Synthesis and antiperoxidant activity of new phenolic O-glycosides

Article abstract of DOI:10.1016/S0008-6215(00)00313-X

We describe the synthesis of some 3-tert-butyl-4-hydroxyphenyl D-glycopyranosides by reaction of tert-butylhydroquinone with β-D-pentaacetyl-glucose, β-D-pentaacetyl-galactose, 2-acetamido- and 3,4,6-tri-O-acetyl-2-butanamido-2-deoxy-β-D-glucopyranosyl chlorides as well as the formation of anomeric 3-tert-butyl-4-hydroxyphenyl 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-eno-pyranosides by reaction between tert-butylhydroquinone and 3,4,6-tri-O-acetyl-D-glucal. All compounds, except 3-tert-butyl-4-hydroxyphenyl α- and β-D-glucopyranosides, inhibited lipid peroxidation with a degree of potency comparable to that of tert-butyl hydroxyanisole.

Full text of DOI:10.1016/S0008-6215(00)00313-X

www.elsevier.nl/locate/carres
Carbohydrate Research 330 (2001) 459–468
Synthesis and antiperoxidant activity of new phenolic
O-glycosides
Fabio Ponticelli,a,* Antoaneta Trendafilova,a,1 Massimo Valoti,b Simona Saponara,b
GianPietro Sgaraglib
aInstitute of Organic Chemistry, Uni6ersity of Siena, I-53100 Siena, Italy
bInstitute of Pharmacological Sciences, Uni6ersity of Siena, 53100 Siena, Italy
Received 23 October 2000; received in revised form 10 November 2000; accepted 1 December 2000
Abstract
We describe the synthesis of some 3-tert-butyl-4-hydroxyphenyl
droquinone with b- -pentaacetyl-glucose, b- -pentaacetyl-galactose, 2-acetamido- and 3,4,6-tri-O-acetyl-2-bu-
tanamido-2-deoxy-b- -glucopyranosyl chlorides as well as the formation of anomeric 3-tert-butyl-4-hydroxyphenyl
4,6-di-O-acetyl-2,3-dideoxy- -erythro-hex-2-eno-pyranosides by reaction between tert-butylhydroquinone and 3,4,6-
tri-O-acetyl- -glucopyranosides, inhibited
D-glycopyranosides by reaction of tert-butylhy-
D
D
D
D
D
-glucal. All compounds, except 3-tert-butyl-4-hydroxyphenyl a- and b-
D
lipid peroxidation with a degree of potency comparable to that of tert-butyl hydroxyanisole. © 2001 Elsevier Science
Ltd. All rights reserved.
Keywords: Antioxidants; O-Glycosylated tert-butylhydroquinones; Glucals; Inhibition of lipid peroxidation
1. Introduction
oils and lipid-containing foods.4 Recently,
Sgaragli et al.5 have reported that some hin-
dered phenols like BHA exhibit both antispas-
mogenic and antioxidant activity. It was
proposed that these two potentially useful
properties could be combined in properly
functionalised phenols and might thus be ef-
fective drugs in the prevention of tissue dam-
age from ischemia-reperfusion injury.6 We
previously have synthesised7 a series of BHA
analogues with different water solubility and/
or modified antioxidant properties in order to
verify their activity either in the extracellular
or in the intracellular environment. In the
present study tert-butylhydroquinone (BHQ)
(1), selected as a suitable target compound,
It is well established that phenols, in their
capacity as hydrogen donors, react with lipid
radicals1 and form stable phenoxy radicals,
therefore being effective chain breaking an-
tioxidants.2 Phenol itself is inactive as an an-
tioxidant, but substitution of alkyl groups into
the ortho or para position increases the elec-
tron density on the hydroxyl group by an
inductive effect and thus increases its reactiv-
ity with lipid radicals.3 tert-Butyl hydroxyan-
isole (BHA) is
antioxidant widely used as a stabiliser for fats,
a
synthetic phenolic
was O-glycosylated with different sugars (
D
-
* Corresponding author.
E-mail address: ponticelli@unisi.it (F. Ponticelli).
1 Present address: Institute of Organic Chemistry with Cen-
tre of Phytochemistry, Bulgarian Academy of Sciences, 1113
Sofia, Bulgaria.
glucose, -galactose, -glucosamine, -glu-
D
D
D
cal). The difficulties in the preparation of
glycosides of a diphenol, such as BHQ, arise
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00313-X

460
F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
from the presence of different sites of attack
and, as usual for sugar molecules, from the
anomerism at C-1. Eventual site- and stereose-
lectivity of the process is an attractive aspect
of the reactions involving this type of
molecules.
b-3a anomer almost exclusively (Table 1). The
addition of Yb(OTf)3 to the reaction mixture9
reduced the reaction time, but did not affect
the chemical yield and stereoselectivity (Table
1).
The condensation of 1 with b- -galactose
D
pentaacetate (2b) under the modified Helferich
conditions afforded the corresponding galac-
tosides 3b (10:90, a:b ratio) in 40% combined
yield (Table 1).
For the synthesis of glucosamine derivatives
of BHA, 2-acetamido-2-deoxy-3,4,6-tri-O-ace-
2. Results and discussion
b- -Glucose pentaacetate (2a) reacted with
D
1 in the presence of p-toluenesulfonic acid
under Helferich conditions8 to give a mixture
of anomers 3a in a 33% of combined yield
(Table 1). In addition, the glycoside 4 (2%)
was isolated from the reaction mixture as a
result of glycosylation of 1 at the hindered
hydroxy group (Scheme 1). The yield could be
improved up to 67% with the formation of
tyl-b-
D
-glucopyranosyl chloride (2c) was pre-
pared
according
to
the
published
procedures10,11 and reacted in Zn(Cl)2 and
dichloromethane.12 The glycosides 3c were ob-
tained in 60% yield, with the b anomer as the
major product (Table 1).
