In the search of glycogen phosphorylase inhibitors: Synthesis of C-D-glycopyranosylbenzo(hydro)quinones - Inhibition of and binding to glycogen phosphorylase in the crystal

Article abstract of DOI:10.1002/ejoc.200600548

Penta-O-acetyl-β-D-glycopyranoses and 1,4-dimethoxybenzene led selectively by electrophilic substitution to C-β-D-glycopyranosyl-1,4- dimethoxybenzenes which were converted by simple and efficient reactions (oxidation, reduction and deacetylation) to the

Full text of DOI:10.1002/ejoc.200600548

FULL PAPER
DOI: 10.1002/ejoc.200600548
In the Search of Glycogen Phosphorylase Inhibitors: Synthesis of C- -
D
Glycopyranosylbenzo(hydro)quinones – Inhibition of and Binding to Glycogen
Phosphorylase in the Crystal[‡]
Li He,[a,b] Yun Zhi Zhang,[a,b] Marcelle Tanoh,[a] Guo-Rong Chen,[b] Jean-Pierre Praly,*[a]
Evangelia D. Chrysina,[c] Costas Tiraidis,[c] Magda Kosmopoulou,[c] Demetres D. Leonidas,[c]
and Nikos G. Oikonomakos[c]
Keywords: C-Glycosides / Aromatic substitution / Inhibitors / X-ray diffraction / Glycogen phosphorylase
Penta-O-acetyl-β-
D-glycopyranoses and 1,4-dimethoxyben-
whereas C-β-
D-glucosylhydroquinone 17 was not effective
zene led selectively by electrophilic substitution to C-β-
D-
up to a concentration of 8 mM. In order to elucidate the struc-
glycopyranosyl-1,4-dimethoxybenzenes which were con-
verted by simple and efficient reactions (oxidation, reduction
and deacetylation) to the corresponding C-glycosylhydro-
and C-glycosylbenzoquinones, with either an acetylated or
tural basis of inhibition, we determined the crystal structures
of 19 and 23 in complex with GPb at a 2.03–2.05 Å resolution.
The complex structures reveal that the inhibitors can be ac-
commodated at the catalytic site at approximately the same
deprotected sugar moiety. C-β-
and C-β- -Glucosylhydroquinone 23 were found to be com-
petitive inhibitors of rabbit muscle glycogen phosphorylase
b (GPb), with respect to the substrate α- -glucose-1-phos-
respectively,
D
-Glucosylbenzoquinone 19
position as α-D-glucose and stabilise the transition state con-
D
formation of the 280s loop by making several favourable con-
tacts to Asp283 and Asn284 of this loop.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
D
phate, with Ki values of 1.3 and 0.9 mM,
stable than O-glycosides, C-linked analogues[3] can inhibit
sugar-processing enzymes such as glycosidases, glycosyl
transferases and phosphorylases.[3–5] Their synthesis is well
developed and uses free radical chemistry,[6] nucleophilic C-
glycosyl donors[7,8] and other methods.[9–11] C-Glycosylated
flavonoids[12] and C-glycosylarenes[13,14] have also attracted
much attention.
In studies towards antithrombotic sugar derivatives,[15]
we prepared C-glycosyl derivatives of phloroglucinol, resor-
cinol and phenol. Analogues derived from hydroquinone
appeared, in contrast, quite rare,[16–19] although hydroqui-
none O-glycosides are known,[20] or even commercially
available as naturally occurring arbutin (4-hydrobenzene β-
Introduction
Besides common sugars, Nature provides a variety of
sugar analogues which can be regarded as molecular tools
for diverse applications in glycoscience. These findings have
spurred intensive researches in the field of glycomimics.[1]
Among them, C-glycosyl derivatives[2] have attracted special
attention due to the resistance of the glycosidic C–C bond
towards acid- or enzyme-catalyzed hydrolysis. Being more
[‡] In the Search of Glycogen Phosphorylase Inhibitors. 4. Part 3:
M. Benltifa, S. Vidal, B. Fenet, M. Msaddek, P. G. Goekjian,
J.-P. Praly, A. Brunyánszki, T. Docsa, P. Gergely, Eur. J. Org.
Chem. 2006, 4242–4256. Part 2: M. Benltifa, S. Vidal, D. Gueyr-
ard, P. G. Goekjian, M. Msaddek, J.-P. Praly, Tetrahedron Lett. -glucopyranoside). Because benzo(hydro)quinone moieties
2006, 47, 6143–6147. Part 1: N. G. Oikonomakos, M. Kosmo-
offer many synthetic opportunities, and because they might
poulou, S. E. Zographos, D. D. Leonidas, E. D. Chrysina, L.
favour diverse bioactivities, as shown by the properties of
many related molecules,[21] we developed routes to acety-
lated C-glycosylhydro-, and C-glycosylbenzoquinones, as
well as to C-glycosyl analogues of vitamin E.[22] Upon de-
acetylation, such compounds would afford eventually var-
ied water-soluble materials to be tested in particular as in-
Somsák, V. Nagy, J.-P. Praly, T. Docsa, B. Tóth, P. Gergely, Eur.
