FeCl3-promoted and ultrasound-assisted synthesis of resveratrol O-derived glycoside analogs

Article abstract of DOI:10.1016/j.ultsonch.2014.05.022

Phenol derived O-glycosides were synthesized using a direct and convenient O-glycosidation, starting from acetylated sugars in the presence of FeCl ₃, an inexpensive, mild and benign Lewis acid catalyst. The reactions were carried out under bot

Full text of DOI:10.1016/j.ultsonch.2014.05.022

Accepted Manuscript
FeCl3-promoted and ultrasound-assisted synthesis of resveratrol O-derived gly-
coside analogs
Hamid Marazg, Guillaume Robert, Maeva Dufies, Khalid Bougrin, Patrick
Auberger, Rachid Benhida
PII:
S1350-4177(14)00181-3
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2014.05.022
ULTSON 2618
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 November 2013
23 May 2014
26 May 2014
Please cite this article as: H. Marazg, G. Robert, M. Dufies, K. Bougrin, P. Auberger, R. Benhida, FeCl3-promoted
and ultrasound-assisted synthesis of resveratrol O-derived glycoside analogs, Ultrasonics Sonochemistry (2014),
doi: http://dx.doi.org/10.1016/j.ultsonch.2014.05.022
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FeCl3-promoted and ultrasound-assisted synthesis of resveratrol
O-derived glycoside analogs
Hamid Marazg,a,b Guillaume Robert, c Maeva Dufies, c Khalid Bougrin,*b Patrick Auberger, c Rachid
Benhida,*a
a Institut de Chimie de Nice UMR CNRS 7272, Université Nice-Sophia Antipolis, Parc Valrose, 06108 Nice
Cedex 2, France. b Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23,
Université Mohammed V-Agdal, Faculté des Sciences B.P. 1014 Rabat, Maroc. c Centre Méditérranéen de
Médecine Moléculaire UMR INSERM U1065, Equipe 2 Cell Death Differentiation and Cancer, Equipe
Labellisée par la Ligue Nationale contre le Cancer, Université de Nice-Sophia Antipolis, C3M - Bâtiment
ARCHIMED 151 route Saint Antoine de Ginestière, 06204 Nice, France
Abstract
Phenol derived O-glycosides were synthesized using a direct and convenient O-glycosidation, starting
from acetylated sugars in the presence of FeCl3, an inexpensive, mild and benign Lewis acid
catalyst. The reactions were carried out under both conventional and ultrasonic irradiation conditions.
In general, improvement in rates and yields were observed when reactions were carried out under
sonication compared with conventional conditions leading to the corresponding β-O-glycosides as the
major anomer. Post-synthtetic transformations of iodophenol intermediates led to new resveratrol O-
glycoside analogs in good overall yields.
1. Introduction
Polyphenols carrying cabohydrates are important group of chemical substances found in several
medicinal plants. Polyphenols are an important part of the human diet and are present in berries,
grapes-wine, tea, chocolate-cacao, coffee, soybeans, and other fruits and vegetables [1]. Currently,
there is increase interests in the beneficial health effects of dietary polyphenols, because these
compounds may have antiaging, antioxidative, antiinflammatory, anticarcinogenic and epigenetic
activities [2, 3].
Among this class of compounds, resveratrol is undoubtedly the well-known naturally occurring
polyphenol with high therapeutic potential [4-7]. However, the oral bioavailability of resveratrol is
extremely low due to rapid and extensive metabolism and the formation of various metabolites such as
glucuronides and sulfate derivatives [8]. Other analogs of resveratrol were also found in wine and
other natural plant species. Among them, piceatannol has shown anticancer activities and is supposed
to be the first metabolite of resveratrol by the cytochrome p450 enzyme CYP1B1 [9]. Trans-piceid
and astringin, the β-glucoside derivatives of resveratrol and piceatannol, respectively, also occurred in
nature and were found to be their major derivatives in grape juices. Several studies have shown that
piceid has better bioactivities than resveratrol and that, glycosylation of resveratrol protects it from
enzymatic oxidation [10]. The glycosylated analogs of resveratrol are also interesting for their high
water solubility and bioavailability compared to the parent compound [11]. Indeed, glycosylation can
drastically improve both the physicochemical and biological properties of these molecules such as
slow release, better solubility and drug metabolism.
Figure 1. Chemical structure of bioactive natural phenyl-O-glycosides
A large number of O-glycosidation methods have been reported. In general, O-glycosidation reaction
usually involves the coupling of a glycosyl donor with a leaving group at its anomeric center and a
1