Table 1
Reaction of tert-butylhydroquinone 1 with activated sugars 2a–d
Donor
Conditions
Products
Combined yield (%)
Ratio a/b
2a
2a
2a
2b
2c
2d
p-toluenesulfonic acid, 125 °C
a-3a/b-3a+4
a-3a/b-3a
a-3a/b-3a
a-3b/b-3b
a-3c/b-3c
33+2
67
61
40
60
29/71
4/96
10/90
15/85
11/89
5/95
p-toluenesulfonic acid, CH2Cl2, reflux
p-toluenesulfonic acid, Yb(OTf)3, CH2Cl2, reflux
p-toluenesulfonic acid, CH2Cl2, reflux
ZnCl2, CH2Cl2, reflux
ZnCl2, CH2Cl2, reflux
a-3d/b-3d+5
40+13
Scheme 1. Synthesis of O-glycosides.

F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
461
Scheme 2. Deacetylated O-glycosides.
Scheme 4. Possible transition state during the formation of
the quinone 9.
A new glycosyl donor, 3,4,6-tri-O-acetyl-2-
butanamido - 2 - deoxy - b -
D
- glucopyranosyl
be explained by intramolecular (sigmatropic)
rearrangement (Scheme 4) of the product a-8
and subsequent oxidation to the quinone
system.
chloride (2d) was prepared according to the
method of Horton.11 The condensation of 2d
with 1 gave the expected glycosides 3d (5:95,
a:b ratio) in 40% combined yield (Table 1) as
well as the oxazoline 5. This compound was
observed in the reaction mixture and identified
Structure
assignment.—The
anomeric
configuration of the glycosides 3a–d was de-
1
1
termined on the basis of the H NMR spectral
based on the H NMR spectrum of a partially
data (Section 3). As expected, the H-1 signals
of b anomers appeared at l 4.97–5.00 with
coupling constants J1,2=7.9 Hz, while the H-1
signals of a anomers were shifted downfield (l
5.40–5.62) with J1,2=3.0–3.7 Hz. The re-
gioselectivity of the attack on the phenolic
purified fraction, due to its low stability dur-
ing chromatographic separation.
The high b-selectivity in the glycosylation
reactions under acidic conditions is attributed
to the neighbouring group effect of the C-2
substituent via formation of an acyloxonium
(or oxazolinium) ion. This also results in the
blockage of the one face and leads to prefer-
ential 1,2-trans-glycosylation. Evidence of this
mechanistic hypothesis is the isolation of the
oxazoline 5, deriving from the stabilisation of
the oxazolinium intermediate by elimination
of the proton from the amino group.13
Next, the water-soluble analogues of BHA
6 were prepared (Scheme 2) by the deacetyla-
tion of the glycosides 3 with sodium methox-
ide in methanol.14
1
groups could be derived from the H NMR
data of the aromatic moiety, as well as from
the observed NOE experiments. Irradiation of
H-1 signal in a- and b-3a showed enhance-
ment of the signals of the aromatic protons in
position ortho and para to the tert-butyl
group, whereas in the case of the glucoside 4,
as NOE effect only the aromatic proton in
position ortho to the tert-butyl group was
observed. Additionally, irradiation of the OH
signal gave NOE effect of only one aromatic
proton in a- and b-3a, while NOE effects were
observed between OH signal and two aro-
matic protons for 4.
Finally, tert-butylhydroquinone (1) was O-
conjugated (Scheme 3) with 3,4,6-tri-O-acetyl-
D
-glucal (7), performing the reaction under
Ferrier conditions.15 The condensation af-
forded an a/b mixture of unsaturated O-gly-
cosides 8 as well as the quinone 9. The
unexpected formation of this compound could
The structure of the unsaturated glycosides
8 was assigned on the basis of three signals in
the range 6.5–7.0 ppm, with the expected
coupling pattern (Section 3), attributable to
Scheme 3. Reaction of tert-BHQ with triacetylglucal 7.

462
F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
dant activity. Whilst, a-6a and b-6a showed a
significantly lower antiperoxidant activity as
compared to that of BHA. In the microsome
system BHA was the most potent, while b-6a
was the weakest among the phenols tested
(Table 2).
the aromatic protons of the phenolic moiety,
(allowing exclusion of a C-glycosidic structure
for both compounds), the vicinal coupling
constant between the H-4 and H-5 protons
which is highly diagnostic in assigning the C-1
configuration of 2-unsaturated-O-glycosides,16
(J4,5 =9.2 Hz for the a anomer and J4,5=3.0
Hz for the b anomer). In further support was
an NOE effect on H-5 detected by irradiation
of H-1 of b anomer and in the 13C spectrum of
3. Experimental
1
the a anomer the value of heteronuclear J for
General.—NMR spectra were recorded on
C-1 (170.9 Hz) were in agreement with an
equatorial H-1 (whereas a value near to 160
Hz is expected for an axial conformation of
H-117).
a Bruker AC 200 spectrometer at 200.13 MHz
13
for the 1H and 50.33 MHz for the C nucleus.
13C assignments were established based on
1
chemical shift considerations and H–13C 2D-
Inhibition of lipid peroxides formation.—The
compounds in Table 1 were assessed for their
capacity to prevent lipid peroxidation in two
peroxyl generating systems, as described in
Section 3. All compounds were able to inhibit
lipid peroxidation, the degree of inhibition
being generally greater when it was assessed in
the linoleate system. The vehicle Me2SO ex-
erted no significant effects (data not shown) at
the concentration used. As shown in Table 2,
a-8 was the most potent in the linoleate sys-
tem. b-3d, a-3b, b-6b, a-3c, b-3c, a-3a, b-3a
and b-3b also exhibited remarkable antiperoxi-
heterocorrelation experiments. MS spectra
were recorded on a VG 70 250S instrument in
low-resolution mode. TLC was performed on
precoated Silica Gel 60 F254 plates (E. Merck)
with detection by UV light or by spraying
with 50% H2SO4 in CH3OH followed by heat-
ing at 125 °C. Melting points were determined
with a Kofler apparatus and are uncorrected.
