Synthesis of N-glycoside compounds from phthalimide and 5-nitrobenzimidazole via 1,2-O-sulfinyl derivatives and in vitro cytotoxic activity

Article abstract of DOI:10.1007/s13738-020-01877-3

An efficient synthesis of 1,2-trans-N-glycosylated derivatives from phthalimide and nitrobenzimidazole via 1,2-O-sulfinyl monosaccharides has been established. Such S_N2-type displacements at the anomeric center are stereospecific, giving a sing

Full text of DOI:10.1007/s13738-020-01877-3

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01877-3
ORIGINAL PAPER
Synthesis of N‑glycoside compounds from phthalimide
and 5‑nitrobenzimidazole via 1,2‑O‑sulfnyl derivatives and in vitro
cytotoxic activity
Abdelhafd Benksim1,2 · Said Elhizazi2 · Brahim Lakhrissi3 · Mohamed Amine4 · Mohamed Cherkaoui1 ·
Abdessamad Tounsi5 · Anne Wadouachi6
Received: 21 November 2018 / Accepted: 12 February 2020
© Iranian Chemical Society 2020
Abstract
An efcient synthesis of 1,2-trans-N-glycosylated derivatives from phthalimide and nitrobenzimidazole via 1,2-O-sulfnyl
monosaccharides has been established. Such SN2-type displacements at the anomeric center are stereospecifc, giving a single
anomer. The reaction was optimized using a polar aprotic solvent and K2CO3 at 80 °C. Phthalimide and nitrobenzimidazole
1,2-trans-N-glycoside derivatives were easily obtained with a free hydroxyl at C-2, which can be further functionalized.
The compounds 3d–e displayed a signifcant cytotoxic activity exceeding 50% of inhibition at 125 μg/Ml against the human
cancer cell line (Hep-2).
Keywords Glycoside · Cyclic sulfte · Phthalimide · 5-Nitrobenzimidazole · Cytotoxic activity
Introduction
number of well-known drugs are heterocycles, such as qui-
noline antimalarials [2], lactam antibiotics [3], indoles [4],
pyrimidines [5], imidazole derivatives [6], as well as other
important derivatives of considerable pharmaceutical inter-
est [7–9]. For this reason, the development of stereoselective
synthesis of novel derivatives, their structural characteriza-
tions, and their biological properties is a topic of increasing
interest for a large number of research groups. The synthe-
sis of compounds containing the subunit phthalimide and
nitrobenzimidazole has been described as scafolding to
design new drug candidates with diferent biological activi-
ties [1]. Phthalimide is a non-aromatic bicyclic nitrogen
heterocycle, and its derivatives are an interesting class of
compounds having a wide range of applications [10]. These
compounds are lipophilic and neutral compounds and can
also easily cross biological membranes in vivo. These deriv-
atives have been used for their pharmacological activities,
such as hypolipidemic [11], antimicrobial [12], anti-infam-
matory [13], hypoglycemic [14], anticonvulsant [15], anti-
tumor [16], and also antiviral [17].