J. Biochem. 2002, 269, 1684–1696.
[a] Laboratoire de Chimie Organique 2, UMR UCBL-CNRS 5181,
Université Lyon 1,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne,
France
Fax: +33-4-72-44-83-49
E-mail: jean-pierre.praly@univ-lyon1.fr
[b] Laboratory of Advanced Materials, Institute of Fine Chemicals, hibitors and ligands of glycogen phosphorylase (GP).[23]
East China University of Science and Technology (ECUST)
Recent interest in GP stems from the increasing preva-
130 Meilong Road, POB 257, 200237 Shanghai, P. R. China
lence of metabolic disorders such as diabetes and obesity
and from the need for a better understanding of their etiol-
ogy, as well as more adequate treatments.[24] GP has ap-
peared as a possible therapeutic target because: (1) high
[c] Institute of Organic and Pharmaceutical Chemistry, The
National Hellenic Research Foundation,
48, Vas. Constantinou Ave. 116 35 Athens, Greece
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
596
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Synthesis of C--Glycopyranosylbenzo(hydro)quinones
FULL PAPER
blood glucose concentration in type 2 diabetes is in part presence of 1,4-benzoquinone (20 equiv.) provided α-config-
due to abnormal hepatic glucose production; (2) inhibition ured addition product 3 in 40% yield as well as tetraacetyl
of hepatic GP, which catalyses the first step in glycogen α-arbutin 4 (14%). Meanwhile, the reaction of acetylated
breakdown (glycogenolysis), would reduce hepatic glucose β--galactopyranosyl tolyl telluride with 1,4-benzoquinone
production;[25] (3) the efficacy of such inhibitors on control was reported to afford -galacto analogues of 3 (39%) and
of blood glucose and hepatic glycogen balance has been 4 (45%).[20c] Hence, product distribution pointed to a mod-
confirmed.[26] Among the inhibitors of the enzyme,[27] vari- erate selectivity for both reactions, nevertheless ac-
ous glucose-derived motifs were found to bind at the cata- complished with high α-stereoselectivity.
lytic site of GP, and structural information has provided a
better understanding of the mechanism of inhibition of GP.
We describe in full detail herein, routes to acetylated or
deprotected C-glycosyl derivatives of hydroquinone, 1,4-
benzoquinone and dimethylhydroquinone, as well as enzy-
matic and crystallographic studies carried out with -gluco
configured ones when bound to rabbit muscle GPb (un-
phosphorylated isoform).
Therefore, electrophilic coupling appeared more promis-
ing, considering also the early work carried out by Kalvoda
in the -ribofuranosyl series,[16] and its recent extension to
the pyranosyl series.[18,19] At the outset of our work, we
chose penta-O-acetyl-β--galactopyranose 6 because its
coupling to 1,4-dimethoxybenzene (7) was found more ef-
ficient for producing β--glycosyl-1,4-dimethoxybenzenes
(-galacto: 82%, -gluco: 52%).[19] However, experiments
carried out at 0 °C according to the reported pro-
cedures[18,19] afforded mixtures difficult to resolve by
chromatography. The compounds obtained were identified
Results and Discussion
Among the possible accessible pathways to C-glycosyl as α--galactopyranosyl chloride 9, α--galactopyranosyl
compounds, three simple routes were considered for the de- 11α and β--galactopyranosyl 11β. While doubly substi-
sired C-glycosylbenzo(hydro)quinones: (1) rearrangement tuted compounds[15b,15c] with an opened sugar residue can
of O-glycosides to the corresponding C-glycosyl com- result from such reactions,[11] an experiment allowed to pro-
pounds;[13] (2) addition of glycosyl radicals to 1,4-benzoqui- ceed over an extended time afforded unexpectedly low
none, whereby α-configured products can be expected;[28] amounts of β--galactofuranosyl 12, probably through
(3) coupling of glycopyranosyl units to electron-rich ar- pathways controlled by complexation between SnIV species
yls[18,19] by electrophilic substitution. Attempted rearrange- and oxygen-containing intermediates. Although electro-
ment of 4-hydroxyphenyl tetra-O-acetyl-β--galactopyrano- philic coupling of 1,4-dimethoxybenzene (7) with such a re-
side 1[20d] failed to produce C-glycosyl compounds. Since, active glycosyl donor as -fucose tetraacetate might proceed
to the best of our knowledge, neither the rearrangement of well at 0 °C as reported,[18,19] the α-chloride and α-config-
1 nor that of analogous O-glycosides has been reported, ured C-glycosyl compound isolated were kinetic products
this route was abandoned. Attempts to react tetra-O-acetyl- formed at the early stage of the reaction (Scheme 1). There-
α--glucopyranosyl bromide with tri-n-butyltin hydride in fore, penta-O-acetyl-β--glycopyranoses 5 and 6 required
view of producing -glycos-1-yl radicals[20c] that could add somehow stronger conditions to shift equilibria towards the
to 1,4-benzoquinone[29,30] failed and afforded mainly hydro- thermodynamically more stable β-configured C-glycosyl
quinone as the product. Therefore, precursors able to pro- compounds. By maintaining the reaction temperature at
duce -glycosyl radicals by monomolecular homolytic path- 25–30 °C for 4–5 h, and with the use of anhydrous alcohol-
ways appeared more suitable. Thus, illuminating a solution free dichloromethane as the solvent, the desired β--gluco-
of peracetylated α--glucopyranosyl cobaloxime 2[31] in the and --galacto-configured compounds were obtained in
Scheme 1. Products isolated upon electrophilic substitution of dimethylhydroquinone by sugar peracetates, and probable reaction path-
ways.