protected glycoside acceptor. Among them, the Koenigs-Knorr and trichloroacetimidate methods are
the most polpular [12]. This reaction can be activated under basic or acidic conditions depending on
the sugar substrate used. Several examples of O-glycosidation of phenols have been reported. Among
them, the utilization of trichloroacetimidates seems to be the most studied approch [12, 13]. However,
even if this strategy gave good yields it has some drawbacks, i.e., the synthesis of the apropriate
trichloroacetimidate prior glycosylation and the use of strong Lewis acids, such as TMSOTf and BF3-
Et2O. Furthermome, only limited examples were reported with green and begnin promoters such as
FeCl3 particularly in combination with ultrasound activation and, a direct and selective glycosylation
of resveratrol generaly gives very low yields [14].
In continuation of our investigations directed at the development of original procedures for the
synthesis of bioactive nucleoside analogs [15], we report herein an efficient two-step procedure of
phenol derived O-glycosides as resveratrol analogs. This procedure involves (i) a direct O-
glycosidation, using iron catalysis and ultrasound activation, followed by (ii) modular transformation
of the obtained iodinated derivatives using Pd-catalyzed Heck cross-coupling (Figure 2).
Figure 2. Two-step procedure for the synthesis of 4a-4e
2. Results and discussions
As a model reaction, we investigated the ribosylation of p-iodophenol using commercially available
tetra-O-acetylribose 1a and various Lewis acid catalysts, in the presence and absence of ultrasound
irradiation, respectively (Table 1). In our first attempt using zinc, tin and indium catalysts no reaction
occured and only marginal amounts of the desired product 1b were detected by 1H NMR (entries 1-3).
In similar way, AlCl3 only gave poor yield (entry 4). Interestingly, FeCl3 led to increased yield and
reaction was significantly accelerated under ultrasound irradiation (entry 5). After further
optimization, the best result was obtained using 1 equivalent of FeCl3 leading to 1b as a major product
in 82% yield and within a short reaction time (20 min, entry 6), compared to conventional conditions
(71% after 4 h). This result clearly demonstrates that the high-energy effects of acoustic cavitation
with the expected mechanical pulverization and ultimate dissolution of suspended iron catalyst were
responsible for the enhanced reaction rate and yield [16]. Furthermore, a dramatic solvent effect was
observed for this transformation since, when the same reaction was carried out in toluene, a dramatic
decrease in yield was observed (82% vs 15%, entry 6 vs 7) even with a prolonged reaction time and
increased amount of catalyst. Moreover, this reaction is completely prevented in polar solvents such as
CH3CN and DMF (data not shown). Furthermore, we also observed that other FeII and FeIII catalysts
such as Fe(acac)3, FeCl2, FeSO4 and Fe2O3 were not effective for this transformation (entries 8-11).
These results clearly show that FeCl3, a stronger Lewis acid catalyst than FeCl2, and ultrasound
irradiation in CH2Cl2 are the best conditions for this transformation. The integrity of the β-
configuration was unambiguously attested by 1H and 2D-Noesy NMR spectra (δ H1’= 5.52 ppm and
Noesy correlation between H1’ and H4’).
Table 1. Effect of Lewis acid catalyst and ultrasound activation on the O-ribosylation reaction
Encouraged by these results and considering the efficiency of the procedure that involved a
cooperative effect of iron and ultrasound activation in promoting O-glycosidation, the scope of this
transformation was examined with a range of sugars and phenols under ultrasound irradiation (Table
2). Fortunately, reaction of ribose 1a and different substituted phenols 2b, 2c and 2d gave moderate to
good yields of the corresponding products 3b, 3c and 3d, respectively and after short reaction times
2

(20-30 min, entries 1-3). Surprisingly, the same reaction when conducted with 2-nitro-resorcinol 2e
only provided a C-nucleoside analog 3e as a mixture of two anomers (α/β: 1/3), in 80% yield. The β-
stereochemistry was attested by comparison of the chemical shift (δ) of the two obtained anomers
[17]. This total C- versus O-chemoselectivity is probably due to steric and electronic factors induced
by NO2 group. Indee, the O-glycosidation is prevented by both electronic and steric effects of the α-
NO2 group. In contrast, the carbon center, which is in the meta position relative to NO2 group, is not
affected by these electronic and steric factors. Concerning the stereoselectivity, we observed an
increase in the proportion of the α-anomer (α/β: 1/3) compared to the O-glycosylation reaction. This
decrease in selectivity can be explained by (i) β-to-α epimerization, a thermodynamically disfavored
process [18] or (ii) O-to-C rearrangement thus increasing the amount of the α- anomer [19]. Further
experiments are needed to clarify this situation.
Furthermore, in the case of other six-membered ring sugar derivatives 1b-1d, the glycosylation
reaction also occurred in similar way to afford the desired products 3f-3k, respectively (entries 5-10).
We also observed that phenols 2a (p-iodo), 2b (p-allyl) and 2d (naphtyl) were more reactive than 2c
(p-acetamide) and gave better yields. This result may be explained by the expected electronic effect of
the phenol substituent, which participates to the nucleophilicity (electronic density) of the phenol
derivative in the key addition step to the oxonium intermediate.
Table 2. Scope of FeCl3 and US-mediated glycosidation.
With this optimized procedure in hand, we investigated further functional group transformations,
starting from p-iodophenyl glycosides 3a and 3f. At first, we focused on the introduction of styryl
substituents in order to access close resveratrol-glycoside analogs using Heck cross-coupling [20]. For
the survey of the Heck coupling conditions we used O-nucleoside derivative 3a and methoxy styryl
anisole (Table 3, entry 1). Our first attempt under classical Heck coupling failed to give the desired
product, even at high temperature and in the presence of different solvents, indicating that this
coupling is problematic (entries 1 and 2). When the reaction was carried out in dioxane in the presence
of Pd(OAc)2, PPh3 and Et3N, the desired producted was obtained in 30% yield (entry 3). Further
optimization of this reaction led to increased yield (75%, entry 4) by addition of TBAB in refluxing
toluene [21]. These conditions were then applied for the coupling of O-glycosides 3a and 3f with
different styryl derivatives as shown in Table 3. Indeed, by applying these conditions both 3a and 3f
undrego clean transformations to afford the corresponding products 4a-4f, respectively, in good yields
(Table 3).
Table 3. Modular transformation of iodo-dervatives.
3. Conclusion
In summary we have developed a clean, efficient and rapid protocol for the synthesis of resveratrol O-
glycosides using an inexpensive, mild and benign Lewis acid catalyst [22]. This new methodology
is based on sequential two-step procedure that involves (i) a cooperative effect of iron catalysis and
ultrasound activation for the creation of C-O bond in streoselective way and (ii) modular
transformation of iodophenyl O-glycosides to their corresponding stilbene-like derivatives. These
glycosylated analogs of resveratrol will probably have better solubility and bioavailability. The
biological evaluation of this class of compounds is currently under way and will be reported in due
course.
Acknowledgements
This work is supported by ARCUS-CERES, MAE, Egide PHC Volubilis, Conseil régional PACA,
3