[h] values were determined on an Optical Ac-
tivity polarimeter. Column chromatography
(CC) was performed on Silica gel (E. Merck,
0.063–0.2 mm). Dichloromethane was dis-
,
tilled from CaH2 and stored over 4 A molecu-
Table 2
Rank order of inhibition of peroxides formation by novel antioxidants
Radical generating system–substrate
ABAP–linoleic acid
Compound
Fe2+–ascorbic acid–microsomes
IC50 (M) a
Compound
IC50 (M) a
a-8
9.7490.45×10−8 (7.01)
1.0090.13×10−7 (7.00)
1.3990.13×10−7 (6.86)
4.2890.04×10−7 (6.37)
6.6090.86×10−7 (6.18)
6.9790.27×10−7 (6.16)
9.8190.12×10−7 (6.01)
9.8392.53×10−7 (6.01)
1.0490.33×10−-6 (5.98)
1.1590.07×10−6 (5.94)
7.4992.62×10−6 b (5.13)
9.9192.48×10−6 b (5.00)
BHA
b-3a
a-3a
a-8
b-3b
a-3b
b-3d
a-3c
b-6b
a-6a
b-3c
b-6a
3.5290.30×10−6 (5.45)
4.6290.71×10−6 (5.33)
8.5090.46×10−6 (5.07)
9.7390.71×10−6 (5.01)
1.3390.12×10−5 (4.88)
1.3790.01×10−5 (4.86)
5.0490.26×10−5 (4.30)
6.6190.29×10−5 (4.18)
1.0390.22×10−4 (3.99)
1.5290.22×10−4 (3.82)
1.6690.12×10−4 (3.78)
1.2690.58×10−3 b (2.90)
b-3d
a-3b
BHA
a-3c
b-6b
b-3c
a-3a
b-3a
b-3b
a-6a
b-6a
a Values represent mean9SEM, n=3–5 (linoleic and microsome preparations). IC50 (M) is the molar concentration at which
the substance inhibits by 50% the maximal response. Values in brackets represent pIC50 (M), the negative log10 of the IC50.
Statistical analysis was performed by one-way analysis of variance (ANOVA) followed by Dunnett’s test for multiple comparison.
b PB0.01, with respect to BHA alone (Dunnet’s test).

F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
463
tracted with 0.5 M aq NaOH to remove the
unreacted tert-butylhydroquinone. The or-
ganic layer was washed with water, dried
(Na2SO4) and concentrated under reduced
pressure. The resulting residue was further
separated by CC (1.5:1, Et2O–petroleum
ether) affording the anomers a-3a (0.150 g,
10%) and b-3a (0.340 g, 23%) as well as the
glucoside 4 (0.030 g, 2%).
lar sieves. O2 consumption was monitored by
an O2 electrode (model 5300 Biological Oxy-
gen monitor, Yellow Spring Instrument Co.,
Inc. Yellow Spring, OH, USA), equipped with
a dual pen recorder.
Preparation of the starting materials.—The
starting sugar derivatives 2a–c were prepared
according to published procedures10,11,18 and
their spectroscopic data (1H NMR and MS)
were in agreement with their structures and, if
available, with previously reported values.
Preparation of 3,4,6-tri-O-acetyl-2-bu-
3-tert-Butyl-4-hydroxyphenyl 2,3,4,6-tetra-
O-acetyl-h- -glucopyranoside (a-3a): Colour-
D
less oil; [h]2D0 +118.24° (c 0.3, CHCl3); Rf 0.50
(2:1, Et2O–petroleum ether); 1H NMR
(CDCl3): l 1.39 (s, 9 H, tert-Bu), 2.04, 2.05,
2.06 and 2.07 (4s, each 3 H, 4 Ac), 4.03–4.30
(m, 3 H, H-5, H-6a, H-6b), 5.01 (dd, 1 H, J1,2
3.6, J2,3 10.0 Hz, H-2), 5.15 (t, 1 H, J3,4 =J4,5
10.0 Hz, H-4), 5.56 (exch. br s, 1 H, OH), 5.60
(d, 1 H, J1,2 3.6 Hz, H-1), 5.70 (t, 1 H,
J2,3=J3,4 10.0 Hz, H-3), 6.59 (d, 1 H, J5%,6% 8.5
Hz, H-5%), 6.75 (dd, 1 H, J2%,6% 3.1 Hz, H-6%),
6.97 (d, 1 H, H-2%); 13C NMR (CDCl3): l
20.54, 20.62, 20.63, and 22.53 (4 C, COCH3),
29.32 (3 C, C(CH3)3), 34.63 (1 C, C(CH3)3),
61.77 (C-6), 67.72 (C-2), 68.44 (C-3), 70.18
(C-5), 70.61 (C-4), 95.02 (C-1), 114.11, 116.41
and 116.65 (C-2%, 5% and 6%), 137.70 (C-3%),
149.74 (C-4%), 150.32 (C-1%), 169.72 (2 C,
COCH3), 170.29 and 170.76 (2 C, COCH3);
MS(EI): m/z (rel. int.) 496 [M]+ (0.8), 331
(22), 169 (79), 151 (13), 127 (22), 109 (57), 43
(100); Anal. Calcd for C24H32O11: C, 58.06; H,
6.50. Found: C, 58.45; H, 6.90.
tanamido-2-deoxy-h-
D
-glucopyranosyl chloride
(2d)10.—
D
-Glucosamine hydrochloride (5.39
g) was placed in 80 mL of anhyd MeOH in
which 0.56 g of Na was dissolved. Upon gen-
tle swirling, NaCl separated and was removed
by filtration. Butanoic anhydride (1.2–1.5
equiv) was added in portions while stirring the
solution of
tallisation, the crude 2-butanamido-2-deoxy-
-glucopyranose was removed by filtration,
washed with cold MeOH, and dried at rt.
Then, 5 g of 2-butanamido-2-deoxy- -glu-
D-glucosamine at rt. After crys-
D
D
copyranose was added in portions to 10 mL of
acetyl chloride. After being stirred for 16 h at
rt, the reaction mixture was diluted with
CHCl3 (40 mL) and poured into 50 mL of ice
water. The organic layer was washed with
saturated NaHCO3 (40 mL) and dried over
MgSO4. Evaporation of the solvent and subse-
quent crystallisation from dry Et2O gave 2d as
1
colourless crystals, mp 144–146 °C; H NMR
(CDCl3): l 0.93 (t, 3 H, J 7.1 Hz, CH3), 1.60
(m, 2 H, CH2), 2.04, 2.05 and 2.11 (3s, each 3
H, COCH3), 2.20 (m, 2 H, CH2), 4.10–4.40
(m, 3 H, H-5, H-6a and H-6b), 4.53 (ddd, 1 H,
J1,2 3.7, J2,3 9.0 Hz and J2,NH 8.8 Hz, H-2),
5.22 (t, 1 H, J3,4=J4,5 10.0 Hz, H-4), 5.33 (dd,
1 H, H-3), 5.80 (d, 1 H, NH) and 6.19 (d, 1 H,
H-1).