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J.-P. Praly et al.
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good and reproducible yields on the gram scale (caution:
the amount of SnCl4 recommended in a published pro-
cedure[19] appears to be erroneous).
The availability of C-glycosyl compounds in sufficient
quantities allowed further developments (Scheme 2). Oxi-
dation of 10β and 11β with ceric ammonium nitrate (CAN)
in aqueous acetonitrile led to glycosylbenzoquinones 13
and 14 in high isolated yield, as moderately stable brown
solids.[32] Upon deacetylation, water-soluble derivatives
suitable for in vitro assays were expected. Attempts to
achieve base-catalyzed deacetylation (MeONa in MeOH or
NEt3/MeOH/H2O) were, in our hands, not encouraging, as
reported for a related analogue.[21] Acid-catalyzed deacety-
lation of 13 (MeOH containing acetyl chloride in large ex-
cess, for example 25/100 equiv.) occurred with simultaneous
unselective addition of hydrochloric acid to the 1,4-benzo-
quinone moiety, to afford a mixture of C-5Ј and C-6Ј chlori-
nated isomers (≈ 10:7 ratio, 65% yield).[22] However, when
deacetylation was carried out with catalytic acetyl chloride
in MeOH, 13 and 14 were converted within one week to
single products 15 (80%) and 16 (94%) having a 1,2,3,5-
tetrasubstituted phenyl ring with one chlorine atom and
one methoxy group, as indicated by mass spectrometry and
NMR studies. Indeed, this unexpected reaction has some
precedent,[33] and may result from an initial protonation of
the carbonyl group at C-4Ј (probably because of better sta-
bilization of the positive charge distributed at C-2Ј and C-
4Ј by resonance) followed by nucleophilic attack by chloride
ions at C-6Ј. In a next step, the resulting hydroquinone may
undergo tautomerization preferentially at the 4Ј-OH group
Scheme 2. a)
5
or 6, p-dimethoxybenzene (2 equiv.), SnCl4
(3 equiv.), CF3CO2Ag (1.5 equiv.), CH2Cl2, 25–30 °C, ≈ 5 h; b)
to give a carbonyl flanked with a methylene, a process ener- CAN (3 equiv.), CH3CN/H2O, 1:1 or 2:3, 25 min; c) MeOH con-
taining 0.5% AcCl, 1 week, room temp.; d) MeOH/NEt3/H2O,
getically less demanding (minimal steric hindrance, least
8:1:1, room temp., 10–12 h; e) for 10β/11β or 21/22, respectively,
molecular motion), as compared to tautomerization at C-
0.1  or 0.033  MeONa in MeOH, room temp., ≈ 2 h; f) CAN
(3 equiv.), H2O, room temp., 30 min; g) NaBH4 (2 equiv.), EtOAc,
1Ј, which should accommodate the pyranosyl and chloro
substituents at C-2Ј and C-6Ј. Then, nucleophilic attack of
the carbonyl by methanol in large excess would form hemi-
ketals which may loose water to afford 15 or 16.
To overcome difficulties arising from additions to benzo-
quinones, routes ending by oxidation of either 1,4-dime-
thoxybenzene or hydroquinone moieties in deacetylated
sugar derivatives were considered. Hence, deacetylation of
room temp., 30 min; h) MeOH containing 1% AcCl, 5 d, room
temp.; i) Ag2O (8 equiv. with 23, oxidation almost complete;
3 equiv. with 24, ≈ 95% conversion), 2-propanol, room temp., 2 h;
j) PhI(OAc)2 (1.5 equiv.), MeOH, room temp., 40 min; nd: not de-
termined.
10β and 11β (conditions d or e) efficiently afforded 17 and Compounds could also be distinguished from the colour
18, which upon CAN oxidation yielded desired glycosylben- that appeared on TLC plates at the first stage of charring,
zoquinones 19 and 20 as polar substances contaminated by after acidic spray (see Experimental Section). On the basis
1
coloured materials probably derived from CAN and diffi- of the vicinal couplings measured by H NMR, all β-ano-
4
cult to remove by chromatography. Although less direct, a mers displayed pyranosyl rings in a C1-D chair conforma-
three step sequence from 13 and 14 [NaBH4 reduction, de- tion, whereas α--glucosylbenzoquinone 3 and 11α exhib-
acetylation conditions e or h, oxidation with Ag2O or ited distorted conformations in solution.[31] Mass spec-
PhI(OAc)2] afforded pure glycosylbenzoquinones 19 and 20 troscopy proved the presence of a chlorine atom in 15 and
1
in good overall yield, via corresponding hydroquinones 23 16, whereas H NMR spectroscopy indicated two meta re-
and 24.
lated aromatic protons (J ≈ 3 Hz). Long range correlations
TLC monitoring of the reactions and checking of the (HMBC) were found between the sugar protons 1-H, 2-H,
fractions collected after column chromatography, some- and the aromatic carbons C-1Ј, C-2Ј and C-3Ј by way of J
3
times difficult because of similar mobilities of substrates couplings. Thus, the C-4Ј signal, deshielded because of O-
and products, were facilitated by examining the plates under substitution, could be assigned and was found to correlate
UV light at different wavelength (254, 312 nm). Depending (HMBC) to the OMe group. Accordingly, NOESY corre-
on the UV absorbance of the compounds examined, the lations recorded for 15 and 16 showed no NOE contact
observed spots might differ in terms of colour, or intensity. between the anomeric proton and the 4-OMe group. These
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Synthesis of C--Glycopyranosylbenzo(hydro)quinones
FULL PAPER
data proved the location of the methoxy group and the taking into consideration their equivalent positions. The
chlorine atom at the 4Ј- and 6Ј-positions, respectively, in 15 schematic representation of the crystal structures presented
and 16.
