Efficient and first regio- and stereoselective direct C-glycosylation of a flavanone catalysed by Pr(OTf)3 under conventional heating or ultrasound irradiation

Article abstract of DOI:10.1002/ejoc.201201518

A simple, regio- and stereoselective one-step methodology for the mono-C-glycosylation of flavanone has been established. Naringenin was directly C-glycosylated with D-glucose by catalysis with rare-earth metal triflates in acetonitrile/water. Different reaction conditions, namely the solvent system, reaction time, energy source and catalyst were studied. Commercially available lanthanide triflates were evaluated as catalysts and praseodymium triflate proved to be the most effective for this coupling reaction. The optimized reaction conditions were applied to other monosaccharidyl donors, such as D-mannose, D-galactose and L-rhamnose, as well as disaccharides, such as lactose and maltose, leading regio- and stereoselectively to 8-C-glycosyl derivatives with equatorial glycosidic bonds in yields ranging from 28 to 38 %. Ultrasound irradiation was used to enhance the reaction outcome and a considerable improvement in reaction time and efficiency was achieved, allowing selective access to the target C-glycosylflavanones in yields of 43-56 %. A highly selective one-step mono-C-glycosylation of flavanone has been developed. Pr(OTf)₃-catalysed coupling of naringenin with unprotected and free monosaccharides/disaccharides provided 8-C-glycosyl derivatives with equatorial glycosidic bonds in yields of 28-38 %. The use of ultrasound considerably improved the reaction outcome, giving the target C-glycosyl flavanones in yields of up to 56 %. Copyright

Full text of DOI:10.1002/ejoc.201201518

FULL PAPER
DOI: 10.1002/ejoc.201201518
Efficient and First Regio- and Stereoselective Direct C-Glycosylation of a
Flavanone Catalysed by Pr(OTf)3 Under Conventional Heating or Ultrasound
Irradiation
Rui G. Santos,[a,b] Nuno M. Xavier,[a] João C. Bordado,[b] and Amélia P. Rauter*[a]
Dedicated to the centenary of the Portuguese Chemical Society on the occasion of the
6th Spanish Portuguese Japanese Organic Chemistry Symposium
Keywords: Synthetic methods / Glycosylation / Ultrasound / Green chemistry / Flavonoids
A simple, regio- and stereoselective one-step methodology
charidyl donors, such as D-mannose, D-galactose and L-
for the mono-C-glycosylation of flavanone has been estab-
rhamnose, as well as disaccharides, such as lactose and malt-
lished. Naringenin was directly C-glycosylated with
D-
ose, leading regio- and stereoselectively to 8-C-glycosyl de-
glucose by catalysis with rare-earth metal triflates in acetoni- rivatives with equatorial glycosidic bonds in yields ranging
trile/water. Different reaction conditions, namely the solvent
system, reaction time, energy source and catalyst were
studied. Commercially available lanthanide triflates were
evaluated as catalysts and praseodymium triflate proved to
be the most effective for this coupling reaction. The opti-
mized reaction conditions were applied to other monosac-
from 28 to 38%. Ultrasound irradiation was used to enhance
the reaction outcome and a considerable improvement in re-
action time and efficiency was achieved, allowing selective
access to the target C-glycosylflavanones in yields of 43–
56%.
Friedel–Crafts reaction.[4,9–11] Currently, a range of ap-
proaches for C-glycosylation are known, including the nu-
cleophilic attack of aromatic Grignard reagents on glycosyl
halides,[6,7] the use of anomeric anions derived from lithi-
ated compounds,[12] reactions promoted by transition met-
als or samarium iodide,[13] intermolecular free-radical reac-
tions and C-glycosylation by intramolecular aglycon deliv-
ery.[7] This final method covers the strategy developed by
Suzuki[14] and Kometani[15] and their co-workers and is a
straightforward methodology for the C-glycosylation of
phenols by a Lewis acid catalysed rearrangement of a
glycoside to a C-glycosyl derivative, known as a Fries-type
reaction. It has been exploited by some research groups and
successfully applied to the synthesis of C-glycosyl flavono-
ids[16–19] and other complex natural products.[20,21]
Introduction
C-Glycosylpolyphenols are ubiquitously distributed in
nature and commonly found as plant or bacteria secondary
metabolites.[1–3] Such molecular entities often show interest-
ing biological activities and the C–C bond that links the
sugar to the aglycon appears to be of great importance be-
cause it is not enzymatically degraded in vivo and is stable
under physiological conditions, whereas the O-glycosidic
bond is easily cleaved in acidic medium and by enzymes.[3]
The synthesis of this type of compounds has become a
challenge for organic chemists and some useful synthetic
approaches for preparing such bioactive principles have
been reported.[1,4–8]
Formation of the C–C bond between carbohydrate units
and electron-rich aromatic moieties was first achieved by
The Fries-type reaction involves a glycosyl donor, a
phenol and an activator (Scheme 1). This one-pot reaction
[a] Centro de Química e Bioquímica/Departamento de Química e proceeds via the formation of a glycoside at low tempera-
Bioquímica, Faculdade de Ciências da Universidade de Lisboa,
Ed. C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
Fax: +351-21-7500088
E-mail: aprauter@fc.ul.pt
Homepage: http://carbohydrate.cqb.fc.ul.pt/Profiles/
aprauter.pdf
[b] Instituto de Biotecnologia e Bioengenharia, Departamento de
Engenharia Química e Biológica, Torre Sul, Instituto Superior
Técnico,
Av. RoviscoPais, 1049-001 Lisboa, Portugal
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201518.