3-tert-Butyl-4-hydroxyphenyl 2,3,4,6-tetra-
O-acetyl-i- -glucopyranoside (b-3a): Colour-
D
less crystals, mp 137–138 °C (hexane–Et2O);
[h]2D0 −8.79° (c 1.13, CHCl3); Rf 0.40 (2:1,
1
Et2O–petroleum ether); H NMR (CDCl3): l
1.35 (s, 9 H, t-Bu), 2.01, 2.02, 2.05 and 2.06
(4s, each 3 H, 4 Ac), 3.80 (m, 1 H, H-5), 4.15
(dd, 1 H, J5,6a 4.8, J6a,6b 12.3 Hz, H-6a), 4.26
(dd, 1 H, J5,6b 2.3, J6a,6b 12.3 Hz, H-6b), 4.94
(d, 1 H, J1,2 7.3 Hz, H-1), 5.13 (dd, 1 H, J2,3
9.0 Hz, H-2), 5.23 (t, 1 H, J3,4 9.0 Hz, H-3),
5.25 (t, 1 H, J4,5 9.0 Hz, H-4), 6.08 (exch. br s,
1 H, OH), 6.59 (d, 1 H, J5%,6% 8.6 Hz, H-5%),
6.67 (dd, 1 H, J2%,6% 2.7 Hz, H-6%), 6.90 (d, 1 H,
H-2%); 13C NMR (CDCl3): l 20.50, 20.58,
20.75, and 22.53 (4 C, COCH3), 29.25 (3 C,
C(CH3)3), 34.58 (1 C, C(CH3)3), 62.07 (C-6),
68.34 (C-2), 71.31 (C-3), 71.85 (C-5), 72.82
Reaction of tert-butylhydroquinone (1) and
i- -glucose pentaacetate (2a)
D
With p-toluenesulfonic acid under Helferich
conditions8. A well powdered mixture of 1 (3.2
g, 19 mmol), 2a (1.17 g, 3 mmol) and p-tolue-
nesulfonic acid (0.03 g, 0.18 mmol) in a
round-bottom flask was heated at 125 °C for
30 min (oil bath). The reaction was controlled
by TLC (2:1, Et2O–petroleum ether). The
mixture was dissolved in CH2Cl2 and ex-

464
F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
g, 0.11 mmol) in CH2Cl2 (40 mL). The reac-
tion mixture was refluxed through a column
containing molecular sieves 4 A (10–15 g) for
(C-4), 100.28 (C-1), 115.32, 116.55 and 116.97
(C-2%, 5% and 6%), 137.44 (C-3%), 150.28 (C-4%),
150.89 (C-1%), 169.49 (2 C, COCH3), 170.36
and 170.82 (2 C, COCH3); MS(EI): m/z (rel.
int.) 496 (0.5) [M]+, 331 (30), 169 (100), 151
(23), 127 (28), 109 (70), 43 (81); Anal. Calcd
for C24H32O11: C, 58.06; H, 6.50. Found: C,
58.06; H, 6.47.
,
3 h (TLC control). The above mentioned
work-up procedure and separation by CC af-
forded the anomers a-3a (0.03 g, 6%) and
b-3a (0.270 g, 55%).
Reaction of tert-butylhydroquinone (1) with
2-tert-Butyl-4-hydroxyphenyl 2,3,4,6-tetra-
i- -galactose pentaacetate (2b).—p-Toluene-
D
O-acetyl-i- -glucopyranoside (4): Colourless
D
sulfonic acid (0.019 g, 0.11 mmol) was added
to a solution of 1 (0.199 g, 1.2 mmol) and 2b
(0.390 g, 1 mmol) in CH2Cl2 (40 mL). The
reaction mixture was carried out as described
above (Section 3.4.2, procedure). The crude
material was chromatographed (1.5:1, Et2O–
petroleum ether) to give the anomers a-3b
(0.030 g, 6%) and b-3b (0.170 g, 34%).
crystals, mp 233–235 °C (hexane–Et2O); Rf
1
0.30 (2:1, Et2O–petroleum ether); H NMR
(CDCl3): l 1.29 (s, 9 H, t-Bu), 1.99, 2.01,
2.03 and 2.05 (4s, each 3 H, 4 Ac), 3.85 (m, 1
H, H-5), 4.10–4.20 (m, 2 H, H-6a and H-6b),
5.15 (d, 1 H, J1,2 7.3 Hz, H-1), 5.16 (dd, 1 H,
J2,3 9.0 Hz, H-2), 5.27 (t, 1 H, J3,4 9.0 Hz,
H-3), 5.30 (t, 1 H, J4,5 9.0 Hz, H-4), 5.41
(exch. br s, 1 H, OH), 6.60 (dd, 1 H, J3%,5% 2.5,
J5%,6% 8.5 Hz, H-5%), 6.79 (d, 1 H, H-3%), 6.88
(d, 1 H, H-6%); 13C NMR (CDCl3): l 20.46,
20.53, 20.62 (4 C, COCH3), 29.67 (3 C,
C(CH3)3), 34.63 (1 C, C(CH3)3), 62.06 (C-6),
68.43 (C-2), 71.31 (C-3), 71.74 (C-5), 73.19
(C-4), 98.03 (C-1), 112.58, 114.49 and 115.43
(C-3%, 5% and 6%), 140.12 (C-2%), 149.07 (C-4%),
150.98 (C-1%), 169.18, 169.32, 170.36 and
170.82 (4 C, COCH3); MS(EI): m/z (rel. int.)
496 (0.2) [M]+, 331 (29), 169 (100), 127 (18),
109 (64); Anal. Calcd for C24H32O11: C,
58.06; H, 6.50. Found: C, 58.22; H, 6.72.