in all figures were prepared with the programs MolScript[43]
and BobScript[44] and rendered with Raster3D.[45] The co-
ordinates of the new structures have been deposited with
the RCSB Protein Data Bank (http://www.rcsb.org/pdb)
with codes 2FF5 (GPb-19 complex), and 2FET (GPb-23
complex).
Kinetic and Crystallographic Studies with Glycogen
Phosphorylase
Rabbit muscle unphosphorylated glycogen phosphoryl-
The kinetic results also showed that glucosylhydroqui-
ase (GPb) was isolated, purified, recrystallised and assayed none 17 was not an inhibitor when tested at 1–8 m. How-
as described.[34] Kinetic experiments were performed in the ever, the kinetic parameters indicated that glucosylhydro-
direction of glycogen synthesis by the release of orthophos- quinone 23 was a slightly better competitive inhibitor [Ki
phate from Glc-1-P, in the presence of constant concentra- = (0.9 Ϯ0.1) m] than glucosylbenzoquinone 19 [Ki = (1.3
tions of glycogen (1% w/v), AMP (1 m) and various con- Ϯ0.1) m]. In order to elucidate the structural basis of inhi-
centrations of Glc-1-P (3–20 m) and inhibitors (0.5– bition we have determined the crystal structure of GPb in
5.0 m). Native GPb crystals, grown in the tetragonal lat- complex with 19 and 23. The resulting electron density map
tice[35] space group P43212, were soaked with 100 m of for compound 17 showed no binding to the catalytic site,
compound 17 (for 5.5 h), 45 m of compound 19 (for 1 h) in agreement with the kinetic results. For complexes 19 and
or 100 m of 23 (for 5 h) in a buffered solution (10 m Bes, 23, the 2Fo-Fc Fourier electron density maps indicated that
0.1 m EDTA, 0.02% sodium azide, pH 6.7), prior to data compounds 19 and 23 bound tightly at the catalytic site.
collection. Diffraction data (see Supporting information) Electron density maps (Scheme 3) clearly defined the posi-
were collected from single crystals at EMBL-Hamburg out- tion of each inhibitor within the catalytic site, consistent
station (Beamline X13) to a resolution of 2.03–2.05 Å, with the kinetic results.
respectively for 19 and 23. The reflections were recorded
with an ADSC Q4 CCD detector. Data reduction and inte-
gration followed by scaling and merging of the intensities
obtained were performed with Denzo and Scalepack,
respectively, as implemented in HKL suite.[36]
Crystallographic refinement of the four complexes was
performed with CNS version 1.1[37] by using positional and
individual B-factor refinement with bulk-solvent correction.
The starting model employed for the refinement of the com-
plexes was the structure of the GPb-α--glucose complex
determined at 2.1 Å resolution.[38] 2Fo-Fc and Fo-Fc elec-
tron density maps calculated were visualised by using the
program for molecular graphics “O”.[39] Ligand models,
constructed and minimized by using the program SYBYL
6.8 (Tripos Associates Inc., St. Louis, MO, USA), were fit-
ted to the electron density maps after adjustment of their
torsion angles. Alternate cycles of manual rebuilding with
“O” and refinement with CNS improved the quality of the
models.
The stereochemistry of the protein residues was validated
by PROCHECK.[40] Hydrogen bonds and van der Waals in-
teractions were calculated with the program CONTACT as
implemented in CCP4[41] by applying a distance cut off of
Scheme 3. Structure of compounds 19 and 23, with the numbering
used for crystallography, and inhibition constants. Diagrams of the
3.3 Å and 4.0 Å, respectively. The program calculates the
2Fo-Fc electron density maps, contoured at 1σ, for the bound com-
pounds at the catalytic site of GPb are also shown.
hydrogen position for those target nitrogen atoms where the
hydrogen position is unambiguous, and the angle O···H···N
is calculated and printed. For source···oxygen hydrogen
bonds, the angle source···O···bonded carbon is calculated.
The mode of binding and the hydrogen bonding network
Limits on both of these angles must be supplied, and bonds to the peripheral hydroxy groups of the glucopyranose moi-
with angles less than these limits are rejected. Suitable val- ety of 19 and 23 are analogous to those observed for the α-
ues are 120° and 90°. A Luzatti plot[42] suggests an average -glucose complex.[46] The benzo(hydro)quinone groups
positional error for all structures of approximately 0.24– can be accommodated at the β-pocket of the catalytic site,
0.26 Å. GPb complex structures were superimposed over a side channel from the catalytic site with no access to the
well-defined residues using LSQKAB.[41] Comparisons of bulk solvent, lined by both polar and nonpolar groups,[46]
the water molecules in the complex structures were made and stabilize the closed conformation of the 280s loop.
