyl-benzopyran-4-one moiety, is the presence of a single
C-3 stereogenic center (Fig. 1). Therefore, finding a convenient
means to define the absolute configuration of isoflavanones is cru-
cial for further studies of isoflavanones.
3
3'
4
1'
6
O
6'
4'
Figure 1. Chemical backbone of isoflavanones.
dispersion (ORD) and circular dichroism (CD) are widely used to
define the stereochemistry of chiral isoflavanones.6 However, CD
signals are not observed if a molecule is present in its racemic
form. For X-ray diffraction analysis, obtaining a high-quality crys-
tal is always the prerequisite, and is thus a limitation.7 Nuclear
magnetic resonance (NMR) spectroscopy is one of the indirect or
relative methods to achieve a quick determination of the enan-
tiomeric excess of chiral compound when the amount of the com-
pounds is only a few milligrams; it also possesses other advantages
such as easy performance, small sample size, and low cost.8 Three
NMR technologies have been used in the determination of the
enantiomeric purity including chiral derivatizing agents method,
chiral lanthanide shift reagents method and chiral solvating agents
method.9 Among them, the chiral solvating agents method is gen-
erally more attractive because of the advantages that it is quick
and simple to perform, with no problems in terms of kinetic reso-
lution or sample racemization, provided that the complexes
remain in solution. The chiral solvating agent can bind with test
compounds through noncovalent, intermolecular forces, allowing
for the separation of the signals of the enantiomers in the 1H
NMR spectrum. A wide number of chiral solvating agents such as
alkaloids,10 porphyrins,11 cyclodextrins,12 binols,13 trianglamines14
and diamines15 have been studied for various applications.16 It has
Some analytic techniques have been reported for the chiral
discrimination of isoflavanones. For example, optical rotatory
⇑
Corresponding authors.
E-mail addresses: ymlius@163.com (Y. Li), gfj@shutcm.edu.cn (F. Guo).
Co-first author.
y
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0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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J. Yi et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
1
sativanone R , R2 = H
HO
O
O
A,17 promethazine,18 O-heterocycles,19 and antiasthmatic drug
montelukast.20
In our previous study, we reported that the enantiomeric purity
and absolute configuration of flavanones could be determined by
1
OCH3
R2
1 = H; R2 = OCH3
R
1 = OH; R2 = H
2
3'-O-methylviolanone
R
R1
3
homoferreirin
OCH3
using (S)-3,3-dibromo-1,1-bi-2-naphthol as
a chiral solvating
agent by means of 1H NMR spectroscopy.21 Herein, three isofla-
vanones sativanone 1, 30-O-methylviolanone 2, homoferreirin 3
(Fig. 2) isolated from Dalbergia odorifera, were chosen as represen-
tatives. Their enantiomeric purity and absolute configuration were
determined using commercially available binaphthyl-type
Figure 2. Structures of three isoflavanones isolated from Dalbergia odorifera.
been reported that enantiopure BINOL was a good NMR chiral sol-
vating agent for the determination of the enantiomeric purity of
different chiral compounds, including antitumor alkaloid crispine
Figure 3. Overlaid 1H NMR spectra (600 MHz in CDCl3) of natural sativanone 1 (3.5 mg) in the presence of (S)-BINOL (0–12 equiv).
Figure 4. Overlaid 1H NMR spectra (600 MHz in CDCl3) of natural sativanone 1 (0.5–3.0 mg) in the presence of 9 equiv of (S)-BINOL.
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J. Yi et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
binaphthol (BINOL) as a chiral solvating agent. To the best of our
knowledge, this is the first successful attempt to develop an
approach for the enantiomeric purity determination of isofla-
vanones using an NMR method.