Scheme 1. Phenol C-glycosylation by a Fries-type rearrangement.
Eur. J. Org. Chem. 2013, 1441–1447
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. G. Santos, N. M. Xavier, J. C. Bordado, A. P. Rauter
FULL PAPER
1
ture, which undergoes, on warming, an in situ OǞC re-
The structure of 3 was established by H and 13C NMR
arrangement to give regioselectively an ortho-hydroxy C- as well as 2D NMR analyses (COSY, HMQC and HMBC).
glycosyl aromatic derivative in good yield.[22,23]
The monosubstitution at C-8 was confirmed by the disap-
The efficiency of rare-earth metal triflates as water-toler- pearance of the signal for 8-H from the 1H NMR spectra. A
ant Lewis acids has recently been confirmed.[24–26] These doublet at δ = 4.78 ppm, assigned to 1ЈЈ-H, shows a COSY
catalysts are easy to manipulate, reusable, non-toxic and ef- correlation with a broad triplet at δ = 4.12 ppm, which cor-
fective under mild reaction conditions.[25] Such properties responds to 2ЈЈ-H, with a coupling constant J1ЈЈ,2ЈЈ of
contribute to economically attractive, safer and environ- 9.9 Hz, which is indicative of a β anomer. In the 13C NMR
mentally friendly methodologies that meet the requirements spectrum, the signal for C-1ЈЈ, assigned by HMQC, appears
of green and sustainable chemistry.[24,27,28] Fries-type re- at δ = 75.2 ppm, a resonance characteristic of C-glycosyl
arrangement promoted by scandium(III) triflate has been derivatives. The HMBC spectrum of 3 provides further and
reported,[29–31] and the C-glycosylation of unprotected poly- conclusive evidence for its structure, presenting correlations
phenols with unprotected sugars mediated by this catalyst between 1ЈЈ-H and C-7, C-8 and C-8a, thus corroborating
revealed its potential use for direct access to C-glycosyl- that the glucosyl group is linked to the 8-position (Fig-
substituted flavonoids.[27,32] The results of this type of reac- ure 1). The assignment of C-8a was confirmed by its
tion with naringenin (2; see Scheme 2) have been pub- HMBC correlation with 2-H. Moreover, a singlet at δ =
lished,[27] but a bis-C-glycosyl derivative was also obtained. 5.97 ppm, assigned to 6-H, showed a correlation with C-4a,
In this research we envisaged exploring and evaluating which clearly implies that the 6-position is not glycosylated.
the use of the whole series of lanthanide(III) triflates, with
the exception of promethium(III) triflate, which is not com-
mercially available, as promoters for the direct C–C anom-
eric coupling of sugars to naringenin. We attempted to
screen their performance and efficiency to select the best
catalytic system and optimize the reaction conditions using
either conventional heating or ultrasound irradiation, aim-
ing to establish a selective, direct, reliable and simple meth-
odology for flavanone mono-C-glycosylation.
Results and Discussion
Figure 1. Key HMBC correlations for the structural assignment of
The direct mono-C-glycosylation of naringenin (2) ap-
pears to be the most attractive route to C-glycosylnaring-
enin. Sato et al.[27] showed that the Sc(OTf)3-promoted
glucosylation of (Ϯ)-naringenin, carried out in a mixture of
acetonitrile and water at reflux for 48 h, afforded 6,8-di-C-
glucosylnaringenin in 17% yield and the products of mono-
6-C- or mono-8-C-glucosylation, isolated as the acetate de-
rivatives, in 19% yield. In our hands, this synthetic pro-
cedure gave the desired 8-(β-d-glucopyranosyl)naringenin
(3) in 12% yield (Scheme 2) along with unreacted naring-
enin after stirring overnight.
compound 3, which is depicted showing glycon conformation and
compound numbering.
This preliminary experiment, although affording a low
yield, allowed a straightforward and stereoselective access
to the desired C-glycosylflavanone. Hence, we were moti-
vated to optimize the reaction conditions for the direct cou-
pling reaction by first screening other commercially avail-
able rare-earth metal triflates to look for the most appropri-
ate catalyst (Table 1).
The validated experimental procedure for the reaction
between (Ϯ)-naringenin and d-glucose was repeated with
each catalyst. After removal of unreacted d-glucose and cat-
alyst, the phenolic content was recovered and fractionated
by HPLC by using the previously synthesized 8-(β-d-gluco-
pyranosyl)naringenin (3) as standard. The highest yield
(41.2%) was obtained with praseodymium triflate as cata-
lyst (entry 5).
With these results in hand, the acetonitrile/water ratio
and reaction time were investigated for the Pr(OTf)3-cata-
lysed C-glycosylation of naringenin. By increasing the re-
flux time to 24 and 48 h, isolated yields for 3 of 32 and
34%, respectively, were obtained. Thus, the reaction time in
the range of 24 to 48 h did not significantly affect the yield.
Varying the ratio of the solvent system (Table 2) did not
lead to an improvement of the reaction yield. Instead, an
acetonitrile/water ratio other than 2:1 led to a decrease in
the reaction yield due to the poor solubility of glucose or
naringenin above or below this ratio, respectively.