CNRS, CNRST, the Ligue Nationale Contre le Cancer (LNCC Equipe labellisée 2011), the
Association pour la Recherche sur le Cancer (ARC), the Institut national du cancer INCa-PL2011-
0249. Egide-Eiffel and AUF are also acknowledged for grant to HM. The authors would like to thank
Jean-Marie Guigonis for HRMS data, Marc Gaysinski for NOESY spectra and Dominique Bonhomme
for HPLC and αD data.
4. Experimental
4.1. General
All organic solvents were purchased from commercial sources and used as received or dried using
standard procedures, unless otherwise stated. All chemicals were purchased from Aldrich, Merck or
Alfa Aesar and used without further purification; thin-layer chromatography (TLC) was performed on
precoated Merck 60 GF254 silica gel plates and revealed by spraying (p-anisaldehyde or
1
H2SO4/EtOH), and detection by means of UV light at 254 and 360 nm. H and 13C NMR spectra were
recorded on a Bruker Avance 200 MHz spectrometer using tetramethylsilane (TMS) as the internal
standard. Mass spectra (ESI MS) were recorded on a Brucker (Daltonics Esquire 3000+). High
resolution mass spectra (HRMS) were obtained with a LTQ Orbitrap hybrid mass spectrometer with
an electronspray ionization probe (Thermoscientific, San Jose, CA) by direct infusion from a pump
syringe to confirm correct molar mass and high purity of compounds. The purity of compounds was
further verified to be >95% by HPLC analysis using analytical columns Hypersil (C18 (ELITE), 4.6
mm x 250 mm) or Nucleosil (120-5C8 (HICHROM), 4.6 mm x 250 mm) with an isocratic elution of
CH3CN/H2O, 90/10. The ultrason-assisted reactions were carried out
using the sonometer UIP1000 hd Hielsher (20kHz, 1000W and amplitude = 7.5 µm, Figure 3). The
reactions were carried out in 25-100 mL vial flashed with nitrogen and the sonotrode was dipped in
the solution.
Figure 3. Ultrasound reactor UIP1000 hd Hielsher
4.2. General procedure for the synthesis of compounds 3a-k
The sugar derivative (2 mmol) and the appropriate phenol (2 equiv) were solubilized in 10 ml of
dichloromethane containing 4Å molecular sieve, then the Lewis acid catalyst was added to the media.
The reaction mixture is left under stirring or was sonicated in UIP1000 hd Hielsher reactor, according
to the time reported in Table 2. After the completion of the reaction (TLC monitoring), the mixture
was quenched with saturated aqueous NaHCO3 solution and extracted with dichloromethane (3 x 50
ml). The combined organic layers were dried (MgSO4), concentrated in vacuum to give the crude
product, which was purified by flash silica gel (cyclohexane/AcOEt: 90/10 to 70/30) to afford the pure
adducts 3a-k.
3a:
-61.2 (c 1, MeOH); MS (ESI+): m/z = 500 [M+Na]+, 978,1 [2M+Na]+; HRMS (ESI+): calcd
for C17H19O8INa+ 501.0022, found 501.0028; 1H NMR (200 MHz, CDCl3): δ ppm 1.85 (s, 3H, Ac),
2.02 (s, 3H, Ac), 2.07 (s, 3H, Ac), 3.95 (m, 1H, H3’), 4.33 (m, 2H, H5’), 5.35-5,47 (m, 2H, H2’ and
H4’), 5.52 (br s, 1H, H1’), 6.70 (d, 2H, J = 8.9 Hz, H2, H6), 7.48 (d, 2H, J = 8.9 Hz, H3, H5); 13C
NMR (50 MHz, CDCl3): δ ppm 24.31, 24.38, 24.55, 67.13, 74.79, 78.79, 83.15, 89.04, 106.95, 122.52,
142.24, 159.82, 173.68, 173.84, 174.71
3b:
-32.8 (c 1, MeOH); MS (ESI+): m/z = 444.2 [M+Na]+, 866.3 [2M+Na]+; calcd for
C21H26O9Na+ 445.1475, found 445.1471; 1H NMR (200 MHz, CDCl3): δ ppm 1.94 (s, 3H, Ac), 2.02
(s, 3H, Ac), 2.07 (s, 3H, Ac), 3.26 (d, 2H, J = 6.6 Hz, CH2), 3.75 (s, 3H, OMe), 4.11 (m, 1H, H3’),

