Chiral separation of novel iminonaringenin derivatives

Article abstract of DOI:10.1002/chir.22812

A series of 4-iminonaringenin derivatives 2-6 have been prepared in good overall yields from a condensation reaction between naringenin and primary amines. The structures of all products were confirmed by ultraviolet, infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques. These derivatives were analyzed by high-performance liquid chromatography using polysaccharide-based chiral stationary phases, namely, Chiralpak IB and Chiralcel OD, using various mobile phases. 2-Propanol showed a high enantioselectivity for naringin and its derivatives using achiral column containing immobilized polysaccharides (Chiralpak IB).

Full text of DOI:10.1002/chir.22812

Received: 3 November 2017
DOI: 10.1002/chir.22812
Revised: 8 December 2017
Accepted: 11 December 2017
R E G U L A R A R T I C L E
Chiral separation of novel iminonaringenin derivatives
Meriem Bouanini1 | Nasser Belboukhari1 | J. Carlos Menéndez2 | Khaled Sekkoum1 |
Abdelkarim Cheriti3 | Hassan Y. Aboul‐Enein4
1 Bioactive Molecules and Chiral
Abstract
Separation Laboratory, Faculty of Science
A series of 4‐iminonaringenin derivatives 2‐6 have been prepared in good overall
and Technology, University of Bechar,
Bechar, Algeria
2 Pharmaceutical and Organic Chemistry
yields from a condensation reaction between naringenin and primary amines.
The structures of all products were confirmed by ultraviolet, infrared, proton
Department, School of Pharmacy,
nuclear magnetic resonance, and carbon‐13 nuclear magnetic resonance
University of Madrid (Complutense),
Madrid, Spain
3 Phytochemistry and Organic Synthesis
spectroscopic techniques. These derivatives were analyzed by high‐performance
liquid chromatography using polysaccharide‐based chiral stationary phases,
Laboratory, Faculty of Science and
namely, Chiralpak IB and Chiralcel OD, using various mobile phases. 2‐
Technology, University of Bechar, Bechar,
Propanol showed a high enantioselectivity for naringin and its derivatives using
achiral column containing immobilized polysaccharides (Chiralpak IB).
Algeria
4 Pharmaceutical and Medicinal Chemistry
Department, Pharmaceutical and Drug
Industries Research Division, National
Research Center, Cairo, Egypt
KEYWORDS
Chiralcel OD, Chiralpak IB, HPLC, N‐ 4‐iminonaringenins, naringin, naringenin, polysaccharide‐
based chiral stationary phases
Correspondence
Hassan Y. Aboul‐Enein, Pharmaceutical
and Medicinal Chemistry Department,
Pharmaceutical and Drug Industries
Research Division, National Research
Center, Dokki, Cairo, Egypt.
Email: haboulenein@yahoo.com
1 | INTRODUCTION
various bioactivities potentially useful in promoting
human health, being an antioxidant that acts as a reactive
Flavonoids are polyphenolic compounds that are widely
distributed in plants and preserve their health against
infections and parasites.1,2 They possess beneficial effects
against several serious human diseases, such as AIDS,
cancer, cardiovascular disease, and neurodegenerative
disorders.3-5 In vitro experimental studies show that flavo-
noids act as antioxidants, antimicrobials, antivirals, and
anti‐inflammatories.6-9 Naringin, (S)‐7‐(((2S,3R,4R,5S,6R)‐
oxygen species scavenger, with neuroprotective proper-
ties.11 It has anticancer effects12,13 and has been investi-
gated as a cancer preventive agent. Some naringin
derivatives have also been investigated for their pharma-
cological properties; for instance, its oxime was screened
for antioxidant activity by Ozyurek et al,14,15 and several
naringenin derivatives have been also studied in this
regard.16,17 It is relevant to note that naringin inhibits
some drug‐metabolizing cytochrome P450 enzymes,
including CYP3A4 and CYP1A2, which may result in
drug‐drug interactions.18 The ingestion of naringenin
and related flavonoids can also affect the intestinal
absorption of certain drugs, leading to either an increase
or decrease in circulating drug levels. To avoid interfer-
ence with drug absorption and metabolism, the
4,5‐dihydroxy‐
6‐(hydroxymethyl)‐3‐(((2S,3R,4R,5R,6S)‐
3,4,5‐trihydroxy‐6 ethyl tetrahydro‐2H‐pyran‐2‐yl) oxy)
tetrahydro‐2H‐pyran‐2‐yl)oxy)‐5‐hydroxy‐2‐(4‐hydroxyphenyl)
chroman‐4‐one, Figure 1, is the conjugate of naringenin
with neohesperidose (rhamnosyl‐ α‐1,2‐ glucose).10 It is
found in abundance in citrus, especially grape fruit, being
partly responsible for its bitter taste. Naringenin shows
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wileyonlinelibrary.com/journal/chir
Chirality. 2018;30:484–490.