Scheme 2. Reagents and conditions: a) cat. Sc(OTf)3, acetonitrile/
water (2:1), reflux, overnight.
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C-Glycosylation of a Flavanone Catalysed by Pr(OTf)3
Table 1. C-Glycosylation of naringenin with d-glucose catalysed by
rare-earth metal triflates.[a]
Entry
Cat. [M3+(OTf)3]
Yield of 3[b] [%]
RSD[c] [%]
1
2
3
4
5
6
7
8
Sc
Y
La
Ce
Pr
Nd
Sm
Eu
Gd
Tb
Dy
Ho
Er
18.9
18.0
6.2
2.3
41.2
9.5
1.1
1.1
0.7
0.7
2.2
0.8
0.8
1.1
1.2
0.7
0.9
1.1
1.0
1.1
0.7
1.0
9.0
16.9
21.4
4.3
13.5
18.8
14.8
17.5
2.2
9
10
11
12
13
14
15
16
Tm
Yb
Lu
15.4
[a] Reagents and conditions: naringenin (1 equiv.), d-glucose
(3 equiv.), acetonitrile/water (2:1), rare-earth metal triflates
(0.2 equiv.), reflux, 12 h. [b] Obtained by HPLC analysis. [c] Rela-
tive standard deviation.
Scheme 3. Reagents and conditions: a) cat. Pr(OTf)3, acetonitrile/
water (2:1), reflux, 24 h.
Table 2. Optimization of the solvent system for the Pr(OTf)3-cata-
lysed C-glycosylation of naringenin with d-glucose.
Entry MeCN/H2O
Pr(OTf)3 [equiv.]
Time [h] Yield[a] [%]
We were prompted to determine whether this C-glycosyl-
ation procedure would be feasible for attaining disac-
charide-containing derivatives. Lactose (10) and maltose
(11) were chosen as glycosyl donors.
First, the stability of the disaccharide glycosidic bond
under the reaction conditions was investigated. A few tests
were carried out by stirring a solution of lactose or maltose
in acetonitrile/water in the presence of the catalyst. As ob-
served by TLC, hydrolysis of the glycosidic bond occurred
only after 96 h and by increasing the amount of catalyst
(entries 4 and 8, Table 3) for both disaccharides.
1
2
3
4
5
6
7
1:0
3:1
2:1
1:1
1:2
1:3
0:1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
24
24
24
24
24
24
24
9
28
32
29
23
16
0
[a] Isolated yield.
An ethanol/water mixture was not used because it has
been reported that in related Sc(OTf)3-catalysed C-glycosyl-
ation reactions, such a solvent system is not selective
towards mono-C-glycosylation, leading to the additional
formation of bis(C-glycosyl) derivatives.[32]
Table 3. Results of stability tests on the glycosidic bonds of maltose
and lactose.
Having found the optimum reaction conditions, we next
investigated the scope of this methodology for other sugars
(Scheme 3). All the reactions proceeded to give satisfactory
yields, ranging from 32 to 38%, and with complete regio-
and stereoselectivity. Naringenin was effectively glyc-
osylated at C-8 leading to compounds with aglycon in an
equatorial position, that is, d-glucosylnaringenin (3) and d-
galactosylnaringenin (7) with the β configuration, and d-
mannosylnaringenin (8) and l-rhamnosylnaringenin (9)
with the α configuration. Compounds 3, 7 and 9 have the
1C4 conformation, as expected, whereas compound 8
adopts a 1,4B conformation, as determined from its 1H
NMR spectrum. The resonance of the anomeric 1ЈЈ-H ap-
pears as a doublet at δ = 5.05 ppm with a coupling constant
3
J1ЈЈ,2ЈЈ of 9.2 Hz, and the coupling constants J3ЈЈ,4ЈЈ
=
3J4ЈЈ,5ЈЈ = 9.5 Hz are consistent with the boat conformation.
In the 13C NMR spectra, the C-1ЈЈ resonance of 7, 8 and 9
is observed at δ = 74.7, 77.0 and 76.8 ppm, values that lie
within the range typical of C-glycosyl flavonoid anomeric
carbon atoms.
[a] Observed by TLC; n.h.: no hydrolysis; h.: hydrolysis.
Eur. J. Org. Chem. 2013, 1441–1447
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. G. Santos, N. M. Xavier, J. C. Bordado, A. P. Rauter
FULL PAPER
The coupling of lactose (10) and maltose (11) with narin- yield and selectivity of a wide range of chemical reactions
genin following the procedure previously applied to mono- while meeting the requirements of green chemistry by the
saccharides furnished 8-(β-lactosyl)naringenin (12) and 8- minimization of waste and reduction of energy.[33] The use
(β-maltosyl)naringenin (13) in yields of 28 and 34%, respec- of ultrasound to mediate organic reactions in carbohydrate
tively, after 48 h (Scheme 4).
chemistry has been reported, particularly in O-glycosylation
reactions.[34] To the best of our knowledge, sonication has
never been employed to facilitate C-glycosylation reactions.
Therefore, with the aim of improving the yield and short-
ening the reaction time, the previously studied Pr(OTf)3-
catalysed C-glycosylation of naringenin with unprotected
and reducing mono- and disaccharides was performed un-
der ultrasound irradiation. An ultrasound heating bath was
maintained at 80 °C and 8-(β-d-glucopyranosyl)naringenin
(3) was isolated in 56% yield after 8 h (Table 4, entry 1).