Heterocycles are a major class of organic compounds char-
acterized by their physical and chemical properties. The
interesting biological and pharmaceutical properties of het-
erocyclic derivatives made these compounds very attractive
for organic synthesis. These structures are present in several
natural products such as nucleic acids, coenzymes, alkaloids,
and glyco-conjugated compounds [1]. Nowadays, a large
* Abdelhafd Benksim
benksima@gmail.com
1
Laboratory of Human Ecology, Cadi Ayyad University,
Marrakesh, Morocco
2
Direction régionale de la santé, Marrakech-Saf (ISPITS de
Marrakech), Marrakech, Morocco
3
Laboratoire de Chimie des Agroressources, Université Ibn
Tofail, Kénitra, Morocco
4
Epidemiology Laboratory, Faculty of Medicine
Benzimidazole compounds are nitrogen heterocycles
which play a key role in medicinal and pharmaceutical dis-
coveries as biologically active compounds, such as antitu-
mor [18], antifungal [19], antiprotozoal [20], anticonvul-
sant [21], antihypertension [22], and antibacterial agents
[23]. The therapeutic signifcance of these clinically active
and Pharmacy, Marrakesh, Morocco
5
Polydisciplinary Faculty, Moulay Slimane University,
Béni-Mellal, Morocco
6
Laboratoire de Glycochimie des Antimicrobiens et
Agroressources, Université de Picardie Jules Verne, Amiens,
France
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Table 1 Optimization of N-glycosylation reaction via cyclic sulfte 1
drugs particularly in the treatment of infectious diseases has
promoted the development of potent compounds in com-
bination with monosaccharides. Carbohydrates, as chiral
pools, have been intensively studied for stereospecifc and
selective reactions in order to develop several families of
compounds of interest. The presence of functionalized and
stereo-controlled centers on sugar can ofer many possibili-
ties to synthesize a new generation of biologically active
compounds, for example, for the inhibition of cell prolif-
eration [24–26]. Our goal was to synthesize new glycoside
derivatives of phthalimide and nitrobenzimidazole for better
cell penetration and therefore to determine their in vitro anti-
tumor activities on human cancer cell line of Hep-2.
and phthalimide
Entry Solvent
Base (3.1 eq.) Reaction time Yield%
1
2
3
4
4
DMF
DMF
DMF
DMF
NaH
6 h
Hydrolysis
Hydrolysis
94
60
Hydrolysis
n-Butyllithium 8 h
K2CO3
K2CO3
30 min
3 h
1 h
HMPA/DMAC K2CO3
Reaction conditions: cyclic sulfte 1 (1 mmol), phthalimide (3 mmol),
base (3.1 mmol), and solvent (35 mL)
Nucleophilic opening of the cyclic sulfte derivative 1 using
phthalimide anion is regio- and stereospecifc at the ano-
meric center through a SN2-type mechanism (Scheme 1).
The structure of N-(3,5,6-tri-O-benzyl-β-d-glucofuranosyl)-
phthalimide 1a was confrmed by NMR and MS analyses
(Table 2) with the presence of phthalimide moiety at the
anomeric position of the tetrabenzylated glucose. The [13]
C NMR spectrum showed the signal of the anomeric carbon
atom of compound 1a highly shielded by about 20 ppm at
85.18 ppm and a chemical shift value of 167.80 ppm cor-
responding to both carboxyl functions. 1H NMR spectrum
showed anomeric proton of compound 1a at δ 5.82 ppm with
a coupling constant J1,2 =0 Hz, which confrmed the fura-
nose form and indicating the 1,2-trans confguration, and the
signals between 7.87 and 7.49 ppm correlated to four aro-
matic protons proved the introduction of phthalimide part.
Infrared spectrum showed an absorption band corresponding
to the hydroxyl on the C-2 at 3398 cm−1. ESI–MS analysis
showed an ion at m/z 618.34 [M+ K]+. In the same way,
the glucopyranoside 2a and arabinopyranoside 3b deriva-
tives were prepared from cyclic sulftes compounds 2 and 3,
respectively, and characterized by NMR analysis. The ano-
meric protons appeared between δ 5.00 and 5.77 ppm and
coupling constants J1,2 between 9.77 and 9.99 Hz, respec-
tively, indicated the pyranose derivatives. 13C NMR spectra
showed the anomeric carbon signal at δ 86.6 and 74.2 ppm
for compounds 2a and 3b, respectively.
Results and discussion
Chemistry
In our previous works, we have described an easy process
leading to C-glycosyl cyanides and O-glycosylation of
diethyl oxoglutarate via 1,2-O-sulfnyl monosaccharides
[27–29]. Furthermore, we synthesized two new water-solu-
ble benzimidazolone derivatives from 1,2-cis cyclic sulfte
[30]. This approach made it possible to introduce an anion
such as the heterocyclic nitrogen onto the anomeric center.