4.34 (m, 2H, H5’), 4.95 (t, 1H, J = 1,6 Hz, H2’), 5.01 (m, 1H, H4’), 5.46 (m, 1H, allyl), 5.51 (br s, 1H,
H1’), 5.74-5.97 (m, 1H, allyl), 6.61 (d, 1H, J = 8.4 Hz, H5), 6.63 (s, 1H, H3), 6.90 (d, 1H, J = 8.4 Hz,
H6); 13C NMR (50 MHz, CDCl3): δ ppm 24.29, 24.37, 24.42, 43.71, 59.56, 67.99, 75.24, 78.82, 83.04,
108.74, 116.64, 119.64, 122.50, 124.52, 139.77, 141.21, 147.16, 154.06, 173.68, 173.78, 174.86.
3c:
-45.5 (c 1, MeOH); MS (ESI+): m/z = 431.1 [M+Na]+, 840,3 [2M+Na]+; calcd for
C19H23NO9Na+ 432.1271, found 432.1269; H NMR (200 MHz, CDCl3): δ ppm 1.94 (s, 3H, OAc),
1.95 (s, 3H, OAc), 2.07 (s, 3H, OAc), 3.25 (s, 3H, NHAc), 3.90 (m, 1H, H3’), 4.19-4.34 (m, 2H, H5’),
5.26-5.40 (m, 2H, H2’, H4’), 5.44 (br s, 1H, H1’), 6.78 (d, 2H, J = 9.2 Hz, H2, H6), 7.28 (d, 2H, J =
9.2 Hz, H3, H5); 13C NMR (50 MHz, CDCl3): δ ppm 24.31, 24.37, 24.42, 27.57, 67.36, 74.98, 78.84,
82.98, 107.38, 120.60, 125.36, 137.05, 156.44, 173.35, 173.79, 173.94, 174.88.
1
1
3d: MS (ESI+): m/z = 424.1 [M+Na]+, 826,3 [2M+Na]+; H NMR (200 MHz, CDCl3): δ ppm 1.94 (s,
3H, OAc), 1.95 (s, 3H, OAc), 2.07 (s, 3H, OAc), 4.05 (m, 1H, H3’), 4.39-4.58 (m, 2H, 2xH5’), 5.23
(s, 1H, H2’), 5.69 (m, 1H, H4’), 5.84 (br s, 1H, H1’), 7.1 (d, 1H, J = 7.2 Hz, H2), 7.49-7.52 (m, 4H,
H3, H4, H7, H8), 7.79 (m, 1H, H6), 8.2 (m, 1H, H9); 13C NMR (50 MHz, CDCl3): δ ppm 20.38,
20.56, 20.60, 63.25, 71.10, 75.11, 79.32, 103.38, 108.47, 121.76, 122.18, 125.55, 125.66, 125.68,
126.50, 127.54, 134.48, 151.74, 169.63, 169.78, 170.62.
3e: MS (ESI+): m/z = 435.2 [M+Na]+, 848.6 [2M+Na]+; calcd for C17H19NO11Na+ 436.0856, found
1
436.0861; β anomer (major): H NMR (200 MHz, CDCl3): δ ppm 2.02 (s, 3H, OAc), 2.04 (s, 3H,
OAc), 2.06 (s, 3H, OAc), 4.06-4.42 (m, 3H, 2xH5’ and H4’), 5.13 (m, 1H, H3’), 5.18 (d, 1H, J = 5.0
Hz, H1’), 5.28 (dd, 1H, J = 5.0 and 5.2Hz, H2’), 6.59 (d, 1H, J = 8.8 Hz, H-Ar), 7.61 (d, 1H, J = 8.8
Hz, H-Ar). 13C NMR (50 MHz, CDCl3): δ ppm 20.51, 20.59, 20.79, 63.13, 70.76, 74.77, 77.90, 78.43,
109.26, 118.15, 123.60, 136.80, 153.26, 156.19, 169.25, 169.66, 170.51; α anomer (minor): 1H NMR
(200 MHz, CDCl3): δ ppm 1.80 (s, 3H, OAc), 1.98 (s, 3H, OAc), 2.06 (s, 3H, OAc), 4.06-4.42 (m, 3H,
2xH5’ and H4’), 5.39 (dd, 1H, J = 8.1 and 4.3 Hz, H3’), 5.45 (d, 1H, J = 3.2 Hz, H1’), 5.70 (dd, 1H, J
= 4.3 and 3.2 Hz, H2’), 6.59 (d, 1H, J = 8.8 Hz, H-Ar), 7.67 (d, 1H, J = 8.8 Hz, H-Ar); 13C NMR (50
MHz, CDCl3): δ ppm 20.39, 20.44, 20.80, 63.54, 71.84, 72.47, 75.62, 76.95, 108.71, 116.11, 123.15,
137.59, 152.29, 155.81, 169.25, 169.66, 170.66.
3f:
-61.9 (c 1.1, MeOH); MS (ESI+): m/z = 572.03 [M+Na]+, 1122,06 [2M+Na]+; calcd for
C20H23O10INa+ 573.0234, found 573.0237; H NMR (200 MHz, CDCl3): ppm 2.01 (s, 3H, OAc),
2.02 (s, 3H, OAc), 2.03 (s, 3H, OAc), 2.05 (s, 3H, OAc), 3.76 (m, 1H, H3’), 4.18 (m, 2H, 2xH6’),
4.96-5.31 (m, 4H, H1’, H2’, H4’ and H5’), 6.74 (d, 2H, J = 8.9 Hz, H2, H6), 7.55 (d, 2H, J = 8.9 Hz,
H3, H5); 13C NMR (50 MHz, CDCl3): δ ppm 20.60, 20.68, 61.85, 68.14, 71.04, 72.08, 72.56, 86.18,
98.89, 119.23, 138.43, 156.61, 169.19, 169.33, 170.15, 170.46.
1
3g:
-69.7 (c 1.1, MeOH); MS (ESI+): m/z = 516.2 [M+Na]+, 1010.4 [2M+Na]+; calcd for
C24H30O11Na+ 517.1686, found 517.1676; 1H NMR (200 MHz, CDCl3): δ ppm 2.00 (s, 6H, 2xOAc),
2.05 (s, 6H, 2xOAc), 3.31 (d, 2H, J = 6.6 Hz, CH2-allyl), 3.71 (m, 1H, H3’), 3.77 (s, 3H, OMe), 4.18
(m, 2H, 2xH6’), 4.88 (m, 1H, H4’), 4.98-5.29 (m, 5H, H1’, H2’, H5’and CH2-C9), 5.91 (m, 1H, H8),
6.65 (d, 1H, J = 8.0 Hz, H5), 6.69 (s, 1H, H3), 7.01 (d, 1H, J = 8.0 Hz, H6); 13C NMR (50 MHz,
CDCl3): δ ppm 20.57, 20.63, 20.68, 39.87, 55.94, 61.90, 68.40, 71.18, 71.85, 72.60, 101.00, 112.99,
115.93, 120.26, 120.58, 136.79, 137.19, 144.34, 150.51, 169.36, 169.40, 170.25, 170.58.
1
3h:
-47.6 (c 1.2, MeOH); MS (ESI+): m/z = 503.2 [M+Na]+, 984.3 [2M+Na]+; H NMR (200
MHz, CDCl3): δ ppm 1.99 (s, 3H, OAc), 2.01 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.03 (s, 3H, OAc),
2.09 (s, 3H, NAc), 3.82 (m, 1H, H3’), 4.17 (m, 2H, 2xH6’), 4.98 (m, 1H, H4’), 5.09-5.29 (m, 3H, H1’,