BOUANINI ET AL.
485
OH
2.2 | Synthesis of iminonaringenins 2‐6
HO
HO
O
O
O
HO
Naringenin (1 mmol) and the suitable primary amine
(2 mmol) were refluxed in methanol (5 mL) for 24 hours.
The mixture was cooled to room temperature, and, by
adding 10 mL diethyl ether, a solid precipitated out,
which was filtered and recrystallized from ethanol.
O
O
H3C
HO
OH
O
OH
OH
1
Neohesperidoside
Naringenin
Naringin
FIGURE 1 Structure of naringin
2.3 | Characterization data for compounds
2‐6
consumption of citrus (especially grapefruit) and other
juices with medications is advised against. All these phar-
macological properties are due to naringenin, which is
generated by the liver enzyme naringinase by succes-
sively hydrolyzing its 2 glycoside bonds. This enzyme
occurs widely in nature and is of potential industrial
interest for citrus juice debittering and other
applications.19
Because of the presence of a stereogenic center at their
C2 position, flavanones can exist in enantiomeric forms.
For many years, the research in our laboratory has been
directed towards the synthesis and chiral separation of fla-
vanone derivatives.20-22 In the case of naringin, owing to
the presence of additional stereo centers at the
neohesperidoside moiety, the 2 possible species are diaste-
reomers (epimers), but naringenin exists as 2 enantio-
mers. It is worth mentioning at this point that
epimerization processes at the naringinand naringenin
C‐2 stereo center are well known,23 and in fact, the com-
mercially available materials consist of mixtures of both
possible isomers at this stereo center. Interestingly, both
enantiomers of naringenin have shown divergent biologi-
cal properties,24,25 which make their separation particu-
larly important.
2‐(4‐Hydroxy phenyl)‐4‐(propylimino) chromane‐
5,7‐diol (2): yellow powder, yield 65%, mp 200°C to
202°C, UVmax (MeOH): 239 (band I); 315 (band II), IR
(KBr, cm−1): 3377 (OH, strong), 2967 (CH3), 2962‐2918
1
(CH2), 1601 (CN), 1514 (C═C), 1066 (C─O), H NMR
(250 MHz, MeOD, δppm) 7.31 (2H, d, J = 7.5 Hz, H‐2′,
and H‐6′), 6.29 (2H, d, J = 7.5 Hz, H‐3′, and H‐5′), 6.04
(1H, s, H‐8), 5.0 (1H, dd, J = 7.5 and 2.5 Hz, H‐2), 3.60
(2H, m, N─CH2), 2.86 (1H, dd, J = 12.5 and 2.5 Hz,
H3b), 2.62 (1H, dd, J = 12.5 and 7.5 Hz, H3a), 1.27 (2H,
m, CH2), 0, 71 (3H, m, CH3). 13C NMR (63 MHz, MeOD,
ppm): 168.1 (C‐4), 164.4 (C‐7), 159.9 (C‐5), 157.4 (C‐4′),
156.7 (C‐9), 128.7 (C‐2′, C6′), 116.9 (C‐3′,C5′), 95.1 (C‐6),
94.2 (C‐8), 76.7 (C‐2), 59.8 (CH2─N), 40.3 (C‐3), 21.1
(CH2−CH2─N), 11.3 (CH3).
2‐(4‐Hydroxy phenyl)‐4‐(isobutylimino) chromane‐
5,7‐diol (3): brown yellowish powder, yield 60%, mp 210°C
to 212°C, UVmax (MeOH): 225 (band I); 310 (band II), IR
(KBr, cm−1): 3388 (OH, strong), 1607 (C═N), 1508 (C═C),
1126 (C─O).
1H NMR (250 MHz, MeOD, δppm) 7.22 (2H, d,
J = 7.5 Hz, H‐2′, and H‐6′), 6.72 (2H, d, J = 7.5 Hz,
H‐3′, and H‐5′), 6.50 (2H, m, H‐6, and H‐8), 5.07 (1H,
dd, J = 7.5 and 2.5 Hz, H‐2), 3.06 (1H, d, N─CH), 2.85
(1H, dd, J = 2.5 and 12.5 Hz, H3b), 2.61 (1H, dd, J = 7.5
and 12.5 Hz, H3a), 1.32 (6H, m, 2CH3).
The aim of this work is to study the chiral separation
of iminonaringenin diastereoisomer by high‐performance
liquid chromatography (HPLC) and to optimize the ana-
lytical conditions using polysaccharide‐based chiral sta-
tionary phases (CSPs). These derivatives were
synthesized in 1 step by reaction between naringenin
and primary amines.
13C NMR (63 MHz, MeOD, ppm): 168.1 (C‐4,C‐7),
163.6 (C‐5), 160.0 (C‐9), 158.2 (C‐4′),129, 5 (C‐1′),128.7
(C‐2′,‐C6′), 115.6 (C‐3′,C5′), 95.0(C‐6), 94.6 (C‐8), 77.7
(C‐2), 44.6 (CH‐N), 39.6 (C3), 24.3 (2CH3).
2‐(4‐Hydroxyphenyl)‐4‐(tert‐butylimino)
chromane‐5,7‐diol (4): brown powder, yield 62%, mp
206°C to 208°C, UVmax (MeOH): 230 (band I); 300 (band
II), IR (KBr, cm−1): 3420 (OH, strong), 1569 (C═N),
2 | MATERIALS AND METHODS
2.1 | Reagents and solvents
1
1514 (C═C), 1181 (C─O). H NMR (250 MHz, MeOH,
δppm) 7.54 (2H, d, J = 7.2 Hz, H‐2′, and H‐6′), 6.34 (2H,
d, J = 7.2 Hz, H‐3′, and H‐5′), 5.79 (2H, m, H‐6, and
H‐8), 5.12 (1H, dd, J = 7.5 and 2.5 Hz, H‐2), 2.95 (1H,
dd, J = 12.5 and 2.5 Hz, H3b), 2.64 (1H, dd, J = 12.5 and
7.5, H3a), 1.30 (9H, s, 3CH3).
Naringenin was purchased from Sigma‐Aldrich
(Schnelldorf, Germany).
The primary amines used were propylamine,
isobulylamine, tert‐butylamine, 2‐furfurylamine, and
hexylamine, all of which were purchased from
FlukaBuches.
13C NMR (63 MHz, MeOD, ppm): 164.2 (C‐4), 164.1
(C‐7), 162.7 (C‐5), 160.0 (C‐9), 157.4 (C‐4′), 130.9 (C‐1′),