To achieve our objective, various tests were carried out for
optimizing the N-glycosylation reaction. Due to its symme-
try, phthalimide by its nitrogen between two carbonyl func-
tions was chosen as a perfect nucleophile for this N-glyco-
sylation [9].
The N-glycosylation reaction was first studied with
3,4,6-tri-O-benzyl-1,2-O-sulfnyl-α-d-glucofuranose 1 [27]
in the presence of phthalimide and NaH or n-BuLi. Unfor-
tunately, these conditions only led to the hydrolysis of the
cyclic sulfte and obtaining of the corresponding 1,2-diol
glucofuranose tribenzylated. In literature, enantiopure vici-
nal aminoalcohols bearing a phthalimide moiety were pre-
pared by reaction of non-carbohydrate cyclic sulftes with
phthalimide using NaH in DMF, and no hydrolysis was
observed [31]. Under an argon atmosphere, an efcient syn-
thetic route was optimized by changing the base. In the pres-
ence of a weak base such as K2CO3, in DMF at 80 °C, the
N-(3,5,6-tri-O-benzyl-β-d-glucofuranosyl)-phthalimide 1a
was obtained in 94% yield in shorter reaction time (Table 1,
Scheme 1). The phthalimide derivative 1a was already syn-
thesized from 2,3,4,6-tetra-O-benzyl-α-d-glucosyl iodide,
the nucleophilic displacement of the α-iodide anomeric atom
by the phthalimide anion gave the corresponding phthal-
imido β-glycoside derivative in 66% yield [32].
The nitrobenzimidazole derivatives of α-d-
arabinopyranose 3d–e and β-d-xylofuranose 4a–b were pre-
pared from the corresponding 1,2-O-sulfnyl sugars using
the same protocol (Table 2). Compounds 3d and 3e were
prepared after highly efcient and selective deprotection
[34] of 3b–c with 90% yield, and the ratio between 3d/3e
was evaluated at 8/2. HRMS data of the two diasteroiso-
mers showed one ion at m/z 318.0705 [M+Na]+. The latter
1
compounds were characterized by H NMR spectroscopy
showing two signals at 5.50 and 5.51 ppm with a coupling
constant J1,2 =9.22 Hz corresponding to the d-arabinopyra-
noside derivatives 3d–e (Table 2). 13C NMR spectra showed
the peaks between δ 69.2 and 73.8 ppm correlated to three
To the best of our knowledge, there are few references
relating to the nucleophilic substitution of cyclic sulftes
with nitrogen heterocyclic anion at anomeric carbon [33].
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Journal of the Iranian Chemical Society
O
O
OH
BnO
N
O
N
OH
O
N
BnO
1a
BnO
SO(Im)2 THF ; -15°C
O
OH
O
BnO
Y
OH
BnO
4a
4b
X
: X = NO2 et Y = H
: X = H et Y= NO2
Phthalimide
Base / Solvent
Heating
O
5-nitrobenzimidazole
Base / Solvent
Heating
O
O
N
BnO
BnO
N
S
O
N
O
O
O
2a
OH
1 - 4
OBn
OH
Y
Nu
O
N
O
O
X
3b/3c
O
N
SN2 mechanism
CH3CO2H/H2O
O
OH
O
3a
N
O
O
N
OH
Y
HO
HO
X
3d
3e
: X = NO2 et Y = H
: X = H et Y= NO2
Scheme 1 General pathway to obtain nitrobenzimidazole and phthalimide derivatives
free hydroxyls (C-1, C-3, and C-4). Cyclic sulfte 4 was
treated with 5-nitrobenzimidazole anion freshly prepared,
in DMF and in the presence of K2CO3 at 80 °C for giving
two isomers 4a and 4b with 90% yield. Mass spectrometry
analysis showed a single ion at m/z 514.23 [M+K]+, cor-
responding to both isomers, which cannot be separated by
silica gel chromatography. The β-d-xylofuranoses 4a and 4b
were characterized by NMR spectroscopy, which showed
two signals for the anomeric proton between δ 5.88 and
δ 6.01 ppm. In 13C NMR spectrum, the peaks at δ 146.6,
145.5, 144.1, 142.7, and 147.8 confrmed the introduction
of nitrobenzimidazole moiety and two signals correspond-
ing to the anomeric carbon at δ 92.4 and δ 91.9 ppm for
compounds 4a and 4b. This introduction has been reported
in previous studies [19].