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Thus, O12 makes direct polar interactions with Leu136 N, gands. Furthermore, Wat12 and Wat233 (numbering from
and Asp283 OD1, and water-mediated hydrogen interac- the α--glucose complex) were displaced, and Wat201,
tions with Gly134 N, Gly135 N, Glu88 OE2, Asp283 OD1 Wat417 and Wat510 (Wat229, Wat302 and Wat124 in the
and Asp283 OD2. Atom O9 also forms a hydrogen bond α--glucose complex, respectively) shifted ≈ 0.7–0.8 Å to
with Asp339 OD1 of the β-pocket. In GPb-19 complex, the create more space for the benzo(hydro)quinone groups to
latter hydrogen bond requires Asp339 to be protonated. be accommodated without causing steric hindrance. In ad-
The hydrogen bonds formed between 19 and 23 and the dition, the glucopyranose ring also moved away from
protein are illustrated in Figure 1a.
His377 (shifts of O5 and C1 atoms by ≈ 0.4 Å).
Figure 2. Comparison between GPb-19 complex (red), GPb-23
complex (cyan), and GPb-α--glucose complex (green) in the vicin-
ity of the catalytic site.
Conclusions
In summary, the kinetic and X-ray crystallographic study
of the two enzyme complexes of GPb with ligands of the C-
glucosylbenzo(hydro)quinone type showed that these novel
analogues are competitive inhibitors of the enzyme albeit
with moderate affinity. The two analogues form direct and
water-mediated
hydrogen
bonds
and
extensive
van der Waals interactions with residues of the 280s loop
(Asp283 and Asn284), the glycine helix (Gly134 and
Gly137), Glu88 and Asp339. These interactions provide a
rationale for the potency of glucosylbenzo(hydro)quinones
to inhibit GPb activity, and should assist the design of more
effective compounds. Despite the appearance of an im-
proved network of interactions compared with α--glucose,
Figure 1. Interactions of compounds 19 (a), and 23 (b) with GPb
in the vicinity of the catalytic site, shown in stereo. The hydrogen
bond pattern between the inhibitors, protein residues and water
molecules (w) is represented by dotted lines. The interactions of the
glucopyranose ring are retained throughout the structures analysed
and were not incorporated in the figures for clarity reasons.
Both compounds are moderate inhibitors and bind there is little difference in the free energy of binding be-
slightly better than α--glucose (Ki = 1.7 m),[46] possibly tween 19, 23 and α--glucose (0.16 and 0.38 kcal/mol,
because of the additional interactions of the 1,4-benzo(hy- respectively). It is possible that, in complexes 19 and 23, the
dro)quinone groups with the protein residues. Examination energy gain due to the increased van der Waals interactions
of the van der Waals contacts indicates a number of polar/ is outbalanced by the energy loss due to subtle structural
nonpolar contacts, which may account for moderate inhibi- changes of protein residues, changes in water structure and
tion. Atom C7 makes van der Waals interactions with ND2 accommodation of the benzo(hydro)quinone substituents at
(3.3 Å), C12 with OD1 Asp283 (3.3 Å), O12 with CG a rather unfavourable environment.
Asp283 (3.3 Å), C11 with OD1 Asp283 (3.2 Å) and N
Because C-β--glucopyranosyl-1,4-hydro- and C-β--
Asn284 (3.4 Å), C10 with N Asn284 (3.4 Å), and O9 with glucopyranosyl-1,4-benzoquinones represent a new type of
CG2 Thr378 (3.1 Å). Hydrogen bonds and van der Waals glucose-derived competitive inhibitors of GP which bind at
interactions of the two compounds with residues lining the the catalytic site,[27] further work is currently under progress
catalytic site are given as Supporting Information.
to synthesize and evaluate modified analogues with greater
In Figure 2, we compare the binding of 19, 23 and α-- potency for the β-pocket of the catalytic site of the enzyme.
glucose within the catalytic site of GPb. The comparison This will be reported in forthcoming papers, as well as our
reveals that there were small shifts in the side chain atoms efforts for converting C-glycosylhydroquinones into glycos-
of Leu136, Asp283, Asn284 and Asp339, of between 0.4 ylated analogues of Vitamin E[22] as amphiphilic antioxi-
and 1.2 Å, in order to optimize interactions with the li- dants.
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Synthesis of C--Glycopyranosylbenzo(hydro)quinones
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-galactopyranose 6 (985 mg, 2.5 mmol), 1,4-dimethoxybenzene
(7) (692 mg, 5 mmol, 2 equiv.), silver trifluoroacetate (831 mg,
3.75 mmol, 1.5 equiv.) and dry CH2Cl2 (12.5 mL) were introduced
in a flask equipped with a stirring bar (for removing moisture, the
reagents were maintained overnight under vacuum ca. 1 Torr, ex-
cept for the more volatile 7, which was dried for 0.5 h only). After
the mixture was cooled to 0 °C with an ice bath, a 1  solution of
SnCl4 in CH2Cl2 (7.5 mL, 7.5 mmol, 3 equiv.) was added with stir-
ring. The resulting milky suspension was stirred at 0 °C for 3.5 h,
under an atmosphere of argon. TLC indicated completion of the
reaction after 2.5 h. The galactose pentaacetate (Rf = 0.42, CH2Cl2/
Et2O, 5:0.5) was converted into slightly less polar products (Rf =
0.50 and 0.45), and a trace amount of 2,3,4,6-tetra-O-acetyl--gal-
actopyranose (Rf = 0.15) due to hydrolysis. The reaction was
quenched by the addition of saturated aq. NaHCO3 (36 mL); then,
the solids were filtered off through a bed of Celite and rinsed. The
liquid phase, diluted with CH2Cl2, was washed with saturated aq.