With p-toluenesulfonic acid. p-Toluenesul-
fonic acid (0.019 g, 0.11 mmol) was added to
a solution of 1 (0.199 g, 1.2 mmol) and 2a
(0.390 g, 1 mmol) in CH2Cl2 (40 mL). The
reaction mixture was refluxed through a
3-tert-Butyl-4-hydroxyphenyl 2,3,4,6-tetra-
O-acetyl-h- -galactopyranoside (a-3b). Colour-
D
less oil; [h]2D0 +143.94° (c 0.66, CHCl3);
Rf 0.55 (2:1, Et2O–petroleum ether); 1H
NMR (CDCl3): l 1.39 (s, 9 H, t-Bu), 1.98,
2.03, 2.09 and 2.17 (4s, each 3 H, 4 Ac),
4.10–4.20 (m, 2 H, H-6a, H-6b), 4.37 (brt, 1
H, J4,5 1.0, J5,6a=J5,6b 6.5 Hz, H-5), 5.27 (dd,
1 H, J2,3 10.0, J3,4 3.6 Hz, H-3), 5.58 (dd, 1
H, J1,2 3.6, Hz, H-2), 5.58 (dd, 1 H, J4,5 1.0
Hz, H-4), 5.65 (d, 1 H, H-1), 6.58 (d, 1 H,
J5%,6% 8.6 Hz, H-5%), 6.77 (dd, 1 H, J2%,6% 2.9 Hz,
H-6%), 6.97 (d, 1 H, H-2%). MS(EI): m/z (rel.
int.) 496 (3) [M]+, 331 (55), 169 (67), 166
(17), 151 (13), 127 (16), 109 (36), 43 (100).);
Anal. Calcd for C24H32O11: C, 58.06; H, 6.50.
Found: C, 58.10; H, 6.63.
3-tert-Butyl-4-hydroxyphenyl 2,3,4,6-tetra-
O-acetyl-i- -galactopyranoside (b-3b). Oil;
D
,
column containing molecular sieves 4 A (10–
[h]2D0 +6.60° (c 0.76, CHCl3); Rf 0.43 (2:1,
15 g) for 6 h (TLC control, 1:2, petroleum
ether–Et2O). After cooling, the reaction mix-
ture was diluted with CH2Cl2, washed with
0.5 M aq NaOH and water, dried over anhyd
Na2SO4 and concentrated under reduced
pressure. The residue was separated by CC
on silica gel (petroleum ether–Et2O mixture)
to give the pure anomers a-3a (0.013 g, 3%)
and b-3a (0.319 g, 64%).
1
Et2O–petroleum ether); H NMR (CDCl3): l
1.39 (s, 9 H, t-Bu), 2.02, 2.05, 2.10 and 2.18
(4s, each 3 H, 4 Ac), 4.00–4.20 (m, 3 H, H-5,
H-6a and H-6b), 4.92 (d, 1 H, J1,2 7.9 Hz,
H-1), 5.10 (dd, 1 H, J2,3 10.4, J3,4 3.4 Hz,
H-3), 5.43 (dd, 1 H, H-2), 5.45 (dd, 1 H, J4,5
1.0 Hz, H-4), 6.58 (d, 1 H, J5%,6% 8.5 Hz, H-5%),
6.73 (dd, 1 H, J2%,6% 2.8, H-6%), 6.96 (d, 1 H,
H-2%). MS(EI): m/z (rel. int.) 496 (1) [M]+,
331 (50), 169 (55), 166 (13), 151 (11), 127
(13), 109 (30), 43 (100); Anal. Calcd for
C24H32O11.H2O: C, 56.03; H, 6.66. Found: C,
55.90; H, 7.05.
With combined use of p-toluenesulfonic acid
and Yb(OTf )3. Yb(OTf)3 (0.062 g, 0.1 mmol)
was added to a solution of tert-butylhy-
droquinone (1) (0.199 g, 1.2 mmol), 2a (0.390
g, 1 mmol) and p-toluenesulfonic acid (0.019

F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
465
C, C(CH3)3), 54.73 (1 C, C-2), 62.16 (1 C,
C-6), 63.23 (1 C, C-4), 68.45 (1 C, C-5), 71.72
(1 C, C-3), 99.83 (1 C, C-1), 114.93, 116.45
and 116.83 (3 C, ar), 137.26 (1 C,
arCꢀC(CH3)3), 150.35 and 150.46 (2C, arꢀO),
169.41 (1 C, NHCO), 170.62, 170.76 and
170.84 (3 C, CO); MS(EI): m/z (rel. int.) 495
(3) [M]+, 330 (71), 210 (34),168 (60), 166 (43),
150 (77), 43 (100); Anal. Calcd for
C24H33NO10: C, 58.17; H, 6.71; N, 2.83.
Found: C, 58.38; H, 6.85; N, 2.75.
Reaction of tert-butylhydroquinone (1) with
3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-h-
D-
glucopyranosyl chloride (2c) in the presence of
ZnCl2.—ZnCl2 (0.09 g, 0.6 mmol) was added
to a solution of 1 (0.199 g, 1.2 mmol) and 2c
(0.365 g, 1 mmol) in CH2Cl2 (40 mL). The
reaction mixture was refluxed through a
,
column containing molecular sieves 4 A (10–
15 g) for 6 h (TLC control, 1:1, petroleum
ether–EtOAc). After cooling, the reaction
mixture was diluted with CH2Cl2, washed with
0.5 M aq NaOH and water, dried over anhyd
Na2SO4 and concentrated under reduced pres-
sure. The residue was chromatographed on
silica gel (1:1, petroleum ether–EtOAc) to
give the anomers a-3c (0.03 g, 6%) and b-3c
(0.240 g, 54%).