H2’and H5’), 6.88 (d, 2H, J = 9.0 Hz, H2 and H6), 7.38 (d, 2H, J = 9.0 Hz, H3 and H5); 13C NMR (50
MHz, CDCl3): δ ppm 20.56, 20.61, 20.67, 24.20, 61.87, 68.21, 71.13, 71.91, 72.62, 99.48, 117.55,
121.56, 133.63, 153.32, 168.69, 169.40, 169.46, 170.19, 170.65.
3i:
-67.8 (c 0.6, MeOH/CH2Cl2 9/1); MS (ESI+): m/z = 496.1 [M+Na]+, 970.3 [2M+Na]+; calcd
for C24H26O10Na+ 497.1424, found 497.1431; H NMR (200 MHz, CDCl3): δ ppm 2.03 (s, 3H,
OAc), 2.05 (s, 6H, 2xOAc), 2.06 (s, 3H, OAc), 3.92 (m, 1H, H3’), 4.12-4.41 (m, 2H, 2xH6’), 5.13-
5.59 (m, 4H, H1’, H2’, H4’ and H5’), 7.03 (d, 1H, J = 7.4 Hz, H2), 7.26-7.59 (m, 4H, H3, H4, H7 and
H8), 7.79 (m, 1H, H6), 8.07 (m, 1H, H9); 13C NMR (50 MHz, CDCl3): δ ppm 20.58, 20.63, 20.66,
20.68, 61.94, 68.38, 71.04, 72.04, 72.60, 99.44, 108.94, 121.55, 123.02, 125.45, 125.66, 125.98,
126.63, 127.52, 134.44, 152.73, 169.46, 169.52, 170.22, 170.58.
1
3j: MS (ESI+): m/z = 860.1 [M+Na]+, 1698.2 [2M+Na]+; 1H NMR (200 MHz, CDCl3) δ ppm: 1.94 (s,
3H, OAc), 1.97 (s, 9H, 3xOAc), 1.98 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.03 (s, 3H, OAc), 3.73-3.96
(m, 3H, H4’, 2xH6’), 3.97-4.08 (m, 3H, H5’ and 2xH6’’), 4.18 (m, 2H, H2’, H4’’), 4.41 (dd, 1H, J =
12.0 and 2.5 Hz, H5’’), 4.80 (dd, 1H, J = 10.3 and 4.0 Hz, H3’), 5.01 (m, 2H, H2’’, H3’’), 5.24 (m,
1H, H1’’), 5.37 (d, 2H, J = 4.2 Hz, H1’), 6.69 (d, 2H, J = 8.9 Hz, H2, H6), 7.52 (d, 2H, J = 8.9 Hz,
H3, H5); 13C NMR (50 MHz, CDCl3) δ ppm: 20.55, 20.58, 20.66, 20.69, 20.87, 60.35, 61.53, 67.98,
68.58, 69.24, 69.98, 71.87, 72.32, 72.57, 75.19, 86.12, 95.62, 98.25, 119.21, 138.45, 156.49, 169.37,
169.52, 169.90, 170.14, 170.29, 170.47.
3k: MS (ESI+): m/z = 860.3 [M+Na]+, 1698.3 [2M+Na]+; 1H NMR (200 MHz, CDCl3) δ ppm: 1.90 (s,
3H, OAc), 1.99 (s, 6H, 2xOAc), 2.00 (s, 3H, OAc), 2.01 (s, 3H, OAc), 2.01 (s, 3H, OAc), 2.09 (s, 3H,
OAc), 3.71 (m, 1H, H4’), 3.82 (m, 2H, 2xH6’), 4.05 (m, 3H, H5’ and 2xH6’’), 4.41 (m, 1H, H2’), 4.46
(m, 1H, H4’’), 4.84-4.98 (m, 2H, H5’’ and H3’), 5.09 (m, 1H, H1’’), 5.20 (t, 1H, J = 8.6 Hz, H3’’),
5.29 (d, 1H, J = 3.6 Hz, H1’), 6.68 (d, 2H, J = 8.6 Hz, H2 and H6), 7.51 (d, 2H, J = 8.6 Hz, H3 and
H5); 13C NMR (50 MHz, CDCl3) δ ppm: 20.49, 20.63 (4C), 20.73, 20.76, 60.78, 61.92, 66.57, 69.05,
70.72, 70.90, 71.36, 72.70, 72.84, 76.09, 86.08, 98.55, 101.10, 119.18 (2C), 138.42 (2C), 156.59,
169.05, 169.51, 169.68, 170.02, 170.10, 170.21, 170.31.
4.3. General procedure for the synthesis of compounds 4a-f
A solution of PPh3 (39.3 mg, 0.15 mmol, 0.15 equiv), Pd(OAc)2 (12.25 mg, 0.05 mmol) and
triethylamine (0.27 mL, 2 mmol) in dry toluene (3 mL), was heated to reflux until getting a
homogenous, dark brown-black solution. The temperature is cooled to 60 °C and the styryl substrat (2
mmol) and iodo-derivative (3a or 3f, 1 mmol) were successively added. The mixture was stirred under
gentle reflux for 3h and a further propotion of triethylamine (0.067 mL, 0.5 mmol, 0.5 eq.) was added.
The hot mixture was then filtered on celite and washed with hot toluene. The solvent was removed
under reduced pressure and the resulting crude product was purified on silica gel chromatography
(cyclohexane/AcOEt: 8:2 to 6:4) to afford pure compounds 4a-4f (Table 3).
4a:
-28.1 (c 0.7, CHCl3); MS (ESI+): m/z = 536.2 [M+Na]+, 1050.4 [2M+Na]+; calcd for
C27H30O10Na+ 537.1737, found 537.1734; H NMR (200 MHz, CDCl3) δ ppm: 1.86 (s, 3H, OAc),
2.02 (s, 3H, OAc), 2.07 (s, 3H, OAc), 3.81 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.97 (m, 1H, H4’), 4.23-
4.46 (m, 2H, 2xH5’), 5.43 (m, 2H, H2’, H3’), 5.58 (s, 1H, H1’), 6.76 (d, 1H, J = 10 Hz, H13), 6.82-
7.02 (m, 6H, H-Ar); 13C NMR (50 MHz, CDCl3) δ ppm: 20.51, 20.57, 20.60, 55.83, 55.90, 63.34,
71.07, 74.95, 79.18, 103.19, 108.58, 111.21, 116.56, 119.64, 126.03, 127.23, 127.39, 130.54, 132.07,
148.73, 149.07, 155.45, 169.54, 169.69, 170.53.
1