This procedure was applied to the remaining sugar scaffolds
4–6, 10 and 11, and the glycosylation yields were observed
to be considerably higher than those obtained by the con-
ventional thermal method (Table 4).
Table 4. Comparison of the reaction yields for the C-glycosylation
of naringenin catalyzed by Pr(OTf)3 under conventional heating
and sonication.
Scheme 4. Reagents and conditions: a) cat. Pr(OTf)3, acetonitrile/
water (2:1), reflux, 48 h.
1
The H NMR spectrum of 12 shows two anomeric pro-
tons, as expected, which indicates that the disaccharide moi-
ety was not cleaved. The doublet at δ = 4.80 ppm, with a
coupling constant of 10.1 Hz and an HMQC correlation
with a carbon signal at δ = 73.5 ppm, is diagnostic of the
formation of a C-glycosyl derivative with the β configura-
tion. On the other hand, the other anomeric proton, that
is, that of the galactosyl group (1ЈЈЈ-H), appears as a doub-
let at δ = 4.43 ppm with a J1ЈЈЈ,2ЈЈЈ value of 7.4 Hz and an
HMQC correlation with a carbon at δ = 103.5 ppm, which
confirms that the β(1ЈЈЈǞ4ЈЈ) glycosidic bond of the lact-
osyl group remains intact.
As for the monosaccharide-containing derivatives, the
HMBC correlations, particularly that between 6-H and 1ЈЈ-
H, allowed us to establish the structure of an 8-glycosylated
flavonoid.
Similarly, the NMR spectra of the maltosyl derivative 13
show the anomeric proton (1ЈЈ-H) at δ = 4.81 ppm, which
correlates with a carbon at δ = 73.5 ppm, whereas for the
glucosyl residue, the anomeric proton (1ЈЈЈ-H) and carbon
resonances appear at δ = 5.23 and 101.6 ppm, respectively.
The coupling constants J1ЈЈ,2ЈЈ and J1ЈЈЈ,2ЈЈЈ are 10.01 and
3.76 Hz, which correspond to a β and α configuration,
respectively, in accord with the expected structure.
With these remarkable results of reaction efficiency and
selectivity achieved in the one-step flavanone C-glycosyl-
ation method, we sought to evaluate the effect of ultrasonic
irradiation on the reaction outcome. Ultrasound has been
an important tool in organic synthesis, providing an alter-
[a] Isolated yield. [b] US: Ultrasound irradiation (bath temperature:
native source of energy that can be used to enhance the 80 °C).
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C-Glycosylation of a Flavanone Catalysed by Pr(OTf)3
2
H, 4ЈЈ-H, 5ЈЈ-H), 3.13 (dd, 3J2,3a = 12.4, J3a,3e = 17.2 Hz, 1 H, 3a-
Conclusions
H), 2.73 (br. d, J2,3e = 2.4, J3a,3e = 17.2 Hz, 1 H, 3e-H) ppm. 13C
NMR (CD3OD, 100.57 MHz): δ = 198.2 (C-4), 167.3 (C-7), 164.4
(C-8a), 164.3 (C-5), 159.1 (C-4Ј), 130.9 (C-1Ј), 129.1 (C-2Ј, C-6Ј),
116.4 (C-3Ј, C-5Ј), 106.3 (C-8), 103.9 (C-4a), 96.4 (C-6), 82.6 (C-
5ЈЈ), 80.5 (C-3ЈЈ), 80.2 (C-2), 75.2 (C-1ЈЈ), 72.6 (C-4ЈЈ), 71.0 (C-
2ЈЈ), 62.9 (C-6ЈЈ), 44.9 (C-3) ppm. HRMS: calcd. for C21H22O10
457.11052 [M + Na]+; found 457.11013.
3
2
An effective and environmentally friendly methodology
has been developed to access C-glycosylflavanones in one
step by direct glycosylation of an unprotected flavanone
with unprotected and reducing sugars. Praseodymium tri-
flate proved to be a suitable catalyst for the direct coupling
reaction, leading to monoglycosylation products in yields
ranging from 28 to 38% with complete regio- and stereo-
selectivity for 8-C-glycosyl derivatives with an equatorial
glycosidic bond. The efficiency of this method was signifi-
cantly improved when the reactions were assisted by ultra-
sound irradiation. A three-fold decrease in the reaction time
for the monosaccharidyl derivatives and a four-fold de-
crease in the reaction time for disaccharidyl counterparts,
when compared with conventional heating, were achieved,
with the target 8-C-glycosylflavanones obtained in yields of
up to 56%.