BINOL as the chiral solvating agent. Firstly, the effect of the amount
of (S)-BINOL on the signal separation was investigated. Natural
sativanone 1 with (S)-BINOL displayed dramatic changes in the
chemical shift values of the 1H NMR signals for H-2a (trans to H-
3). A gradual increase in the amount of (S)-BINOL resulted in a
gradual increase in the chemical shift difference between the two
enantiomers. The results obtained using 9 equiv and 12 equiv of
(S)-BINOL were more satisfactory than those obtained using less
(S)-BINOL (Fig. 3). Since the addition of 9 equiv and 12 equiv of
2. Result and discussion
Natural sativanone 1 was chosen as the model substrate during
the chiral discrimination experiments of isoflavanones using (S)-
Figure 5. Chiral-SFC analysis of sativanone enantiomers: (a) chiral-SFC analysis of sample sativanone 1; (b) purity check of (S)-sativanone and (R)-sativanone.
Figure 6. CD spectra analysis of sativanone enantiomers: (a) (S)-sativanone; (b) (R)-sativanone. The samples were dissolved in methanol and the concentration was
0.167 mg/mL; the measurement temperature was 25 °C.
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J. Yi et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Figure 7. The dR and dS signs of H-3a: sativanone 1 (3.5 mg) with 9 equiv of BINOL in CDCl3 (600 MHz). (a) (R)-sativanone and (S)-BINOL; (b) (S)-sativanone and (S)-BINOL; (c)
natural sativanone and (S)-BINOL; (d) (R)-sativanone and (R)-BINOL; (e) (S)-sativanone and (R)-BINOL; (f) natural sativanone and (R)-BINOL.
(S)-BINOL resulted in a similarly distinct signal separation, the
optimum amount of (S)-BINOL to be used for the chiral discrimina-
tion of natural sativanone was 9 equiv.
Next, in order to obtain (S)- and (R)-sativanone, the chiral sep-
aration of natural sativanone on a preparative scale was achieved
by using supercritical fluid chromatography (Fig. 5). The determi-
nation of their configurations was based on the detection of CD
spectra (Fig. 6), in which an obvious Cotton effect (CE) was
observed. (S)-Sativanone showed negative CE at 320–340 nm,
while (R)-sativanone showed a positive CE at same absorption.6
The experimental results of (S)- or (R)-sativanone associated
respectively with one enantiomer of BINOL and are shown in Fig-
ure 7. According to the results, when (S)- and (R)-sativanone were
associated with (S)-BINOL as the chiral solvating agent, the chem-
ical shift value of H-2a of (R)-sativanone was greater than that of
H-2a of (S)-sativanone (H-2a: dR > dS). Conversely, when associated
with (R)-BINOL, the chemical shift value of H-2a of (S)-sativanone
Secondly, the effect of the concentration of sativanone 1 with
9 equiv of (S)-BINOL on signal separation was addressed (Fig. 4).
When the addition of sativanone 1 was less than 3 mg/0.5 mL
(0.02 mmol/mL), it showed no obvious signal separation for H-2a.
This result possibly contributed to the weak ability of the hydroxy
group in (S)-BINOL group to form a hydrogen bond at low concen-
trations. Moreover, increasing the amount of BINOL when sati-
vanone 1 was present in lower concentrations also resulted in
incomplete signal separation. Therefore, the appropriate concen-
tration of sativanone 1 to be used for chiral discrimination was
established as no less than 0.02 mmol/mL.
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J. Yi et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Figure 8. (a) Structures of sativanone 1 and (S)-BINOL. The arrows represent the observed intermolecular NOEs; (b) 2D NOESY spectrum of (S)-sativanone (3.5 mg) and
9 equiv of (S)-BINOL; (c) (R)-sativanone (3.5 mg) and 9 equiv of (S)-BINOL (500 MHz in CDCl3).
was greater than that of H-2a of (R)-sativanone (H-2a: dS > dR).
These results indicated that the chemical shifts were affected by
strong aromatic shielding effects or weak shielding effects pro-
duced by the BINOL, which depended on the spatial location of that
hydrogen atom with regards to the naphthyl rings. Therefore,
when two enantiomers of an isoflavanone is associated with one
enantiomer of chiral solvating agent through noncovalent bonds,
a comparison of the chemical shift values of H-2a for two diastere-
omeric complexes can determine their absolute configuration
(dR > dS or dS > dR), i.e., the absolute configuration of isoflavanone
can be constructed by comparing the chemical shifts of H-2a in
the presence of enantiopure BINOL.