4b:
-24.0 (c 1.1, CHCl3); MS (ESI+): m/z = 522.2 [M+Na]+, 1022.3 [2M+Na]+; calcd for
C26H28O10Na+ 523.1580, found 523.1586; H NMR (200 MHz, CDCl3) δ ppm: 1.86 (s, 3H, OAc),
2.02 (s, 3H, OAc), 2.07 (s, 3H, OAc), 3.84 (s, 3H, OMe), 3.97 (m, 1H, H4’), 4.34 (m, 2H, 2xH5’),
5.43 (m, 1H, H3’), 5.58 (s, 1H, H2’), 5.81 (s, 1H, H1’), 6.73-7.01 (m, 7H, H-Ar), 7.31 (d, 2H, H3 and
H5); 13C NMR (50 MHz, CDCl3) δ ppm: 20.52, 20.58, 20.61, 53.47, 55.88, 63.38, 71.08, 74.96, 79.19,
103.19, 108.15, 114.59, 116.56, 120.21, 125.68, 127.35, 130.03, 132.13, 145.46, 146.75, 155.40,
169.60, 169.73, 170.60.
1
1
4c:
-25.3 (c 1, CHCl3); MS (ESI+): m/z = 534,2 [M+Na]+, 1046,3 [2M+Na]+; H NMR (200
MHz, CDCl3) δ ppm: 1.85 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.22 (s, 3H, OAc),
3.97 (m, 1H, H4’), 4.28-4.43 (m, 2H, 2xH5’), 5.43 (m, 2H, H2’ and H3’), 5.58 (s, 1H, H1’), 6.83-7.04
(m, 6H, H-Ar), 7.29-7.46 (m, 4H, H-Ar); 13C NMR (50 MHz, CDCl3) δppm: 20.52, 20.57, 20.60,
21.13, 63.34, 71.05, 74.95, 79.21, 103.13, 116.56, 121.75, 126.39, 127.21, 127.69, 128.14, 131.69,
135.24, 149.86, 155.74, 169.44, 169.54, 169.70, 170.54.
4d:
-25.3 (c 1, CHCl3); MS (ESI+): m/z = 608,2 [M+Na]+, 1194.4 [2M+Na]+; calcd for
C30H34O12Na+ 609.1948, found 609.1951; H NMR (200 MHz, CDCl3) δ ppm: 1.97 (s, 3H, OAc),
1.98 (s, 3H, OAc), 2.00 (s, 3H, OAc), 2.02 (s, 3H, OAc), 3.79 (m, 1H, H5’), 3.82 (s, 3H, OMe), 3.87
(s, 3H, OMe), 4.17 (m, 2H, H6’), 4.98-5.17 (m, 2H, H4’ and H3’), 5.19-5.28 (m, 2H, H2’ and H1’),
6.78 (d, 1H, J = 8.6 Hz, H13), 6.84-7.01 (m, 5H, H-Ar), 7.31-7.45 (m, 3H, H-Ar). 13C NMR (50 MHz,
CDCl3) δ ppm: 20.59, 20.61, 20.64, 20.71, 55.85, 55.92, 61.93, 68.25, 71.16, 72.01, 72.69, 99.07,
108.60, 111.21, 117.18, 119.74, 125.80, 127.37, 127.72, 130.38, 132.97, 148.85, 149.09, 156.09,
169.29, 169.39, 170.23, 170.56.
1
4e:
-5.5 (c 1, CHCl3); MS (ESI+): m/z = 594.2 [M+Na]+, 1166.4 [2M+Na]+; 1H NMR (200 MHz,
CDCl3) δ ppm: 1.97 (s, 3H, OAc), 1.98 (s, 3H, OAc), 2.00 (s, 3H, OAc), 2.02 (s, 3H, OAc), 3.80 (m,
1H, H5’), 3.86 (s, 3H, OMe), 4.17 (m, 2H, 2xH6’), 4.98-5.17 (m, 2H, H4’ and H3’), 5.19-5.27 (m, 2H,
H2’ and H1’), 6.82-6.96 (m, 6H, H-Ar), 7.29-7.39 (m, 3H, H3 and H5); 13C NMR (50 MHz, CDCl3) δ
ppm: 20.58, 20.61, 20.64, 20.70, 55.89, 61.92, 68.26, 71.16, 72.01, 72.70, 99.08, 108.18, 114.64,
117.17, 120.29, 125.42, 127.32, 128.62, 129.85, 131.98, 145.62, 146.78, 156.04, 169.31, 169.41,
170.24, 170.58.
4f: MS (ESI+): m/z = 606.2 [M+Na]+, 1190.4 [2M+Na]+; 1H NMR (200 MHz, CDCl3) δ ppm: 1.97 (s,
3H, OAc), 1.98 (s, 3H, OAc), 2.00 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.23 (s, 3H, OAc), 3.80 (m, 1H,
H5’), 4.16 (m, 2H, 2xH6’), 4.93-5.16 (m, 2H, H4’ and H3’), 5.18-5.33 (m, 2H, H2’ and H1’), 6.83-
7.06 (m, 6H, H-Ar), 7.31-7.47 (m, 4H, H-Ar); 13C NMR (50 MHz, CDCl3) δ ppm: 20.58, 20.61, 20.64,
20.71, 21.14, 61.92, 68.25, 71.13, 72.04, 72.68, 99.02, 117.17, 121.79, 126.88, 127.26, 127.65, 131.96
132.58, 135.08, 149.95, 156.37, 169.29, 169.39, 169.46, 170.22, 170.55.
Reference
[1] Review: C. Manach, A. Scalbert, C. Morand, C. Remesy, L. Jimenez, Am. J. Clin. Nutr. 79 (2004)
727–747.
[2] (a) T.M. de Kok, S.G. van Breda, M.M. Manson, Eur. J. Nutr. 47 (2008) 51–59. (b) N.R. Perron,
J.L. Brumaghim, Cell Biochem. Biophys. 53 (2009) 75–100.
[3] For reviews see: (a) N. Martinet, B.Y. Michel, P. Bertrand, R. Benhida, Med. Chem. Commun. 3
(2012) 263–273. (b) A. Link, F. Balaguer, A. Goel, Biochem Pharmacol. 80 (2010) 1771–1792. (c)
Natural Polyphenols as Potent Inhibitors of DNA Methyltransferases In Studies in Natural Products