Reaction of tert-butylhydroquinone (1) with 2
-butanamido-3,4,6-tri-O-acetyl-2-deoxy-h- -
D
glucopyranosyl chloride (2d) in the presence of
ZnCl2.—To a solution of 1 (0.199 g, 1.2
mmol) and 2d (0.394 g, 1 mmol) in CH2Cl2 (40
mL) ZnCl2 (0.09 g, 0.6 mmol) was added. The
reaction mixture was refluxed through a
3-tert-Butyl-4-hydroxyphenyl 2-acetamido-
3,4,6-tri-O-acetyl-2-deoxy-h- -glucopyranoside
D
,
column containing molecular sieves 4 A (10–
(a-3c). Crystals, mp 223–225 °C (hexane–
Et2O); [h]2D0 +128.2° (c 0.39, CHCl3); Rf 0.24
(1:1, EtOAc–petroleum ether); 1H NMR
(CDCl3): l 1.41 (s, 9 H, t-Bu), 1.98 (s, 3 H,
NH–Ac), 2.05, 2.06 and 2.07 (3s, each 3 H, 3
Ac), 4.00–4.30 (m, 3 H, H-5, H-6a and H-6b),
4.50 (ddd, 1 H, J1,2 3.0, J2,3 9.5, J2,NH 9.2 Hz,
H-2), 5.20 (t, 1 H, J3,4 =J4,5 9.5 Hz, H-4), 5.44
(t, 1 H, H-3), 5.45 (d, 1 H, H-1), 5.86 (d, 1 H,
J2,NH 9.2 Hz, NH), 6.60 (d, 1 H, J5%,6% 8.5 Hz,
H-5%), 6.78 (dd, 1 H, J2%,6% 3.0, H-6%), 6.96 (d, 1
H, H-2%). MS(EI): m/z (rel. int.) 495 (0.5)
[M]+, 330 (100), 210 (35),168 (73), 150 (83),
127 (13), 43 (87); Anal. Calcd for C24H33NO10:
C, 58.17; H, 6.71, N, 2.83. Found: C, 57.99;
H, 7.00; N, 2.98.
15 g) for 6 h (TLC control, 1:1, petroleum
ether–EtOAc). After cooling, the reaction
mixture was diluted with CH2Cl2, washed with
0.5 M aq NaOH and water, dried over anhyd
Na2SO4 and concentrated under reduced pres-
sure. The residue was chromatographed on
silica gel with 1:1, petroleum ether–EtOAc to
give the anomers a-3d (0.01 g, 2%) and b-3d
(0.200 g, 38%) as well as the oxazoline 5
(0.045 g, 13%) contaminated for a small
amount of both previous compounds.
3-tert-Butyl-4-hydroxyphenyl 2-butanamido-
3,4,6-tri-O-acetyl-2-deoxy-h- -glucopyranoside
D
(a-3d). Oil, [h]D20 +66.67° (c 0.15, CHCl3); Rf
1
0.46 (1:1, EtOAc–petroleum ether); H NMR
(CDCl3): l 0.87 (t, 3 H, J 7.3 Hz, CH3),
1.36 (s, 9 H, C(CH3)3), 1.60 (m, 2 H, CH2),
2.02 (s, 9 H, 3×COCH3), 2.20 (m, 2 H,
CH2), 4.00–4.20 (m, 3 H, H-5, H-6a and
H-6b), 4.47 (ddd, 1 H, J1,2 3.7, J2,3 10.0, J2,NH
9.3 Hz, H-2), 5.18 (t, 1 H, J3,4=J4,5 10.0 Hz,
H-4), 5.40 (t, 1 H, H-3), 5.41 (d, 1 H, H-1),
5.85 (d, 1 H, NH), 6.58 (d, 1 H, J5%,6% 8.5 Hz,
H-5%), 6.72 (dd, 1 H, J2%,6% 2.8 Hz, H-6%), 6.91
(d, 1 H, H-2%); MS(EI) m/z (rel. int.) 523 [M]+
(1.5), 403 (2.8), 386 (2.5), 358 (70), 298 (9),
256 (8), 238 (33), 196 (33), 178 (68), 166 (37),
151 (24), 126 (33), 108 (36), 71 (45), 43 (100);
Anal. Calcd for C26H37NO10: C, 59.64; H,
7.12; N, 2.68.Found: C, 59.41; H, 7.39; N,
2.92.
3-tert-Butyl-4-hydroxyphenyl 2-acetamido-
3,4,6-tri-O-acetyl-2-deoxy-i- -glucopyranoside
D
(b-3c). Crystals, mp 137–138 °C (hexane–
Et2O); [h]2D0 −10.2° (c 0.50, CHCl3); Rf 0.14
(1:1, EtOAc–petroleum ether); 1H NMR
(CDCl3): l 1.37 (s, 9 H, t-Bu), 1.98 (s, 3 H,
NH–Ac), 2.05, 2.06 and 2.07 (3s, each 3 H, 3
Ac), 3.85 (m, 1 H, H-5), 4.00–4.30 (m, 3 H,
H-2, H-6a and H-6b), 5.13 (t, 1 H, J3,4 =J4,5
10.0 Hz, H-4), 5.17 (d, 1 H, J1,2 8.3 Hz, H-1),
5.41 (t, 1 H, J2,3 10.0 Hz, H-3), 5.75 (d, 1 H,
J2,NH 7.7 Hz, NH), 6.58 (d, 1 H, J5%,6% 8.5 Hz,
H-5%), 6.67 (dd, 1 H, J2%,6% 2.7, H-6%), 6.93 (d, 1
H, H-2%); 13C NMR (CDCl3): l 20.55, 20.61
and 20.65 (3 C, COCH3), 23.14 (1 C,
ꢀNHCOCH3), 29.21 (3 C, C(CH3)3), 34.52 (1

466
F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
(d, 1 H, J5%,6% 8.6 Hz, H-5%), 6.88 (dd, 1 H, J2%,6%
2-Propyl-4,5-dihydro-(3,4,6-tri-O-acetyl-1,2-
dideoxy- -glucopyranoso)-[2,1-d]-1,3-oxazole
2.8 Hz, H-6%), 7.04 (d, 1 H, H-2%), 7.00 (s, 1 H,
OH); FABMS m/z 351 [M+Na]+ (10), 328
(5), 191, 166, 149, 73 (100), 57. Anal. Calcd
for C16H24O7·H2O: C, 55.48; H, 7.57. Found:
C, 55.33; H, 7.37.
D
(5). Oil, Rf 0.40 (1:1, EtOAc–petroleum
1
ether); H NMR (CDCl3): l 0.98 (t, 3 H, J 7.3
Hz, CH3), 1.68 (sxt, 2 H, J 7.3 Hz, CH2), 2.32
(t, 2 H, CH2), 2.04, 2.06 and 2.07 (3s, 9 H,
3×COCH3), 3.52–3.61 (m, 1 H, H-5), 4.10–
4.21 (m, 3 H, H-2, H-6a and H-6b), 4.87 (dt,
1 H, J2,4=J3,4 2.0, J4,5 9.1 Hz, H-4), 5.25 (t, 1
H, J2,3 2.0 Hz, H-3) and 5.93 (d, 1 H, J1,2 7.4,
H-1).