486
BOUANINI ET AL.
127.9 (C‐2′,‐C6′), 126.8 (C‐3′,C5′), 95.0 (C‐6), 94.6 (C‐8),
78.3 (C‐2), 49, 9 (C‐N), 40.7 (C3), 30.4 (3CH3).
2‐(4‐Hydroxy phenyl)‐4‐(furfurylimino)chromane‐
5,7‐diol (5): brown powder, yield 70%,mp 196°C to
198°C, UVmax (MeOH): 225 (band I); 320 (band II), IR
(KBr, cm−1): 3366 (OH, strong), 1607 (C═N), 1514
(C═C), 1170 (C─O).
1H NMR (250 MHz, MeOD, δppm) 7.22 (2H, d,
J = 7.5 Hz, H‐2′, and H‐6′), 6.71 (2H, d, J = 7.5 Hz,
H‐3′, and H‐5′), 6.10 (1H, t, H‐6), 5.76 (1H, dd, J = 7.5
and 2.5 Hz, H‐2), 3.40 (2H, m, H1″), 3.20 (1H, dd, J = 15
and 2.5 Hz, H3b) 2.68 (1H, dd, J = 7.5 and 15 Hz, H3a),
1.63 (2H, m, H2″), 1.37 (2H, m, H5″), 1.29 (6H, m, H3″,
4″), 0.82 (3H, m, H6″).
1H NMR (250 MHz, MeOD, δppm), 7.51 (1H, d,
J = 7.5 Hz, H‐3″), 7.31 (2H, d, J = 7.5 Hz, H‐2′ and
H‐6′), 6.82 (2H, d, J = 4.61 Hz, H‐3′, and H‐5′), 6.48
(1H, m, H‐4″), 6.28 (3H, m, H‐6, 8, and 5″), 5.79 (1H,
dd, J = 7.5 and 2.5 Hz, H‐2), 4.81 (2H, s, N─CH2), 2.90
(1H, dd, J = 15 and 2.5 Hz, H3b), 2.73 (1H, dd, J = 15
and 7.5 Hz, H3a).
13C NMR (63 MHz, MeOD, ppm): 167.9 (C‐4 and C‐7),
163.5 (C‐5), 160.0 (C‐9),158.2 (C‐4′),129.7 (C‐1′), 128.8
(C‐2′&6′), 115.6 (C‐3′ and 5′), 95.6 (C‐6), 94.7 (C‐8), 77.7
(C‐2), 45.1 (C‐1″), 39.7 (C‐3), 31.3 (C‐2″ and C‐4″), 26.5
(C‐3″), 22.5 (C‐5″),14.3 (C‐6″).
13C NMR (63 MHz, MeOD, ppm): 168.5 (C‐4), 167,5
(C‐7), 162.5 (C‐5), 159.9 (C‐9), 158.1 (C‐4′), 152.1 (C‐1″),
143.1 (C‐3″), 129.7 (C‐1′), 128.8 (C‐2′ and 6′), 115.6 (C‐3′
and 5′), 110.6 (C‐4″),108.2 (C‐10), 107.7 (C‐5″), 95.3
(C‐6), 94.8 (C‐8), 77.7 (C‐2), 44.2 (CH2─N), 39.1(C‐3).
2‐(4‐Hydroxy phenyl)‐4‐(hexylimino) chromane‐
5,7‐diol (6): yellow powder, yield 45%, mp 194°C to
196°C, UVmax (MeOH): 225 (band I); 315 (band II), IR
(KBr, cm−1): 3382 (OH, strong), 1596 (C═N), 1552
(C═C), 1125 (C─O).
2.4 | Chromatographic separation
The enantiomeric separations were conducted on a
SHIMADZU LC 20‐A system equipped with a vacuum
degasser, PerkinElmer (Norwalk, Connecticut), Shimadzu
LC 20 AD (Kyoto, Japan) 200 LC pump, injector with
20 μL Rheodyne 1907 sample loop equipped with a UV
detector Shimadzu SPD‐20 A (Kyoto, Japan). All analytes
were dissolved in methanol at concentrations in a 0.5 to
1 mg mL−1 range. Injection volume was 20 μL, and the
UV detector was set at 280 nm. Chromatographic separa-
OH
OH
RO
RO
H
N
O
O
CH3
HO
O
N
O
RO
O
RO
O
HO
O
O
R=
O
R NH2
OR
OR
n
MeOH, Δ,24h
OH
CH3
OH
R
2-6
1
FIGURE
4
Chiralpak
IB
(cellulose
tris‐(3,5‐
FIGURE 2 Synthesis of 4‐iminonaringenins 2‐6
dimethylphenylcarbamate)
FIGURE 3 Structures and yields of 4‐
iminonaringenin derivatives 2‐6