8-(β-D-Galactopyranosyl)naringenin (7): C-Glycosylation of naring-
enin with d-galactose (566 mg, 3.14 mmol) according to the general
procedure afforded compound 7 (279 mg, 35%) as a dark-yellow
oil after purification by CC (EtOAc/acetone/AcOH/water,
45:15:2:1). Rf = 0.49 (EtOAc/acetone/AcOH/water, 30:15:2:1). 1H
3
NMR (CD3COCD3, 400 MHz): δ = 7.37 (d, J2Ј,3Ј
= =
3J5Ј,6Ј
3
3
8.7 Hz, 2 H, 2Ј-H, 6Ј-H), 6.88 (d, J2Ј,3Ј = J5Ј,6Ј = 8.7 Hz, 2 H, 3Ј-
H, 5Ј-H), 5.95 (s, 1 H, 6-H), 5.45 (dd, 3J2,3e = 3.1, 3J2,3a = 12.5 Hz,
3
3
1 H, 2-H), 4.81 (d, J1ЈЈ,2ЈЈ = 9.7 Hz, 1 H, 1ЈЈ-H), 4.06 (td, J1ЈЈ,2ЈЈ
= 9.7, 3J2ЈЈ,3ЈЈ = 9.5, 3J2ЈЈ,OHЈ = 2.4 Hz, 1 H, 2ЈЈ-H), 4.03 (td, 3J4ЈЈ,OH
= J3ЈЈ,4ЈЈ = 2.4, J4ЈЈ,5ЈЈ = 3.0 Hz, 1 H, 4ЈЈ-H), 3.77–3.68 (m, 3 H,
3
3
3
3
5ЈЈ-H, 6aЈЈ-H, 6bЈЈ-H), 3.65 (dd, J2ЈЈ,3ЈЈ = 9.5, J3ЈЈ,4ЈЈ = 2.4 Hz, 1
3
2
H, 3ЈЈ-H), 3.18 (dd, J2,3a = 12.5, J3a,3e = 15.8 Hz, 1 H, 3a-H),
2.75 (dd, 3J2,3e = 3.1, 2J3a,3e = 15.8 Hz, 1 H, 3e-H) ppm. 13C NMR
(CD3COCD3, 100.57 MHz): δ = 191.0 (C-4), 164.4 (C-7), 162.2 (C-
5), 160.9 (C-8a), 158.1 (C-4Ј), 129.4 (C-1Ј), 128.2 (C-2Ј, C-6Ј), 115.1
(C-3Ј, C-5Ј), 105.2 (C-8), 102.3 (C-4a), 95.7 (C-6), 79.1 (C-2), 78.9
(C-5ЈЈ), 75.1 (C-3ЈЈ), 74.7 (C-1ЈЈ), 70.2 (C-4ЈЈ), 68.9 (C-2ЈЈ), 61.3
(C-6ЈЈ), 42.8 (C-3) ppm. HRMS: calcd. for C21H22O10 457.11052
[M + Na]+; found 457.11043.
Experimental Section
General Methods: All the reactions were monitored by TLC on
Merck 60 F254 silica gel aluminium plates with detection under
UV light (254 nm) and/or by spraying with a solution of 10%
H2SO4 in EtOH or ferric chloride stain. Column chromatography
8-(α-D-Mannopyranosyl)naringenin (8): C-Glycosylation of naring-
1
was performed on silica gel 60 (0.040–0.063 mm, Merck). H and
enin with d-mannose (564 mg, 3.13 mmol) according to the general
procedure afforded compound 8 (303 mg, 38%) as a yellow oil after
purification by CC (EtOAc/acetone/AcOH/water, 45:15:2:1). Rf =
13C NMR spectra were acquired with a Bruker Avance 400 spec-
1
trometer operating at 400 MHz for H NMR and at 100 MHz for
13C NMR. The chemical shifts are expressed in ppm and are refer-
enced to solvent residual peaks. Assignments were made by COSY,
HMQC and HMBC experiments. HRMS spectra were acquired
with an Apex Ultra FTICR mass spectrometer equipped with an
Apollo II Dual ESI/MALDI ion source from Bruker Daltonics and
a 7 T actively shielded magnet from Magnex Scientific. The ultra-
sound-assisted C-glycosylation reactions of naringenin were carried
out in the commercial USC200T ultrasound bath from VWR Col-
lection at a frequency of 45 kHz (power: 80 W) set for 80 °C. The
coupling reactions disaccharides were performed with the ultra-
sonic processor UP200S from Hielscher with a variable working
frequency of 24 kHz set to 100% (power: 200 W).