from phthalimide and nitrobenzimidazole via 1,2-O-sulf-
nyl monosaccharides as starting materials in polar aprotic
solvent. This new method will be adopted for studying
the novel complex glycosides in which the C-2 position
could be functionalized by other derivatives of potential
biological interest.
Cytotoxic evaluation
Although the advances in oncology are leading to efective
treatments and cure, the cancer is a leading cause of human
death in the worldwide [35]. Therefore, laryngeal cancer is
one of the most common types of head and neck cancers. It
accounts for about 2.7% and 2.1% of all cancers and deaths
due to it, respectively [35].
These provided isomers can be explained by intramo-
lecular mesomeric equilibrium between two nitrobenzi-
midazole anions a and b (Scheme 2). In this case, the
NO2 group leads to the stabilization of anion b. It can
be hypothesized that anion a was more nucleophilic than
anion b. Therefore, compounds (4a–b) cannot be sepa-
rated by column chromatography and the ratio between
isomers: 4a/4b was also evaluated at 8/2 (Scheme 2).
Based on these results, we have developed an efcient
method for the synthesis of new 1.2-trans-N-glycosides
The aim of this investigation was to screen the cyto-
toxic activity of N-glycoside derivatives from phthalimide
and nitrobenzimidazole against human cancer cell lines of
Hep-2 in vitro, using the MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide) colorimetric assay [35].
Cytotoxic index was calculated: %IC = [1 − (Mean
absorbance of treated group/Mean absorbance of negative
control)]×100. The absorbance values obtained per treat-
ment were converted to percentage proliferation [36].
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Journal of the Iranian Chemical Society
Table 2 Synthesis of N-glycoside derivatives of phthalimide and 5-nitrobenzimidazole
1,2-O-sulfnyl deriva- N-glycoside deriva-
% Yield Reac-
δ Anomeric proton J1,2 (Hz) δ Anomeric carbon δ CO δ C-NO2
tives
tives
tion time
(min)
BnO
BnO
O
95
30
5.82
0
85.2
167.8 –
BnO
BnO
O
O
O
N
S
O
O
O
BnO
OH
BnO
1
1a
O
N
BnO
BnO
75
94
60
30
5.70
9.77
9.99
9.22b
86. 6
167.3 –
167.8 –
O
BnO
BnO
O
O
S
O
O
BnO
O
OH
BnO
2
2a
5.05b
74.2
O
O
O
O
O
S
N
O
O
O
O
O
OH
O
3
3a
5.50/5.51b
5.88/6.01
87.3/87.3
–
–
144.3/142.7
O
N
90
90
40
O
O
N
O
S
HO
O
O
O
OH
HO
NO2
3
3d/3e
N
O
100
2.42/2.37 92.4/91.9
144.1/142.7
O
O
N
BnO
S
BnO
O
O
BnO
BnO
OH
NO2
4a/4b
4
NMR spectra were recorded at 300 MHz in CDCl3 or CD3OD
Scheme 2 Isomers of nitroben-
N
6
zimidazole
N
5
O
N
5
N
O
O
N
6
N
a
b
O
After 48 h of incubation, cytotoxic activity of each mol-
ecule tested on the tumor cell lines Hep-2 is summarized
in Fig. 1.
tested, we found that the compound 3d–e can inhibit more
than 50% of the number of viable cells at 125 µg/mL, which
proves that the cytotoxic efects were suitable against Hep-2
cell line. A positive antitumor efect of nitrobenzimidazole
derivatives was observed against breast cancer (MCF7) [37].