BOUANINI ET AL.
487
tions were conducted at ambient temperature under
isocratic mode at a flow rate of 0.2 to 0.4 mL min−1, which
may be changed in particular cases.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis of 4‐iminonaringin
derivatives
The synthesis of 4‐iminonaringenin derivatives (com-
pounds 2‐6) was achieved directly from naringenin 1,
which was treated with various primary amines in
refluxing methanol without the addition of any external
catalyst as shown in Figure 2. The reaction yields ranged
45% to 70% as shown in Figure 3. The structures of the
synthesized compounds were confirmed by the analysis
2.5 | Chiral stationary phases
Two polysaccharide CSPs were evaluated in this study,
namely, cellulose derivatives: Chiralcel OD and Chiralpak
IB purchased from Chiral Technologies Europe (Illkirch,
France). HPLC‐grade solvents used were 2‐propanol,
methanol, and ethanol.
FIGURE 5 Chromatograms of enantiomeric separation of compounds 1 and 5 under polar organic phase mode using 100% EtOH in
Chiralpak IB, temperature 25°C, and UV detector set at 280 nm.
FIGURE 6 Chromatograms showing the enantiomeric separation of compounds 1, 2, 3, 4, 5, and 6 under polar organic phase mode using
100% 2‐propanol in Chiralpak IB, temperature 25°C, and UV detector set at 280 nm