3-tert-Butyl-4-hydroxyphenyli- -glucopyran-
D
oside (b-6a from b-3a). Oil, [h]2D0 −53.13° (c
1.6, CH3OH), Rf 0.38 (4:1, CHCl3–MeOH),
1H NMR (CD3CN): l 1.40 (s, 9 H, C(CH3)3),
3.40–3.60 (m, 4 H, H-2, H-3, H-4, H-5), 3.85
(m, 2 H, H-6a and H-6b), 4.82 (d, 1 H, J1,2 7.1
Hz, H-1), 6.73 (d, 1 H, J5%,6% 8.6 Hz, H-5%), 6.82
(dd, 1 H, J2%,6% 2.8 Hz, H-6%), 7.02 (d, 1 H,
3-tert-Butyl-4-hydroxyphenyl
acetyl-2-butanamido-2-deoxy-i-
3,4,6-tri-O-
-glucopyran-
D
oside (b-3d). Crystals, mp 168–170 °C
(EtOAc–petroleum ether); [h]2D0 −5.05° (c
0.99, CHCl3); Rf 0.26 (1:1, EtOAc–petroleum
13
H-2%), 7.11 (s, 1 H, OH). C NMR (CD3OD):
l 20.50, 20.58, 20.75, and 22.53 (4 C,
COCH3), 29.83 (3 C, C(CH3)3), 35.43 (1 C,
C(CH3)3), 62.38 (C-6), 71.21 (C-2), 74.71 (C-
3), 74.85 (C-5), 77.71 (C-4), 103.47 (C-1),
115.82, 117.19 and 117.33 (C-2%, 5% and 6%),
138.00 (C-3%), 151.72 (C-4%), 152.43 (C-1%);
FABMS m/z 351 [M+Na]+ (3), 328 (5), 325,
191, 166 (100), 149, 73, 57. Anal. Calcd for
C16H24O7·H2O: C, 55.48; H, 7.57. Found: C,
55.35; H, 7.25.
1
ether); H NMR (CDCl3): l 0.87 (t, 3 H, J 7.3
Hz, CH3), 1.34 (s, 9 H, C(CH3)3), 1.60 (m, 2
H, CH2), 2.01 (s, 6 H, 2×COCH3), 2.05 (s, 3
H, COCH3), 2.20 (m, 2 H, CH2), 3.80 (m, 1 H,
H-5), 4.10–4.25 (m, 3 H, H-2, H-6a and H-
6b), 5.12 (t, 1 H, J3,4=J4,5 10.0 Hz, H-4), 5.13
(d, 1 H, J1,2 8.7 Hz, H-1), 5.40 (t, 1 H, J2,3 10.0
Hz, H-3), 5.63 (d, 1 H, NH), 6.64 (d, 1 H, J5%,6%
8.5 Hz, H-5%), 6.65 (dd, 1 H, J2%,6% 2.8 Hz,
H-6%), 6.89 (d, 1 H, H-2%); MS(EI): m/z (rel.
int.) 523 [M]+ (0.4), 403 (0.3), 386 (1), 358
(20), 238 (5), 196 (27), 178 (59), 166 (23), 151
(21), 126 (25), 108 (28), 71 (34), 43 (100);
Anal. Calcd for C26H37NO10: C, 59.64; H,
7.12; N, 2.68. Found: C, 59.38; H, 7.49; N,
2.52.
3-tert-Butyl-4-hydroxyphenyl i- -galacto-
D
pyranoside (b-6b from b-3b). [h]2D0 −20.0° (c
1.0, CH3OH), Rf 0.32 (4:1, CHCl3–MeOH) 1H
NMR (Me2SO): l 1.32 (s, 9 H, C(CH3)3),
3.40–3.80 (m, 6 H, H-2, H-3, H-4, H-5, H-6a
and H-6b), 4.58 (d, 1 H, J1,2 7.1 Hz, H-1), 6.64
(d, 1 H, J5%,6% 8.6 Hz, H-5%), 6.68 (dd, 1 H, J2%,6%
2.4 Hz, H-6%), 6.83 (d, 1 H, H-2%). Anal. Calcd
for C16H24O7·1.5H2O: C, 54.07; H, 7.66.
Found: C, 54.21; H, 7.73.
Typical deacetylation procedure.—A 0.2 M
solution of methanolic NaOMe (7.6 mL) was
added to a solution of glycosides b-3a,b and
a-3a (0.25 mmol) in MeOH (10 mL). The
solution was stirred at rt for 1–2 h (TLC
control), and then Amberlyst (H+) resin was
added until the pH was neutral. The resin was
filtered off, washed with MeOH, and the com-
bined solvent was evaporated under reduced
pressure. Further purification by CC (5:1 and
4:1, CHCl3–MeOH) afforded the compounds
b-6a,b and a-6a in 80–95% yields.
Reaction of tert-butylhydroquinone (1) with
3,4,6-tri-O-acetyl- -glucal (7).—tert-Butylhy-
D
droquinone (0.5 g, 3 mmol) and glucal 7
(0.272 g, 1 mmol) were refluxed in chloroben-
zene (4 mL) for 18 h. After removing the
solvent, CH2Cl2 (10 mL) was added and the
mixture was washed with saturated NaHCO3,
dried over anhyd Na2SO4 and concentrated
under reduced pressure. The residue was chro-
matographed on silica gel with a petroleum
ether–Et2O mixture to give the glycosides a-8
(60 mg, 15.8%), mixture of a-8 and b-8 (150
mg, ratio 1:2, 39.7%), and 9 (80 mg, 21%).
3-tert-Butyl-4-hydroxyphenyl 4,6-di-O-ace-
3-tert-Butyl-4-hydroxyphenylh- -glucopyran-
D
oside (a-6a from a-3a). Oil, [h]2D0 +134.45° (c
0.6, CH3OH), Rf 0.34 (4:1, CHCl3–MeOH),
1H NMR (CD3CN): l 1.40 (s, 9 H, C(CH3)3),
3.50–3.80 (m, 6 H, H-2, H-3, H-4, H-5, H-6a
and H-6b), 5.33 (d, 1 H, J1,2 3.0 Hz, H-1), 6.73
tyl-2,3-dideoxy-h-
D
-erythro-hex-2-enopyran-
oside (a-8). Oil, [h]2D0 +106.84° (c 0.47,

F. Ponticelli et al. / Carbohydrate Research 330 (2001) 459–468
467
Inhibition of lipid peroxides formation.—
This test was performed by using two model
systems, as already described.2 The first was
based on the oxidation of linoleic acid initiated
by 2,2%-azobis-2-amidinopropane hydrochlo-
ride (ABAP), a thermolabile azo compound
which, on decomposition, forms radicals that
abstract hydrogen atoms from linoleic acid.