1
0.56 (EtOAc/acetone/AcOH/water, 30:15:2:1). H NMR (CD3OD,
3
3
400 MHz): δ = 7.25 (d, J2Ј,3Ј = J5Ј,6Ј = 8.5 Hz, 2 H, 2Ј-H, 6Ј-H),
6.76 (d, 3J2Ј,3Ј = 3J5Ј,6Ј = 8.55 Hz, 2 H, 3Ј-H, 5Ј-H), 5.87 (s, 1 H, 6-
3
3
H), 5.30 (dd, J2,3e = 3.0, J2,3a = 12.7 Hz, 1 H, 2-H), 5.05 (d,
3J1ЈЈ,2ЈЈ = 9.2 Hz, 1 H, 1ЈЈ-H), 3.93 (br. dd, J2ЈЈ,3ЈЈ = 3.0, J1ЈЈ,2ЈЈ
=
3
3
2
9.2 Hz, 1 H, 2ЈЈ-H), 3.85 (part A, ABX system, J6aЈЈ,6bЈЈ = 12.0,
3J6aЈЈ,5ЈЈ = 1.9 Hz, 1 H, 6aЈЈ-H), 3.72 (part B, ABX system, J6bЈЈ,5ЈЈ
3
2
3
3
= 5.4, J6aЈЈ,6bЈЈ = 12.0 Hz, 1 H, 6bЈЈ-H), 3.61 (t, J3ЈЈ,4ЈЈ = J4ЈЈ,5ЈЈ
3
3
= 9.5 Hz, 1 H, 4ЈЈ-H), 3.58 (dd, J2ЈЈ,3ЈЈ = 3.0, J3ЈЈ,4ЈЈ = 9.5 Hz, 1
H, 3ЈЈ-H), 3.32 (ddd, 3J4ЈЈ,5ЈЈ = 9.5, 3J6aЈЈ,5ЈЈ = 1.9, 3J6bЈЈ,5ЈЈ = 5.4 Hz,
3
3
1 H, 5ЈЈ-H), 3.07 (dd, J2,3a = 12.7, J3a,3e = 17.3 Hz, 1 H, 3a-H),
2.69 (dd, 3J2,3e = 3.0, 3J3a,3e = 17.3 Hz, 1 H, 3e-H) ppm. 13C NMR
(CD3OD, 100.57 MHz): δ = 198.1 (C-4), 166.3 (C-7), 162.4 (C-5),
160.3 (C-8a), 157.9 (C-4Ј), 130.2 (C-1Ј), 129.1 (C-2Ј, C-6Ј), 116.3
(C-3Ј, C-5Ј), 103.39 (C-8), 101.2 (C-4a), 97.4 (C-6), 83.4 (C-5ЈЈ),
80.6 (C-2), 77.0 (C-1ЈЈ), 76.1 (C-3ЈЈ), 73.7 (C-2ЈЈ), 68.3 (C-4ЈЈ), 62.7
(C-6ЈЈ), 44.1 (C-3) ppm. HRMS: calcd. for C21H22O10 457.11052
[M + Na]+; found 457.11118.
General Procedure for the C-Glycosylation of Naringenin with
Monosaccharides: Praseodymium triflate (216 mg, 0.2 equiv.) was
added to a mixture of naringenin (2; 500 mg, 1.84 mmol) and
monosaccharide (1.7 equiv.) in acetonitrile/water (2:1; 6 mL). After
stirring for 12 h at reflux, the reaction mixture was concentrated in
vacuo prior to purification by column chromatography (CC).
8-(β-D-Glucopyranosyl)naringenin (3): C-Glycosylation of naring-
8-(α-L-Rhamnopyranosyl)naringenin (9): C-Glycosylation of naring-
enin with d-glucose (563.5 mg, 3.13 mmol) according to the general
procedure afforded compound 3 (255 mg, 32%) as a yellowish oil
after purification by CC (EtOAc/acetone/AcOH/water, 45:15:2:1).
Rf = 0.45 (EtOAc/acetone/AcOH/water, 30:15:2:1). 1H NMR
enin with l-rhamnose (514 mg, 3.13 mmol) according to the gene-
ral procedure afforded compound 9 (264 mg, 33%) after purifica-
tion by CC (EtOAc/acetone/AcOH/water, 45:15:2:1). Rf = 0.52
(EtOAc/acetone/AcOH/water, 30:15:2:1). 1H NMR (CD3OD,
3
3
3
(CD3OD, 400 MHz): δ = 7.30 (d, J2Ј,3Ј = J5Ј,6Ј = 8.3 Hz, 2 H, 2Ј-
400 MHz): δ = 7.30 (d, J2Ј,3Ј = J5Ј,6Ј = 8.4 Hz, 2 H, 2Ј-H, 6Ј-H),
3
3
3
H, 6Ј-H), 6.81 (d, J2Ј,3Ј = J5Ј,6Ј = 8.3 Hz, 2 H, 3Ј-H, 5Ј-H), 5.97
6.81 (d, J2Ј,3Ј = J5Ј,6Ј = 8.4 Hz, 2 H, 3Ј-H, 5Ј-H), 5.91 (s, 1 H, 6-
3
3
3
3
(s, 1 H, 6-H), 5.34 (dd, J2,3e = 2.4, J2,3a = 12.4 Hz, 1 H, 2-H),
H), 5.34 (dd, J2,3e = 2.9, J2,3a = 12.2 Hz, 1 H, 2-H), 5.04 (d,
4.78 (d, J1ЈЈ,2ЈЈ = 9.9 Hz, 1 H, 1ЈЈ-H), 4.12 (br. t, J1ЈЈ,2ЈЈ = 9.9, 3J1ЈЈ,2ЈЈ = 10.4 Hz,1 H, 1ЈЈ-H), 3.97 (br. t, J1ЈЈ,2ЈЈ = J2ЈЈ,3ЈЈ = 10.4,
3
3
3
3
3J2ЈЈ,3ЈЈ = 9.7 Hz, 1 H, 2ЈЈ-H), 3.85 (part A, ABX system, J6aЈЈ,6bЈЈ 3J2ЈЈ,OH = 3.6 Hz, 1 H, 2ЈЈ-H), 3.58 (br. t, 3J3ЈЈ,4ЈЈ = 9.1 Hz,1 H, 3ЈЈ-
2
3
3
3
= 12.4, J6aЈЈ,5ЈЈ = 1.6 Hz, 1 H, 6aЈЈ-H), 3.70 (part B, ABX system,
H), 3.46 (t, J3ЈЈ,4ЈЈ = 9.1, J4ЈЈ,5ЈЈ = 9.4 Hz, 1 H, 4ЈЈ-H), 3.39 (m, 1
2J6aЈЈ,6bЈЈ = 12.4, J6bЈЈ,5ЈЈ = 5.3 Hz, 1 H, 6bЈЈ-H), 3.37 (m, 3 H, 3ЈЈ- H, 5ЈЈ-H), 3.12 (dd, J2,3a = 12.2, J3a,3e = 17.2 Hz, 1 H, 3a-H),
3
3
2
Eur. J. Org. Chem. 2013, 1441–1447
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1445

R. G. Santos, N. M. Xavier, J. C. Bordado, A. P. Rauter
FULL PAPER
3
2
3
2.73 (dd, J2,3e = 2.9, J3a,3e = 17.2 Hz, 1 H, 3e-H), 1.36 (d, J6ЈЈ,5ЈЈ mixture was subjected to ultrasound for 12 h. Compounds 3, 7–9,
= 5.9 Hz, 3 H, CH3) ppm. 13C NMR (CD3OD, 100.57 MHz): δ =
12 and 13 were isolated in yields of 56, 49, 46, 51, 43 and 51%,
198.4 (C-4), 163.9 (C-7), 161.9 (C-8a), 160.8 (C-5), 159.3 (C-4Ј), respectively.