NaCl (3ϫ50 mL), then with water (10 mL) and dried (MgSO4).
The clear oil (1.33 g) obtained upon concentration under reduced
Experimental Section
General Methods: Dichloromethane was washed three times with
water, dried (CaCl2) and distilled from CaH2 before use. Other or-
ganic solvents were distilled. Thin-layer chromatography (TLC)
was carried out on aluminium sheets coated with silica gel 60 F254
(Merck, Darmstadt, Germany). TLC plates were inspected under
UV light (254, 312 nm), and/or developed by treatment with a mix-
ture of 5% H2SO4 in EtOH followed by heating. Silica gel column
chromatography was performed with Geduran silica gel Si 60 (40–
63 µ) purchased from Merck. 1H- and 13C NMR spectra were
recorded at 23 °C with Bruker AC200, DRX300 or DRX500 spec-
trometers with the residual solvent as the internal standard. The
following abbreviations are used to indicate the observed multi-
plicities: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q,
quadruplet; m, multiplet; br., broad. In the description of NMR
spectra, atoms in pyranosyl rings and aglycons are numbered,
respectively, with simple and primed figures. NMR solvents were
purchased from Euriso-Top (Saint Aubin, France). HRMS
(LSIMS) mass spectra were recorded in the positive mode (unless
stated otherwise) with a Thermo Finnigan Mat 95 XL spectrome-
ter. MS (ESI) mass spectra were recorded in the positive mode with
a Thermo Finnigan LCQ spectrometer. Optical rotations were
measured with a Perkin–Elmer polarimeter. Elemental analyses
were performed at the Service Central dЈAnalyses du CNRS (Ver-
naison, France).
1
pressure was shown by H NMR, on the basis of the comparison
of the intensity of the acetyl signals, to contain four products (pro-
portion: 7, 27, 23, 15%) with estimated weights of 80, 360, 310 and
200 mg, respectively. After chromatography (two successive separa-
tions) on silica gel (≈ 150 g) with CH2Cl2/Et2O [5:0.5, then 5:0.35
(more efficient)] as the mobile phases, the mixture led successively
to three products identified as 2,3,4,6-tetra-O-acetyl-α--galactopy-
ranosyl chloride (9), (26 mg, 0.14 mmol, ≈ 2.5 %), 11α (290 mg,
0.62 mmol, 25%) and 11β (220 mg, 0.47 mmol, 19%). Product 11β
was an admixture with an unidentified side product (estimated
2-(2,3,4,6-Tetra-O-acetyl-α-
and 4-Hydroxyphenyl 2,3,4,6-Tetra-O-acetyl-α-
(tetraacetyl α-arbutin 4): A solution of sugar cobaloxime 2 (-gluco)
D-glucopyranosyl)-1,4-benzoquinone (3)
D-glucopyranoside
(140 mg, 0.2 mmol) and 1,4-benzoquinone (432 mg, 4 mmol, amount: 65 mg) inseparable by chromatography with CH2Cl2/Et2O