ABAP (11 mM) was added to a suspension
of linoleic acid (33 mM) in 50 mM Na–phos-
phate buffer pH 7.4, in the chamber of an O2
electrode thermostatted at 37 °C. O2 consump-
tion was monitored for approximately 6 min
before adding the antioxidant at different con-
centrations. O2 consumption due to ABAP
decomposition was determined separately and
subtracted from the peroxidation rate of
linoleic acid. In the second system, peroxida-
tion of rat liver microsomes initiated by addi-
CHCl3); Rf 0.45 (1:1, petroleum ether–Et2O);
1H NMR (CDCl3): l 1.39 (s, 9 H, C(CH3)3),
2.03 and 2.12 (2s, 6 H, 2 COCH3), 4.10–4.40
(m, 3 H, H-5, H-6a and H-6b), 5.39 (brd, J4,5
9.2 Hz, H-4), 5.56 (brs, 1 H, H-1), 6.01 (brs, 2
H, AB-system, H-2 and H-3), 6.59 (d, 1 H, J5%,6%
8.5 Hz, H-5%), 6.85 (dd, J2%,6% 2.5 Hz, H-6%), 6.99
(d, H-2%); 13C NMR (CDCl3): l 20.74 and 20.94
(2 C, COCH3), 29.43 (3 C, C(CH3)3), 34.63 (1
C, C(CH3)3), 62.84 (1 C, C-6), 65.15 (1 C, C-4),
67.54 (1 C, C-5), 94.06 (1 C, C-1), 114.95 (1 C,
C-6%), 116.68 (1 C, C-5%), 117.15 (1 C, C-2%),
127.35 (1 C, C-3), 129.78 (1 C, C-2), 137.10 (1
C, C-3%), 149.93 (1 C, C-4%), 150.79 (1 C, C-1%),
170.49, 171.10 (2 C, CO); MS EI m/z: 378
[M]+ (2), 213 (28), 166 (5), 153 (32), 111 (90),
81 (9), 43 (100). Anal. Calcd for C20H26O7: C,
63.48; H, 6.93. Found: C, 63.22; H, 7.12.
3-tert-Butyl-4-hydroxyphenyl 4,6-di-O-ace-
tyl-2,3-dideoxy-i- -erythro-hex-2-enopyran-
D
tion
of
peroxidising
mixture
of
oside (b-8). Detected in the 1H NMR spectrum
Fe2+/Fe3+ –ascorbic acid 30 mM, was mea-
sured as O2 consumption at 29 °C. Reaction
mixtures, in a final volume of 3 mL, contained
0.5 mg microsomal protein, 14.7 mM Me2SO
as vehicle and 20 mM KH2PO4–KOH buffer,
pH 6.0.
1
of the mixture; H NMR (CDCl3): l 1.39 (s, 9
H, C(CH3)3), 1.93 and 2.11 (2s, 6 H, 2
COCH3), 4.10–4.40 (m, 3 H, H-5, H-6a and
H-6b), 5.19 (t, J3,4=J4,5 3.0 Hz, H-4), 5.69
(brd, 1 H, H-1), 6.12 (brs, 2 H, AB-system, H-2
and H-3), 6.56 (d, 1 H, J5%,6% 8.5 Hz, H-5%), 6.85
(dd, J2%,6% 2.5 Hz, H-6%), 6.99 (d, H-2%).
(3S,4S,2R)-4-[4-(tert-Butyl)-3,6-dioxo-1,4-
cyclohexadienyl] - 3 - methylcarbonyl oxy - 3,4-
dihydro-2H-2-oxinylmethyl acetate (9). oil,
[h]2D0 −58.33° (c 0.60, CHCl3); Rf 0.76 (1:1,
Acknowledgements
Financial support from Murst and the Ital-
ian Ministry of Foreign Affairs, Rome Italy
(Law 212, 26-2-1992) is gratefully acknowl-
edged. The authors thank Dr G.L. Giorgi,
Centro di Analisi e Determinazioni Strutturali,
Universita` di Siena, Italy for the recording of
MS Spectra.
1
petroleum ether–Et2O); H NMR (CDCl3): l
1.28 (s, 9 H, C(CH3)3), 2.00 and 2.08 (2s, 6 H,
2×COCH3), 3.82 (dt, 1 H, J4,5=J4,6 2.2, J3,4
8.3 Hz, H-4), 4.10 (m, 1 H, H-2), 4.20 (dd, 1
H, J2,7a 2.3, J7a,7b 12.3 Hz, H-7a), 4.38 (dd, 1 H,
J2,7b 4.5 Hz, H-7b), 4.54 (dd, J5,6 6.0 Hz, H-5),
5.00 (dd, J2,3 9.7 Hz, H-3), 6.56 (s, 1 H, H-2%),
6.57 (dd, 1 H, H-6), 6.61 (s, 1 H, H-5%). 13C
NMR (CDCl3): l 20.73 (2 C, COCH3), 29.12
(3 C, C(CH3)3), 35.08 (1 C, C(CH3)3), 37.01 (1
C, C-4), 61.91 (1 C, C-7), 69.19 (1 C, C-3),
74.81 (1 C, C-2), 100.93 (1 C, C-5), 131.62 (1
C, C-2%), 135.02 (1 C, C-6), 144.86 (1 C, C-5%),
147.24 (1 C, C-4%), 155.95 (1 C, C-1%), 169.86
and 170.67 (2 C, COCH3), 187.60 (2 C, CO);
MS E m/z: 376 [M]+ (0.9), 316 (5), 256 (40),
243 (100), 227 (5), 43 (55). Anal. Calcd for
C20H24O7; C, 63.82; H, 6.42. Found: C, 64.11;
H, 6.35.
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