131.4 (C-1Ј), 130.0 (C-2Ј, C-6Ј), 116.2 (C-3Ј, C-5Ј), 105.6 (C-8),
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra for new compounds.
102.9 (C-4a), 97.6 (C-6), 80.6 (C-2), 78.5 (C-5ЈЈ), 76.8 (C-1ЈЈ), 75.6
(C-3ЈЈ), 73.5 (C-4ЈЈ), 73.3 (C-2ЈЈ), 43.6 (C-3), 18.1 (C-6ЈЈ) ppm.
HRMS: calcd. for C21H22O9 441.11560 [M
441.11513.
+
Na]+; found
General Procedure for the C-Glycosylation of Naringenin with Di-
saccharides: Praseodymium triflate (216 mg, 0.2 equiv.) was added
to a mixture of (Ϯ)-naringenin (2; 500 mg, 1.84 mmol) and mono-
saccharide (1.7 equiv.) in acetonitrile/water (1:1; 6 mL). After stir-
ring for 48 h at reflux, the reaction mixture was concentrated under
vacuum prior to purification by CC.
Acknowledgments
The authors acknowledge the Fundação para a Ciência e Tecnolo-
gia (FCT) for the Ph. D. grant to R. G. S. (grant number SFRH/
BD/30699/2006) and for the post-doctoral grant to N. M. X. (grant
supported by project PTDC/QUI/67165/2006). The FCT is also
gratefully acknowledged for additional financial support through
project PTDC/QUI/67165/2006 and the CQB Strategic Project
PEst-OE/QUI/UI0612/2011.
8-(β-Lactosyl)naringenin (12): C-Glycosylation of naringenin with
lactose (1071 mg, 3.13 mmol) according to the general procedure
afforded compound 12 (307 mg, 28%) as a pale-yellow oil after
purification by CC (EtOAc/MeOH/water, 10:4:1). Rf = 0.31
(EtOAc/MeOH/water, 7:2:1). 1H NMR (CD3OD, 400 MHz): δ =
3
3
7.31 (d, J2Ј,3Ј = 3J5Ј,6Ј = 8.1 Hz, 2 H, 2Ј-H, 6Ј-H), 6.82 (d, J2Ј,3Ј
=
[1] T. Bililign, B. R. Griffith, J. S. Thorson, Nat. Prod. Rep. 2005,
22, 742–760.
3J5Ј,6Ј = 8.1 Hz, 2 H, 3Ј-H, 5Ј-H), 5.97 (s, 1 H, 6-H), 5.36 (dd, 3J2,3a
3
3
= 12.4, J2,3e = 1.5 Hz, 1 H, 2-H), 4.80 (d, J1ЈЈ,2ЈЈ = 10.1 Hz, 1 H,
1ЈЈ-H), 4.25 (br. t, 3J1ЈЈ,2ЈЈ = 10.1, 3J2ЈЈ,3ЈЈ = 9.3 Hz, 1 H, 2ЈЈ-H), 4.43
(d, J1ЈЈЈ,2ЈЈЈ = 7.4 Hz,1 H, 1ЈЈЈ-H), 3.45–3.96 (m, 11 H, 3ЈЈ-H, 4ЈЈ-
H, 5ЈЈ-H, 6aЈЈ-H, 6bЈЈ-H, 2ЈЈЈ-H, 3ЈЈЈ-H, 4ЈЈЈ-H, 5ЈЈЈ-H, 6aЈЈЈ-H,
[2] P. G. Hultin, Curr. Top. Med. Chem. 2005, 5, 1299–1331.
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2007, 2, 1175–1196.
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3
2
3
6bЈЈЈ-H), 3.13 (dd, J2,3e = 1.5, J3a,3e = 17.0, J2,3a = 12.4 Hz, 1 [5] D. E. Levy, C. Tang, The Chemistry of C-Glycosides, Pergamon
H, 3a-H), 2.74 (dd, J3a,3e = 17.0 Hz, 1 H, 3e-H) ppm. 13C NMR
(CD3OD, 100.57 MHz): δ = 196.6 (C-4), 166.0 (C-7), 162.5 (C-5),
162.9 (C-8a), 157.4 (C-4Ј), 129.2 (C-1Ј), 127.7 (C-2Ј, C-6Ј), 114.8
(C-3Ј, C-5Ј), 104.4 (C-8), 103.5 (C-1ЈЈЈ), 101.7 (C-4a), 95.1 (C-6),
79.7 (C-5ЈЈ), 78.8 (C-2), 78.7 (C-3ЈЈЈ), 75.8 (C-3ЈЈ), 77.0 (C-5ЈЈЈ),
73.5 (C-1ЈЈ), 73.0 (C-2ЈЈЈ), 71.1 (C-4ЈЈ), 70.5 (C-2ЈЈ), 68.7 (C-4ЈЈЈ),
61.1 (C-6ЈЈЈ), 60.0 (C-6ЈЈ), 42.3 (C-3) ppm. HRMS: calcd. for
C27H32O15 619.16334 [M + Na]+; found 619.16185.