20 equiv.) in benzene (6 mL) was introduced in a pyrex two-wall
reactor (cooled to ≈ 15 °C) receiving the visible light beam emitted
by a slide-projector (halogen lamp: 100 W). After the dark brown
coloured solution, maintained under an atmosphere of argon, was
irradiated for 13 h, TLC showed the almost complete conversion
of the starting material (Rf = 0.1, Et2O/CH2Cl2, 1:5) into two more
mobile products (major: Rf = 0.85, minor: Rf = 0.75, Et2O/CH2Cl2,
1:5). After concentration of the solution under reduced pressure,
the residue was applied to a column of silica gel irrigated with
EtOAc/petroleum ether, 4:6 then EtOAc (100 mL), then EtOAc/
EtOH, 2:1, to afford 3 (31 mg, 40%, based on the transformed
substrate), known tetraacetyl α-arbutin 4 (11 mg, 14%)[20a] and un-
reacted starting material 2 (15 mg). Compound 3: Yellowish oil,
mixtures. With oxolane/petroleum ether (1:3) TLC mobilities for 9,
11α, 11β and side product were as follows: Rf = 0.32, 0.28, 0.25,
0.22, respectively. Note that 11α and 11β appeared on TLC plates
as orange–brown spots during the initial stage of charring, after
H2SO4 spray. Product 11α: Amorphous solid. Rf = 0.50 (CH2Cl2/
1
Et2O, 5:0.5). [α]2D2 = +55 (c = 1, CH2Cl2). H NMR (500.13 MHz,
C6D6): δ = 7.58 (d, 1 H, J3Ј,5Ј = 3.1 Hz, 3Ј-H), 6.72 (dd, 1 H, J5Ј,6Ј
= 8.9 Hz, 5Ј-H), 6.41 (d, 1 H, 6Ј-H), 5.91 (d, 1 H, J1,2 = 1.9 Hz, 1-
H), 5.87 (dd, 1 H, J2,3 = 4.2 Hz, 2-H), 5.84 (dd, 1 H, J3,4 = 3.2 Hz,
J4,5 = 6.4 Hz, 4-H), 5.73 (t, 1 H, 3-H), 5.04 (dd, 1 H, J5,6a = 9.3 Hz,
6a-H), 4.62 (ddd, 1 H, J5,6b = 3.0 Hz, 5-H), 4.40 (dd, 1 H, J6a,6b
=
12.3 Hz, 6b-H), 3.41 (s, 3 H, 4Ј-OMe), 3.34 (s, 3 H, 1Ј-OMe), 1.66,
1.64, 1.55, 1.37 (4s, 3 H each, acetyl) ppm. 1H NMR (500.13 MHz,
CDCl3): δ = 7.07 (d, 1 H, J3Ј,5Ј = 3 Hz, 3Ј-H), 6.78 (dd, 1 H, J5Ј,6Ј
= 9 Hz, 5Ј-H), 6.73 (d, 1 H, 6Ј-H), 5.53 (dd, 1 H, J4,5 = 6.3 Hz, 4-
H), 5.45 (broad s, 1 H, 1-H), 5.33 (m, 2 H, 2-H, 3-H), 4.73 (dd, 1
H, J5,6a = 9 Hz, 6a-H), 4.47 (ddd, 1 H, J5,6b = 3.2 Hz, 5-H), 4.29
(dd, 1 H, J6a,6b = 12.5 Hz, 6b-H), 3.787 (s, 3 H, 4Ј-OMe), 3.77 (s,
3 H, 1Ј-OMe), 2.195, 2.096, 2.044, 1.82 (4s, 3 H each, acetyl) ppm.
In CDCl3, CD3COCD3, or C5D5N as the solvent, the 2-H and 3-
H resonances appeared as superimposed signals. 13C NMR
(50.32 MHz, CDCl3): δ = 171.0 (6-OAc), 169.7 (4-OAc), 169.3,
169.0 (C=O), 153.4 (C-1Ј), 150.1 (C-4Ј), 125.6 (C-2Ј), 113.9, 113.6,
110.8 (C-3Ј, C-5Ј, C-6Ј), 72.2 (C-5), 69.1, 68.2 (C-2, C-3), 65.9 (C-
4), 64.8 (C-1), 59.9 (C-6), 55.9 (4Ј-OMe), 55.9 (1Ј-OMe), 21.0, 20.9,
20.8, 20.5 (acetyl) ppm. A NOESY correlation indicated contacts
in C6D6 between 1Ј-OMe and 2-H (weak), and more interestingly
for proving the α-configuration, between 1-H (anomer) and 6a-H,
but no contact with either 3-H or 5-H. HRMS (CI, isobutane):
calcd. for C22H29O11 [M + H]+ 469.170986; found 469.17090.
C22H28O11 (468.16): calcd. C 56.41, H 6.02, O 37.57; found C
55.73, H 6.05, O 37.38. Product 12: When the reaction was pro-
longed for an extended time, 12 was obtained in low amount after
decomposed after a time. [α]2D2 = +35 (c = 0.75, CH2Cl2), [α]2D2
=
+21 (c = 1.25, acetone). IR (KBr): ν = 1740 (C=O, acetyl), 1655
˜
(C=O, quinone) cm–1. 1H NMR (500.13 MHz, CDCl3): δ = 6.89
(t, 1 H, J3Ј,1 = 2.0 Hz, J = 2 Hz, 3Ј-H), 6.78 (m, 2 H, 5Ј-H, 6Ј-H),
5.21 (t, 1 H, J1,2 = 2.0 Hz, 1-H), 5.14 (t, 1 H, J2,3 = 2.6 Hz, J3,4
=
4.1 Hz, 3-H), 5.12 (t, 1 H, 2-H), 4.96 (t, 1 H, J4,5 = 4.4 Hz, 4-H),
4.53 (dd, 1 H, J5,6a = 7.4 Hz, J6a,6b = 11.9 Hz, 6a-H), 4.27 (dt, 1
H, J5,6b = 4.2 Hz, 5-H), 4.22 (dd, 1 H, 6b-H), 2.19, 2.11, 2.09, 1.98
(4s, 3 H each, acetyl) ppm. 13C NMR (125.76 MHz, CDCl3): δ =
187.5, 186.0 (C=O, quinone), 171.0, 170.0, 169.8, 169.3 (C=O),
144.7 (C-2Ј), 137.1, 136.8 (C-5Ј, C-6Ј), 133.1 (C-3Ј), 73.6 (C-5),
69.1, 68.9 (C-2, C-3), 67.0 (C-4), 66.2 (C-1), 61.5 (C-6), 21.3, 21.3,
21.2, 21.0 (acetyl) ppm. MS (CI, isobutane): m/z = 441 [M + H]+,
benzoquinone reduced to hydroquinone. HRMS: calcd. for
C20H25O11 [M + H]+ 441.1397; found 441.13995. HRMS (EI):
calcd. for C20H22O11 [M]+ 438.11621; found 438.11734.
2-(2,3,4,6-Tetra-O-acetyl-α-
benzene (11α), 2-(2,3,4,6-Tetra-O-acetyl-β-
dimethoxybenzene (11β) and 2-(2,3,5,6-Tetra-O-acetyl-β-
furanosyl)-1,4-dimethoxybenzene (12): 1,2,3,4,6-Penta-O-acetyl-β-
D
-galactopyranosyl)-1,4-dimethoxy-
-galactopyranosyl)-1,4-
-galacto-
D
D
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601

J.-P. Praly et al.