To elucidate the association of the complexes of BINOL and (S)-
and (R)-sativanone, some attempts were made to achieve addi-
tional structural information via 2D NOESY experiments on the
BINOL/sativanone complex. In Figure 8, correlation peaks between
several BINOL aryl signals and the H-2a signals of (S)- and (R)-sati-
vanone were clearly detected, thus indicating the close intermolec-
ular association of BINOL and the sativanone enantiomers.
HPLC-UV absorption peaks for the (S)- and (R)-configuration. The
results suggested that the data obtained using NMR methods clo-
sely matched those obtained using chiral HPLC analysis.
3. Conclusion
The absolute configuration of most natural isoflavanones was
often established as (R)- or (S)- by the CD method. However, an
incorrect result could be obtained when an enantiomeric molecule
is present. In our study, isoflavanones when associated with com-
mercially available chiral solvating agents (R)- or (S)-BINOL per-
mitted their enantiodifferentiation via 1H NMR spectroscopy. The
absolute configuration of enantiomers isoflavanones was assigned
by comparing the corresponding dR and dS with the models. The
formation of H-bond complexes of (S)- and (R)-isoflavanones with
BINOL was supported by the NOE results. In conclusion, the NMR
approach provides a simple and general means to tentatively
assign the enantiomeric purity and absolute configuration of
isoflavanones.
The separating results inspired us to apply this NMR method to
other natural isoflavanones from Dalbergia odorifera. We chose 30-
O-methylviolanone to screen (S)-BINOL as a chiral solvating agent
by using 1H NMR spectrum, recorded in CDCl3. To make this
method suitable for more polar compounds which are difficult to
dissolve in a nonpolar solvent, we recorded the 1H NMR spectrum
of the mixture of homoferreirin and (S)-BINOL in a CDCl3/acetoni-
trile-d3 mixture (v/v, 9:1). In addition, 1H NMR analysis and chiral
HPLC were compared for the determination of the enantiomeric
purity (Table 1). The enantiomeric purity was determined by inte-
grating the corresponding H-2a signals in the 1H NMR spectra and
4. Experimental
4.1. General
1H, 13C and 2D NMR spectra were obtained using a Bruker AV-
400, 500 or a 600 instrument. Circular dichroism (CD) spectra were
recorded on Chirascan CS30049 instrument. Optical rotatory dis-
persion (ORD) values were measured on an Autopol VI instrument,
manufactured by Rudolph Research Analytical, Hackettstown, NJ.
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J. Yi et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 1
Comparison of NMR spectra and chiral HPLC analysis of isoflavanones 1–3
Isoflavanones Spectraa
(S):(R) (%)
(S):(R) (%)
(NMR)
(HPLC)
1
50.5:49.5
50.1:49.9
2
53.1:46.9
54.8: 45.2
3
50.5:49.5
50.1:49.9
a
Sativanone 1 and 30-O-methylviolanone 2 in the presence of 9 equiv of (S)-BINOL in CDCl3 600 MHz; homoferreirin 3 in the presence of 9 equiv of (S)-BINOL in CDCl3/
acetonitrile-d3 (9:1) 500 MHz.
The ESI-MS and HR-ESI-MS analysis were performed on a Finnigan
LCQ Deca XP equipped with an electrospray ionization source mass
ion-trap spectrometer. HPLC analysis was performed on an Agilent
1200 instrument equipped with a quaternary pump and multiple
wavelength detectors (MWD). Supercritical fluid chromatography
(SFC) analysis was performed on a SFC instrument (Thar, Waters).
(S)- and (R)-BINOL were obtained from Daicel Corporation
(Shanghai, People’s Republic of China) and used without further
purification. The deuterated solvents were CDCl3 (99.80%) from
Cambridge Isotope Laboratories (USA) and acetonitrile-d3
(99.80%) from Sigma–Aldrich (Germany). Ethanol, methanol,
ammonia, (CINC, Shanghai, China) were of HPLC grade. High-purity
carbon dioxide (CO2, 99.999%) was from AP BAIF Gases (Beijing,
China).