Chemistry (Bioactive Natural Products) Atta-ur-Rahman (Ed.), Vol. 41, Chapter 7, Elsevier,
Amsterdam, 2014 (ISBN 9780444632944)
[4] (a) S. Quideau, D. Deffieux, L. Pouységu, Angew. Chem. Int. Ed. 51 (2012) 6824–6826. (b) A.
Borriello, D. Bencivenga, I. Caldarelli, A. Tramontano, A. Borgia, V. Zappia, F. Della Ragione,
Cancer Treat. Res. 159 (2014) 167–84. (c) S. Quideau, D. Deffieux, C. Douat-Casassus, L. Pouységu,
Angew. Chem. 123 (2011) 610–646, Angew. Chem. Int. Ed. 50 (2011) 586–621.
[5] J.L. Richard, Arch. Mal. Coeur Vaiss. 80 (1987) 17–21.
[6] (a) K.T. Howitz, K.J. Bitterman, H.Y. Cohen, D.W. Lamming, S. Lavu, J.G. Wood, R.E. Zipkin,
P. Chung, A. Kisielewski, L.-L. Zhang, B. Scherer, D.A. Sinclair, Nature 425 (2003) 191–196. (b)
J.G. Wood, B. Rogina, S. Lavu, K. Howitz, S.L. Helfand, M. Tatar, D. Sinclair, Nature 430 (2004)
686–689.
[7] A. Puissant, G. Robert, N. Fenouille, F. Luciano, J.P. Cassuto, S. Raynaud, P. Auberger, Cancer
Res. 70 (2010) 1042–1052.
[8] (a) T. Walle, Ann. N.Y. Acad. Sci. 1215 (2011) 9–15. (b) C.H. Cottart, V. Nivet-Antoine, C.
Laguillier-Morizot, J.L. Beaudeux, Mol. Nutr. Food Res. 54 (2010) 7−16. (c) C. Bonechi, S. Martini,
L. Ciani, S. Lamponi, H. Rebmann, C. Rossi, S. Ristori, Plos One 7 (2012) 1–11, e41438
[9] G.A. Potter, L.H. Patterson, E. Wanogho, P.J. Perry, P.C. Butler, T. Ijaz, Br. J. Cancer 86 (2002)
774–778.
[10] G. Regev-Shoshani, O. Shoseyov, I. Bilkis, Z. Kerem, Biochem. J. 374 (2003) 157-163
[11] (a) D. Su, Y. Cheng, M. Liu, D. Liu, H. Cui, B. Zhang, S. Zhou, T. Yang, Q. Mei, PloS One 8
(2013) e54505. (b) G. Ravagnan, A. De Filippis, M. Carteni, S. De Maria, V. Cozza, M. Petrzzuolo,
M.A. Tufano, G. Donnarumma, Inflammation 36 (2013) 26–34.
[12] For reviews see (a) X. Zhu, R.R.S. Schmidt, Angew. Chem. 48 (2009) 1900–1934. (b) M.
Jacobsson, J. Malmberg, U. Ellervik, Carbohydr. Res. 341 (2006) 1266–1281. (c) H. Pellissier,
Tetrahedron 61 (2005) 2947–2993. For other examples see: (d) M. Baudry, V. Barberousse, Y.
Collette b, G. Descotes, J. Pires, J-P. Praly, S. Samreth, Tetrahedron 54 (1998) 13783–13792. (e) Y.
Li, G. Wei, B. Yu, Carbohydr. Res. 341 (2006) 2717–2722. (f) A. Lubineau, Elsa Meyer, Carbohydr.
Res. 228 (1992) 191-203. (g) G. Gao, O. Schwardt, B. Ernst, Carbohydr. Res. 339 (2004) 2835–2840.
(h) M. Ohkubo, T. Nishimura, H. Jona, T. Honma, S. Ito, H. Morishima, Tetrahedron 53 (1997) 5937–
5950.
[13] (a) Y. Li, H. Mo, G. Lian, B. Yu, Carbohydr. Res. 363 (2012) 14–22. (b) R. Lucas, D. Alcantara,
J.C. Morales, Carbohydr. Res 344 (2009) 1340–1346. (c) H.R.M. Aitken, M. Johannes, K.M. Looms,
M.A. Brimble, Tetrahedron Letters 54 (2013) 6916–6919. (d) J. Seibel, L. Hilringhaus, R. Moraru,
Carbohydr. Res. 340 (2005) 507–511.
[14] Z. Zhang, B. Yu, R.R. Schmidt, Synthesis 8 (2006) 1301−1306.
[15] (a) M. Driowya, A. Puissant, G. Robert, P. Auberger, R. Benhida, K. Bougrin, Ultrasonics
Sonochem. 19 (2012) 1132–1138. (b) D. Dziuba, V. Y. Postupalenko, M. Spadafora, A. S.
Klymchenko, V. Guérineau, Y. Mély, R. Benhida, A. Burger. J. Am. Chem. Soc. 134 (2012) 10209–
10213. (c) M. Duca, V. Malnuit, F. Barbault, R. Benhida, Chem. Comm. 46 (2010) 6162–6164. (d) V.
Malnuit, M. Duca, A. Manout, K. Bougrin, R. Benhida, Synlett 13 (2009) 2123–2128; (e) C. Peyron,
J.M. Navarre, D. Dubreuil, P. Vierling, R. Benhida, Tetrahedron Lett. 49 (2008) 6171–6174; (f) M.
Spadafora, A. Burger, R. Benhida, Synlett 8 (2008) 1225–1228; (g) M. Spadafora, V. Postopalenko,
A. Klemchenko, Y. Mély, A. Burger, R. Benhida, Tetrahedron 65 (2009) 7809–7816; (h) R.
Guezguez, K. Bougrin, K. El Akri, R. Benhida Tetrahedron. Lett. 47 (2006) 4807–4811.
[16] (a) E.A. Muravyova, S.M. Desenko, V.I. Musatov, I.V. Knyazeva, S.V. Shishkina, O.V. Shishkin,
V.A. Chebanov, J. Comb. Chem. 9 (2007) 797; (b) G. Cravotto, P.J. Cintas, Chem. Soc. Rev. 35
(2006) 180; (c) J.T. Li, Y. Yin, L. Li, M.X. Sun, Ultrason. Sonochem. 17 (2010) 11.
[17] For an excellent review on C-nucleosides see: J. Stambasky, M. Hocek, P. Kocovsky, Chem. Rev.
109 (2009) 6729-6764. For recent article see: (a) T. Kubelka, T. Slavětínská, V. Eigner, M. Hocek,
Org. Biomol. Chem. 11 (2013) 4702–4718. (b) T. Kubelka, L. Slavětínská, M. Hocek, Eur. J. Org.
Chem. (2012) 4969–4981. (c) H. Chapuis, T. Kubelka, N. Joubert, R. Pohl, M. Hocek, Eur. J. Org.
Chem. (2012) 1759–1767. (d) C. Peyron, R. Benhida, Synlett 3 (2009) 472–476. (e) C. Peyron, J.M.
Navarre, D. Dubreuil, P. Vierling, R. Benhida, Tetrahedron Lett. 49 (2008) 6171–6174
[18] Y.L. Jiang, J.T. Stivers tetrahedron Lett. 44 (2003) 4051-4055.
8