488
BOUANINI ET AL.
TABLE 1 Chromatographic data for the separation of 4–iminonaringenins derivatives by Chiral HPLC
CSP
Eluent, % of alcohol
Product
Flow Rate, mL/min
t1
t2
k1
k2
Rs
α
Chiralpak IB
2–Propanol
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
24.70
24.24
23.62
24.47
26.42
26.33
9.59
–
29.32
28.81
27.46
28.83
32.09
31.89
10.99
–
5.17
5.06
4.90
5.11
5.60
5.58
1.39
–
–
–
1.44
–
1.14
–
6.32
6.02
5.86
6.62
7.02
6.97
1.74
–
–
–
1.83
–
1.25
–
2.77
3.00
2.30
2.84
2.83
2.78
2
–
–
–
1.57
–
0.84
–
–
0.88
–
1.22
1.19
1.20
1.29
1.25
1.24
1.25
–
–
–
1.27
–
1.09
–
0.2
EtOH
–
–
–
–
0.4
0.4
9.77
–
8.59
–
–
8.59
11.34
–
9.01
–
–
9.03
MeOH
–
1.14
–
–
–
1.25
–
–
–
1.09
–
–
–
–
–
–
–
Chiralcelk OD
2–Propanol
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
6
22.62
–
–
–
24.09
–
12.96
7.50
13.23
12.63
7.15
–
7.39
–
–
–
37.89
–
–
–
–
–
13.94
–
13.96
13.88
7.46
–
13.91
4.65
–
–
–
5.02
–
2.24
0.87
2.30
2.15
0.78
–
0.84
–
–
–
–
–
8.47
–
–
–
–
–
2.48
–
2.49
2.47
0.86
–
2.47
–
–
–
–
–
2.34
–
–
–
–
–
0.65
–
0.36
0.62
0.62
–
0.68
–
–
–
–
–
1.82
–
–
–
–
–
1.10
–
1.08
1.14
1.10
–
1.88
–
–
–
–
–
0.2
0.4
0.4
EtOH
MeOH
–
–
–
–
–
–
–
Abbreviations: HPLC, high–performance liquid chromatography; CSP, chiral stationary phase.
of their spectral data, including UV/IR (the spectra of all
products did not show any absorption due to the presence
of C═O).
its imino derivatives are unexplored in this regard. Poly-
saccharide‐based (cellulose and amylose) CSPs have
proved to be very efficient materials in HPLC (in both
normal and reversed and polar organic phase modes) for
the resolution of chiral drugs. The chiral discrimination
power of these polysaccharide phases stems from complex
interactive forces (which have not been fully elucidated
yet) with the solutes. In summary, a combination of
hydrophobic interactions, hydrogen bonding, dipole‐
dipole interactions, and charge transfer (π‐π) formation
is believed to explain the chiral recognition mecha-
nisms.27-30 The difference in the chiral recognition ability
between the amylose and the cellulose may be due the dif-
ference in the polysaccharide configuration. Amylose pos-
sesses a more helical configuration than cellulose that is
more rigid and linear in nature.
3.2 | Enantioseparation of the 4‐
iminonaringenin derivatives
The chromatographic conditions were optimized to
achieve the best separation of the 4‐iminonaringin enan-
tiomers under polar organic phase and normal phase
modes using cellulose tris (3,5‐dimethylphenylcarbamate)
coated on 10 μm silica‐gel (Chiralcel OD) and cellulose
tris (3,5‐dimethyl phenylcarbamate) immobilized on
5 μm silica‐gel (Chiralpak IB), whose structure is shown
in Figure 4. HPLC enantioseparation of naringenin has
been previously reported on polysaccharide CSPs,26 but

BOUANINI ET AL.
489
The chiral separation of the 4‐iminonaringenin deriv-
ORCID
atives was assayed in normal and organic polar phase
modes. However, in normal phase mode, no separation
was obtained using mobile phases consisting of hexane‐
EtOH: 95‐5, 50:50 v/v for the compounds under study.
However, under organic polar phase mode using 100%
alcohol, efficient enantioseparations were achieved. In
the first experiment, naringenin was resolved on
Chiralpak IB and Chiralcel OD using a mobile phase
consisting of neat MeOH albeit with a low resolution
(R = 0.8 under Chiralpak IB and R = 0.68 under
Chiralcel OD).
Hassan Y. Aboul‐Enein
7009
http://orcid.org/0000-0003-0249-
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This study describes the synthesis of various 4‐
iminonaringenin derivatives and discusses their
enantioseparation using 2 polysaccharide‐based CSPs,
namely, Chiralpak IB and Chiralcel OD. The best resolu-
tion for naringenin and 4‐iminonaringenins was achieved
when using immobilized type Chiralpak IB columns
under polar organic phase mode using 100% 2‐propanol
as the mobile phase.
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