Besides, the antitumor efect of benzimidazole nucleosides
against the human laryngeal carcinoma Hep-2 cell line was
reported [38]. Antitumor activity of these compounds may
be assigned to their abilities to inhibit Ser/Thr kinase CK2
To our knowledge, it seems that very little data on cyto-
toxic activities of N-glycoside derivatives from phthalimide
and nitrobenzmidazole exist in literature. In vitro cytotoxic-
ity of compounds 3a, 3d–e and phthalimide against human
cancer cell lines of carcinoma (Hep-2) were evaluated after
48 h of exposure (n = 6). Among the various compounds
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Journal of the Iranian Chemical Society
and 75 MHz, respectively). Spectra were recorded in CDCl3
or MeOD. Assignments of 1H and 13C signals were deter-
mined from decoupling experiments, COSY spectra and
HSQC spectra. HRMS spectra in the positive ion mode were
obtained on a Q-TOF Ultima Global hybrid quadrupole/
time-of-fight instrument, equipped with a pneumatically
assisted electrospray (Z-spray) ion source and an additional
sprayer (Lock Spray) for the reference compound. Optical
rotations were measured on a Perkin Elmer 241 polarim-
eter: concentrations are given in g/100 mL. The starting
5-nitrobenzimidazole was prepared in the laboratory, while
phthalimide was purchased already prepared by chemical
companies.
100
3a
90
Phthalimide
3d-e
80
70
60
50
40
30
20
10
0
DMSO
15.62
31.25
62.5
125
250
500
Concentraꢀon of coumpond (μg/mL)
Fig. 1 Cytotoxic activity against human cancer cell line Hep-2 after
48 h of exposure (n=6)
that acts as a regulator of cell apoptosis and carcinogen-
esis [38]. However, the compounds such as phthalimide 3a
showed the modest antiproliferative activities at 500 µg/
mL with only 60% of inhibition. In some reported studies,
2-phthalimide-1-(4-fuoro-phenyl) ethanone showed the best
inhibition of human MDAMB-231 breast carcinoma and
SKHep-1 hepatoma cell lines [9]. In this study, the promis-
ing cytotoxicity of compounds 3d–e will encourage further
researches to explore their potential as chemopreventive and
chemotherapeutic agents against cancer.
General procedure of N‑glycosylation
via 1,2‑O‑sulfnyl monosaccharides
Under an argon atmosphere, solution of the 1,2-O-sulf-
nyl derivatives (1 mmol) in DMF (15 mL) was added by
a solution of phthalimide or 5-nitrobenzimidazole (3 eq.)
previously stirred at 65 °C for 2 h with K2CO3 (3.1 eq.) in
DMF (10 mL). The reaction mixture was stirred at 80 °C
and then the solvent was removed under reduced pressure
(0.1 bar/0.1 mm) at 70 °C and fltered. The fltrate was
extracted with Et2O-H2O (3/1) (3×50 mL). After that, the
combined organic layers were concentrated and the crude
product is purifed by silica gel chromatography (Hexane/
EtOAc: 8/2), giving the corresponding N-glycosides (1a, 2a,
3a, 4a–b, 3b–c).
Conclusion
In summary, the tested compounds exhibiting antiprolifera-
tive activity showed interesting results which would pro-
mote their use as lead compounds on further studies for the
development of the new anticancer agents. This observation
can open the new perspectives for in-depth studies of these
molecules. The study of the “structure–activity” relationship
and the mechanism of action of the active molecule should
lead to a better valorization of these compounds as potential
anticancer agents.