Three substrate compounds for NMR analysis were all naturally
occurring isoflavanones, which were isolated from the plant Dal-
bergia odorifera using a procedure described previously.22 Their
structures were identified by comparing 1H NMR and 13C NMR data
with those of literatures reported, as sativanone,23 30-O-methylvi-
olanone,22 homoferreirin.22
J = 11.0, 11.3 Hz, 1H; H-2a), 4.41 (dd, J = 11.0, 5.3 Hz, 1H; H-2b),
4.15 (dd, J = 11.3, 5.3 Hz, 1H; H-3), 3.75 (s, 3H, 20-OCH3), 3.72 (s,
3H, 40-OCH3); 13C NMR (100 MHz, DMSO-d6, d): 190.3 (C@O),
164.2 (C-7), 163.2 (C-9), 159.9 (C-40), 158.1 (C-20), 130.6 (C-5),
128.9 (C-60), 116.1 (C-10), 113.9 (C-10), 110.5 (C-30), 104.9 (C-50),
102.3 (C-6), 98.8 (C-8), 70.3 (C-2), 55.6, 55.2 (2 ꢀ OCH3), 46.6 (C-
3); ESI-MS (m/z): 301 [M+H]+; [ 20 = 0 (c 1.0, MeOH); (S)-sati-
a]
D
vanone: [
a
]
D
20 = 26 (c 0.5, MeOH); (R)-sativanone: [
a]
20 = ꢁ28 (c
D
0.5, MeOH).24
4.1.2. 30-O-Methylviolanone 2
1H-NMR (400 MHz, DMSO-d6, d): 10.60 (s, 1H, 7-OH), 7.69 (d,
J = 8.6 Hz, 1H; H-5), 6.85 (d, J = 8.6 Hz, 1H; H-60), 6.74 (d,
J = 8.5 Hz, 1H; H-50), 6.53 (dd, J = 8.6, 2.2 Hz, 1H; H-6), 6.35 (d,
J = 2.2 Hz, 1H; H-8), 4.51 (dd, J = 11.5, 11.2 Hz, 1H; H-2a), 4.44
(dd, J = 11. 2, 5.6 Hz, 1H; H-2b), 4.14 (dd, J = 11.5, 5.6 Hz, 1H; H-
3), 3.78 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.70 (s, 3H, OCH3). 13C-
NMR (100 MHz, DMSO-d6, d): 191.0 (C-4), 164.9 (C-7), 163.8 (C-
9), 153.5 (C-40), 151.9 (C-20), 142.2 (C-30), 129.5 (C-5), 125.0 (C-
10), 122.2 (C-60), 114.4 (C-10), 111.1 (C-6), 108.2 (C-50), 102.9 (C-
8), 71.1 (C-2), 61.6 (OCH3), 60.7 (OCH3), 56.3 (OCH3), 47.8 (C-3).
4.1.1. Sativanone 1
ESI-MS (m/z): 331 [M+H]+; [ 20 = +1 (c 1.0, MeOH).
a]
D
1H NMR (400 MHz, DMSO-d6, d): 10.59 (s, 1H, 7-OH), 7.68 (d,
J = 8.7 Hz, 1H; H-5), 6.99 (d, J = 8.4 Hz, 1H; H-60), 6.58 (d,
J = 2.4 Hz, 1H; H-8), 6.52 (dd, J = 8.7, 2.2 Hz, 1H; H-6), 6.48 (dd,
J = 8.4, 2.4 Hz, 1H; H-50), 6.34 (d, J = 2. 2 Hz, 1H; H-30), 4.52 (dd,
4.1.3. Homoferreirin 3
1H NMR (400 MHz, DMSO-d6, d): 12.25 (s, 1H, OH), 10.80 (s, 1H,
OH), 7.05 (d, J = 8.4 Hz, 1H; H-60), 6.60 (d, J = 2.4 Hz, 1H; H-30), 6.51
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J. Yi et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
(dd, J = 8.4, 2.4 Hz, 1H; H-50), 5.91 (d, J = 2.2 Hz, 1H; H-8), 5.90 (d,
J = 2.2 Hz, 1H; H-6), 4.49 (dd, J = 11.1, 10.9 Hz, 1H; H-2a), 4.40
(dd, J = 10.9, 5.5 Hz, 1H; H-2b), 4.31 (dd, J = 11.1, 5.5 Hz, 1H; H-
3), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6, d): 197.4 (C-4), 166.9 (C-7), 164.3 (C-9), 163.5 (C-5),
160.7 (C-4), 158.6 (C-20), 131.4 (C-60), 115.7 (C-10), 105.5 (C-50),
102.5 (C-10), 99.4 (C-30), 96.4 (C-6), 95.3 (C-8), 70.2 (C-2), 56.2
(20-OMe), 55.7 (40-OMe), 46.4 (C-3). ESI-MS (m/z): 317 [M+H]+;
4.4. Determination of the enantiomeric purity by traditional
chiral HPLC
The proportions of the enantiomers of all natural isoflavanones
were also determined using an Agilent 1200 HPLC instrument.