2
Press, Oxford, 1995.
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412.
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Lett. 1989, 30, 6185–6188.
8-(β-Maltosyl)naringenin (13): C-Glycosylation of naringenin with
maltose (1065 mg, 3.11 mmol) according to the general procedure
afforded compound 13 (373 mg, 34%) as a pale-yellow oil after
purification by CC (EtOAc/MeOH/water, 10:4:1). Rf = 0.37
(EtOAc/MeOH/water, 7:2:1). 1H NMR (CD3OD, 400 MHz): δ =
[11] T. Kuribayashi, N. Ohkawa, S. Satoh, Tetrahedron Lett. 1998,
39, 4537–4540.
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2965–2967.
3
3
7.33 (d, J5Ј,6Ј = 3J2Ј,3Ј = 8.7 Hz, 2 H, 2Ј-H, 6Ј-H), 6.84 (d, J5Ј,6Ј
=
3J2Ј,3Ј = 8.7 Hz, 2 H, 3Ј-H, 5Ј-H), 5.99 (s, 1 H, 6-H), 5.38 (dd, 3J2,3a
3
= 12.7, J2,3e = 2.98 Hz, 1 H, 2-H), 5.23 (d, 2J1ЈЈЈ,2ЈЈЈ = 3.8 Hz, 1 H,
[14] T. Matsumoto, M. Katsuki, K. Suzuki, Tetrahedron Lett. 1988,
29, 6935–6938.
3
3
1ЈЈЈ-H), 4.81 (d, J1ЈЈ,2ЈЈ = 10.0 Hz, 1 H, 1ЈЈ-H), 4.23 (br. t, J1ЈЈ,2ЈЈ
[15] T. Kometani, H. Kondo, Y. Fujimori, Synthesis 1988, 12, 1005–
1007.
3
= 10.0, J2ЈЈ,3ЈЈ = 9.2 Hz, 1 H, 2ЈЈ-H), 3.94–3.80 (m, 3 H, 4ЈЈ-H,
6aЈЈ-H, 6bЈЈ-H), 3.63–3.78 (m, 5 H, 3ЈЈ-H, 3ЈЈЈ-H, 4ЈЈЈ-H, 6aЈЈЈ-H,
6bЈЈЈ-H), 3.44–3.53 (m, 2 H, 2ЈЈЈ-H, 5ЈЈ-H), 3.37–3.27 (m, 5ЈЈЈ-H),
[16] J. Mahling, K. Jung, R. R. Schmidt, Liebigs Ann. 1995, 3, 461–
466.
3
2
3.16 (dd, J2,3a = 12.7, J3a,3e = 17.1 Hz, 1 H, 3a-H), 2.76 (dd,
3J2,3e = 3.0, 2J3a,3e = 17.1 Hz, 1 H, 3e-H) ppm. 13C NMR (CD3OD,
100.57 MHz): δ = 181.5 (C-4), 166.4 (C-7), 163.3 (C-8a), 162.4 (C-
5), 157.9 (C-4Ј), 127.5 (C-1Ј), 127.3 (C-2Ј, C-6Ј), 114.9 (C-3Ј, C-
5Ј), 104.6 (C-8), 101.6 (C-1ЈЈЈ), 101.1 (C-4a), 95.0 (C-6), 80.3 (C-
3ЈЈ), 79.8 (C-5ЈЈ), 78.7 (C-4ЈЈ), 73.7 (C-1ЈЈ), 73.3 (C-3ЈЈЈ), 73.3 (C-
2ЈЈЈ), 72.9 (C-4ЈЈЈ), 70.1 (C-2), 70.1 (C-5ЈЈЈ), 70.1 (C-2ЈЈ), 61.3 (C-
6ЈЈЈ), 61.0 (C-6ЈЈ), 42.1 (C-3) ppm. HRMS: calcd. for C27H32O15
619.16334 [M + Na]+; found 619.16528.
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General Procedure for Ultrasound Experiments: For the reactions
with the monosaccharides, praseodymium triflate (216 mg,
0.2 equiv.) was added to a mixture of naringenin (2; 500 mg,
1.84 mmol) and sugar (1.7 equiv.) in acetonitrile/water (2:1; 4 mL).
After 8 h in the ultrasonic bath at 80 °C, the reaction mixture was
concentrated under vacuum prior to purification by column
chromatography. For the reactions with disaccharides, the reaction
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Eur. J. Org. Chem. 2013, 1441–1447

C-Glycosylation of a Flavanone Catalysed by Pr(OTf)3
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Received: November 13, 2012
Published Online: February 12, 2013
Eur. J. Org. Chem. 2013, 1441–1447
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1447