[19] (a) T. Matsumoto, T. Hosoya, K. Suzuki Tetrahedron Lett. 31 (1990) 4629-4632. (b) E.R.
Palmacci, P.H. Seeberger Org. Lett. 3 (2001) 1547-1550.
[20] (a) J.A. Morales-Serna, A. Zúñiga-Martínez, M. Salmón, R. Gaviño, J. Cárdenas, Synthesis 44
(2012) 446-452. (b) A.V. Moro, F.S.P. Cardoso, C.R.D. Correia, Tetrahedron Lett. 49 (2008) 5668–
5671. (c) L. Botella, C. Nájera, Tetrahedron 60 (2004) 5563–5570. (d) T. Jeffery, B. Ferber,
Tetrahedron Lett. 44 (2003) 193–197. (e) M.B. Andrus, J. Liu, E.L. Meredith and E. Nartey,
Tetrahedron Lett. 44 (2003) 4819–4822. (f) M. Guiso, C. Marra, A. Farina, Tetrahedron Lett. 43
(2002) 597–598.
[21] (a) M. Ogino, Y. Yoshimura, A. Nakazawa, I. Saito, K. Fujimoto, Org. Lett. 7 (2005) 2853-2856.
(b) M. Kögler, B. Vanderhoydonck, S. De Jonghe, J. Rozenski, K. Van Belle, J. Herman, T. Louat, A.
Parchina, C. Sibley, E. Lescrinier, P. Herdewijn, J. Med. Chem. 54 (2011), 4847–4862. (c) N.V.
Craynest, D. Guianvarc’h, C. Peyron, R. Benhida, Tetrahedron Lett. 45 (2004) 6243–6247.
[22] (a) A.A.O. Sarhan, C. Bolm, Chem. Soc. Rev. 38 (2009) 2730; (b) B.D. Sherry, A. Fürstner, Acc.
Chem. Res. 41 (2008) 1500-1511.
9

Table 1. Effect of Lewis acid catalyst and ultrasound activation on the O-ribosylation reaction
Entrya
Catalyst
Conventional
Time (h)
Ultrasound
Time (min)
Yield (%)b
Yield (%)b
1
2
3
4
ZnCl2
SnBr4 or SnCl4
InCl3
AlCl3
FeCl3
FeCl3
FeCl3
12
12
12
12
12
12
24
24
24
24
24
nr
<5
<5
25e
43e
71e
10
<5
nr
nr
60
60
30
30
30
20
nr
<5
<5
30e
62e
82 e
15
<5
nr
5
6c
7d
8
60
FeCl2
120
120
120
120
9
Fe(acac)3
FeSO4
Fe2O3
10
11
nr
nr
nr
a Reactions were carried out in CH2Cl2, catalyst (0.5 equiv). b Pure isolated product (bath kept at rt). c 1 equiv of
catalyst. d Reaction carried out in toluene. nr: no reaction.e Small amount of the α-anomer was obtained (< 10%).
10

Table 2. Scope of FeCl3 and US-mediated glycosidation.
Entrya
Sugar
Phenol
Product
Time Yield
(min) (%)b
1
20
73c
1a
2b
2c
2d
3b
3c
2
3
30
25
54
1a
1a
82c
3d
3e
4
5
30
20
80d
71
1a
1b
2h
2a
3f
6
7
30
30
72
58
1b
1b
2b
2c
3g
3h
3i
8
9
25
40
83
2d
2a
1b
69c
1c
3j
10
40
70
2a
1d
3k
a
b
Reactions were carried out under US irradiation, CH2Cl2, FeCl3 (1 equiv). Pure isolated product.c Small
amount of the α-anomer was obtained (< 10%). d α/β: 1/3.

Table 3. Modular transformation of iodo-dervatives.
Styryl
derivative
Entry
Iodo derivative
Product
Yield (%)e
1a
2b
3c
4d
0
0
30
85
3a
4a
5
6
87
82
3a
3a
4b
4c
7
8
9
78
83
76
3f
3f
3f
4d
4e
4f
a Pd(PPh3)4 (5% molar), Cs2CO3, (1 equiv), TBAB (1 equiv), toluene/H2O (4/1), reflux; b PdCl2, PPh3, Na2CO3,
DMF, 140°C; c Pd(OAc)2, PPh3, Et3N, dioxane, reflux;d PdOAc2, PPh3, Et3N, TBAB, toluene, reflux (conditions
d were applied to all other experiments); e Pure isolated product, small amount of the cis-isomer was observed by
NMR of the crude product.

Graphical abstract
13