Separations of compounds 1 and 3 were performed on a Chiral
CD-Ph (5
l
m, 4.6 mm i.d. ꢀ 250 mm; Shiseido, Japan) using mobile
phase of methanol and H2O (80:20, v/v) at a flow rate of 0.5 mL/
min. The retention time of the (S)-enantiomer of 1 was 12.06 min
while that of the (R)-enantiomer was 13.02 min. The retention
time of the (S)-enantiomer of 3 was 9.66 min and that of the (R)-
enantiomer was 10.72 min. Separation of compound 2 was per-
[a]
20 = 0 (c 1.0, MeOH).
D
4.2. Preparation of (S)- and (R)-sativanone
formed on a Chiral OD-RH (5
l
m, 4.6 mm i.d. ꢀ 150 mm; Daicel
(S)- and (R)-sativanone were obtained by separating natural
sativanone via preparative supercritical fluid chromatography
(SFC). Before the enantiomeric separation, an analytical SFC
Corporation, China), using mobile phase of methanol and H2O
(80:20, v/v) at a flow rate of 0.5 mL/min. The retention time of S
enantiomer of 2 was 17.35 min and that of R enantiomer was
18.07 min. The enantiomeric purity of isoflavanones 1–3 was
determined by integrating HPLC-UV absorption peaks (280 nm)
for the S and R configuration, respectively.
method was established. An aliquot of a 3
for analysis. The sativanone 1 solution was separated on a Chiral-
m (Daicel Industries) ((0–6 min,
lL sample was injected
pak IC column 4.6 ꢀ 100 mm, 5
l
CO2/C2H5OH = 85/15, v/v; 0.2% Methanol Ammonia). The flow rate
was 4.0 mL/min, the back pressure regulation (BPR) pressure was
120 Bar, and the column temperature was 40 °C. The UV detection
wavelength was set at 214–359 nm.
Acknowledgement
This work was supported by the Shanghai Science and Technol-
ogy Committee, China funding (16XD1403500, 16401902000).
Similar to that used in the analytical method, the sativanone
(50 mg) was dissolved in 12 mL MeOH and then separated on a
preparative Chiralpak IC column (20 ꢀ 250 mm, 5
lm, Daicel
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spectra and specific rotation values were recorded.
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In the experiments of chiral solvating agent equivalent numbers
effect, the samples were prepared by dissolving sativanone 1
(3.5 mg) with 3–12 equiv of (S)-BINOL in CDCl3; in the experiments
of substrate concentration effect, the samples were prepared by
dissolving sativanone 1 from 0.5 mg to 3 mg with 9 equiv of (S)-
BINOL in CDCl3; in the experiments of NOE studies, the samples
were prepared by dissolving (S)-sativanone (3.5 mg) and (R)-sati-
vanone (3.5 mg) with 9 equiv of (S)-BINOL and (R)-BINOL in CDCl3;
in the experiments of the absolute configuration and enantiomeric
purity analysis of two other natural isoflavanones, 30-O-methylvi-
olanone (3.5 mg) was dissolved with 9 equiv of (S)-BINOL in CDCl3;
homoferreirin (3.5 mg) was dissolved with 9 equiv of (S)-BINOL in
CDCl3 and acetonitrile-d3 (v/v, 9:1).
Please cite this article in press as: Yi, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.09.002