N‑(3,5,6‑tri‑O‑benzyl‑β‑d‑glucofuranosyl) phthalimide
1a Yellow syrup; [α]2D0: −40,6 (c 0,56 CH2Cl2); 1H NMR
(CDCl3, δppm): 5.82 (s, 1H, H1, J1,2 =0 Hz); 4.15–4.48 (m,
2H, H2,4); 3,65 (dd, 1H, H3, J2,3 = 5.21 Hz), 3.85 (d, 1H,
H5, J5,6 = 1.99 Hz), 3.90 (m, 2H, H6-6′), 4.23/4.69 (m, 6H,
CH2-Ph), 7.25/7.43 (m, 15H, CH2Ph), 7.87/7.49 (dd, 4H,
Ph-Phthalimide); 13C NMR (CDCl3, δppm): 85.18 (C-1), 84.55
(C-2), 78.12 (C-3), 74.80 (C-4), 76.59 (C-5), 70.68 (C-6),
72.40/72.95/73.70 (CH2-Ph), 127.70/128.33 (CH2-Ph),
139.24/139.03/138.39 (Cipso), 167.80 (CO), 132.11/124.04
(Ph-Phthalimide), 134.82 (Cipso); IR (ATR) cm−1: 3398 (OH),
1781 (CO), 2918/2850 (Carom); LRMS (ESI) m/z calcd for
C35H33NO7K [M+K]+ 618.19, found 618.34.
Experimental
General methods and materials
All chemical reagents were purchased from Aldrich or Acros
(France), and solvents (analytical grade) were provided by
Prolabo. Reactions were monitored by thin-layer chromatog-
raphy (TLC) performed on silica gel 60 F254 (Merck) plates
with visualization by UV light (254 nm) and/or by charring
with a vanillin-H2SO4 or cerium molybdate reagent. Column
chromatography was performed with Merck silica 60 (230
mesh). Concentrations were realized on a rotary evapora-
tor at a temperature below 40 °C. 1H and 13C NMR spectra
were recorded on a BRUKER DMX300 spectrometer (at 300
N‑(3,5,6‑tri‑O‑benzyl‑β‑d‑glucopyranosyl) phthalimide
2a Yellow syrup; [α]D20: +65.2 (c 0,46 MeOH); H NMR
1
(CDCl3, δppm): 5.70 (d, 1H, H1, J1.2 =9.77 Hz), 3.60–4.90
(m, 6H, H2-6/6′), 5.00/5.30 (m, 6H, CH2-Ph), 7.20/7.50 (m,
15H, CH2Ph), 7.80/8.23 (m, 4H, Ph-Phthalimide); 13C NMR
(CDCl3, δppm): 86.56 (C-1), 69.36 (C-2), 80.55 (C-3), 78.50
(C-4), 78.10 (C-5), 68.99 (C-6), 75.75/75.38/73.89 (CH2Ph),
129.01/128.83/128.22 (CH2-Ph), 135.58/135.31/138.97
(Cipso), 167.28 (CO), 134.73/124.05 (Ph-Phthalimide), 133.36
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Journal of the Iranian Chemical Society
(Cipso); IR (ATR) cm−1: 3487 (OH), 1774 (CO), 2925/2847
(C- arom); HRMS (ESI) m/z calcd for C35H33NO7Na
[M+Na]+ 602.2149, found 602.2726.
bovine serum, using Dulbecco’s modifed Eagle’s medium
(DMEM) for culture cell lines (Hep-2). A standard solu-
tion (1 mg/mL) of each compound was solubilized in 10%
DMSO. For each compound to be tested, a serial dilution is
carried out with culture medium to obtain several concentra-
tions (500; 250; 125; 62.5; 31.3 and 15.6 µg/mL). After that,
cells were incubated (105 cells/each well of microplate) in a
96-well plate for 24 h. After addition of the compound tested
dissolved in fresh medium, the cells were cultured at 37 °C
for 48 h. The absorbance of untreated cells was served as
the negative controls (culture medium/DMSO). Doxorubicin
was used as positive controls [35, 39].
N‑(3,4‑O‑isopropylidène‑α‑d‑arabinopyranosyl)‑phth
alimide 3a Colorless crystals: melting at 121–130′; [α]2D0:
+36,4 (c 1,90 MeOH; 1H NMR (CDCl3), δ (ppm): 5.70 (d,
1H, H1, J1.2 =9.99 Hz), 3.35–4.50 (m, 3H, H2-4), 3.95/4.05
(m, 2H, H5,5′), 1.25/1.60 (2 s, 6H, (CH3)2-C), 3.29 (s, 1H,
OH).13C NMR (CDCl3): 74.22 (C1), 68.31 (C2), 80.15 (C3),
80.09 (C4), 65.82 (C5), 27.37/25.54 (CH3)2-C), 110.01
(CH3)2-C), 167.84 (CO), 134.35/134.82/123.09/123.49
(Ph-Phthalimide), 131.94 (Cipso). IR (ATR) cm−1: 3509 (OH),
1777 (CO), 2918/2850 (Carom). HRMS (ESI) m/z calcd for
C16H17NO6Na [M+Na]+ 342.0954, found 342.0933.
Cytotoxicity index was calculated based on MTT col-
orimetric assay to assess the antiproliferative activity [36,
39]. The absorbance was measured at 570 nm on microplate
reader.
3‑N‑(α‑d‑arabinopyranosyl)‑6‑nitrobenzimidazole 3d
Acknowledgments The authors thank Dr. Dominique Cailleu and Pr.
Serge Pilard (Picardie Jules Verne University) for NMR, MS–MS spec-
trometry and helpful discussion. Special thanks go also to Pr. Mohamed
Massoui (Rabat university, Morocco) for performing the biological
tests.
and 3‑N(α‑d‑arabinopyranosyl)‑5‑nitrobenzimidazole
20
3e Yellowish solid melting at 125–130′. [α]
:+72,4
D mixture
1
(c0,67MeOH). HNMR (CD3OD), (δppm): 5.50 (d, 1H,
H1, J1.2 =9.22 Hz), 3.78 (t, 1H, H2, J2.3 =3.33 Hz), 3.86 (m,
1H, H3), 3.96 (d, 1H, H4, J4.5 =6.40 Hz), 4.165 (dd, 1H, H5,
J4.5′ = 2.30 Hz), 4.22 (t, 1H, H5′, J5.5′ = 9.47 Hz), 8.15 (q,
1H, CHN2), 8.74–7.75 (m, 3H, Ph). 13C NMR (CD3OD):
87.32/87.28 (C1), 70.10/70.00 (C2), 73.84 (C3), 69.24
(C4), 69.68 (C5), 147.50 (NCIV), 147.32/146.46 (CHN2);
144.31/142.66 (CNO2); 137.34/132.56 (NCipso), 119.54/11
8.69/118.32/115.53/112.87/109.39 (CH de Ph); IR (ATR)
cm−1: 3494 (OH), 2986 (Carom). HRMS (ESI) m/z calcd for
C13H17N3O6Na [M+Na]+318.0697, found 318.0705.
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20
syrup. [α]
: -2,4 (c 0,67 CH2Cl2). 1HNMR (CDCl3)
D mixture
δ (ppm): 5.88/6.01 (dd, 1H, H1, J1,2 = 2.42/3.27 Hz),
4,30 (m, 2H, H2,4), 3,55 (m, 1H, H3), 3.95 (m, 2H,
H5,5′), 4.53/4.75 (m, 6H, CH2-Ph), 7.13/7.45 (m, 15H,
CH2Ph), 8.21/8.33 (s,1H, CHN2), 8.47-7.58 (m, 3H,
Ph). 13C NMR (CDCl3): 92.38/91.96 (C1), 81.79/81.16
(C2), 83.26 (C3), 79.14/78.99 (C4), 68.54/66.31 (C5),
138.05/137.45/136.88 (Cipso), 74.11/72.92 (CH2Ph),
128.93/128.59/128.39/128.14 (CH2-Ph), 147.85 (NCIV),
146.57/145.55 (CHN2), 144.15/142.73(CNO2),132.10/137.4
7(NCipso),111.36/108.15/118.80/116.72/120.38/119.72 (CH-
Ph). IR (ATR) cm−1: 3421 (OH), 2987/2955(Carom). HRMS
(ESI) m/z calcd for C13H17N3O6Na [M + Na]+498.1636,
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The cell lines were cultivated at 37 °C in a humidifed atmos-
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