FULL PAPER
repeated chromatographic purifications. On TLC plates, it gave yel-
low spots during the initial stage of charring, after H2SO4 spray.
at 500.13 MHz, 6a-H and 6b-H appeared as a multiplet (δ = 4.17
to 4.09 ppm) and 5-H as a triplet (δ = 4.04 ppm, J5,6a = J5,6b = ≈
1H NMR (500.13 MHz, CDCl3): δ = 7.00 (m, 1 H, J1,3Ј = Ͻ1 Hz, 6.4 Hz). 13C NMR (50.3 MHz, CDCl3): δ = 187.1, 185.7 (C=O,
3Ј-H), 6.80 (m, 2 H, 5Ј-H, 6Ј-H), 5.48 (dd, 1 H, J2,3 = 3.0 Hz, 2-
H), 5.43 (ddd, 1 H, J5,6a = 4.3 Hz, 5-H), 5.31 (br. d, 1 H, J1,2
quinone), 170.4, 170.2, 170.0, 169.9 (C=O), 144.6 (C-2Ј), 136.5,
136.3 (C-5Ј, C-6Ј), 133.9 (C-3Ј), 74.7 (C-5), 72.1 (C-1), 71.7 (C-3),
=
4.4 Hz, J1,3Ј = Ͻ 1 Hz, 1-H), 5.20 (dd, 1 H, J3,4 = 4.3 Hz, 3-H), 70.1 (C-2), 67.4 (C-4), 61.7 (C-6), 20.7, 20.7, 20.6, 20.6 (acetyl)
4.45 (dd, 1 H, J5,6b = 6.9 Hz, 6a-H), 4.39 (t, 1 H, J4,5 = 5.3 Hz, 4-
H), 4.26 (dd, 1 H, J6a,6b = 12.0 Hz, 6b-H), 3.80 (s, 3 H, OMe), 3.77
(s, 3 H, OMe), 2.19, 2.15, 2.10, 2.03 (4s, 3 H each, acetyl) ppm.
13C NMR (125.76 MHz, CDCl3): δ = 171.0, 170.7, 170.4, 170.0
(C=O), 154.0, 151.2 (C-1Ј, C-4Ј), 128.4 (C-2Ј), 113.5 (C-3Ј), 113.5,
111.7 (C-5Ј, C-6Ј), 81.8 (C-2), 81.7 (C-4), 80.8 (C-1), 78.9 (C-3),
70.3 (C-5), 63.2 (C-6), 56.2 (2 C, OMe), 21.43, 21.36, 21.17, 21.17
(acetyl) ppm. The COSY experiment clearly showed a coupling be-
tween 3Ј-H and 1-H. The NOESY spectrum showed correlations
between aromatic 3Ј-H and 2-H, 1-H, and also 4-H.
ppm. MS (CI, isobutane): m/z (%) = 441.4 (100) [M + 3 H]+, 439.3
(13) [M + H]+. HRMS: calcd. for C20H23O11 [M + H]+ 439.12404;
found 439.12405.
1-Chloro-3-(β-D-glucopyranosyl)-2-hydroxy-5-methoxybenzene (15):
Glucosylbenzoquinone 13 (200 mg, 0.427 mmol) was dissolved in
MeOH (20 mL) containing 0.5% v/v AcCl (3.28 equiv. of AcCl).
Upon stirring for 8 d at room temperature, the starting material
was converted into a single more polar compound (6) (Rf = 0.55,
MeOH/CH2Cl2, 1:4). The volatiles were evaporated under reduced
pressure. The residue was subjected to chromatography on silica
gel (MeOH/CH2Cl2, 1:10) to afford compound 15 (110 mg, 80%)
as a pale yellow amorphous solid, amenable to crystallization. M.p.
83–85 °C. Rf = 0.55, MeOH/CH2Cl2 (1:4). [α]2D2 = +24.8 (c = 0.9,
2-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-1,4-benzoquinone
(13): 2-(2,3,4,6-Tetra-O-acetyl-β--glucopyranosyl)-1,4-dimethoxy-
benzene (10β) (280 mg, 0.6 mmol) dissolved in acetonitrile (1.5 mL)
was treated with ceric ammonium nitrate (990 mg, 1.8 mmol,
3 equiv.) dissolved in water (1.5 mL) and stirred efficiently for
25 min at room temperature under a normal atmosphere.[47] Al-
though 10β and glucosylbenzoquinone 13 have the same mobilities
by TLC (Rf = ≈ 0.3, Et2O/petroleum ether, 3:1), they could be dis-
tinguished by examination of the TLC plates under different wave-
lengths: the substrate was not very visible at 254 nm, but gave dark
spot at 312 nm, while the glycosylbenzoquinone appeared very vis-
ible at 254 nm, and visible at 312 nm. After dilution with dichloro-
methane (10 mL), the reaction mixture was washed with aqueous
saturated NaHCO3 (≈ 5 mL), followed by water. It was then dried
(MgSO4) and concentrated under reduced pressure. The residue,
obtained in almost quantitative yield (256 mg) was essentially pure
13 (NMR) and crystallized as yellow needles. M.p. 132–133 °C
1
methanol). H NMR (500.13 MHz, D2O): δ = 7.00 (d, 1 H, J3Ј,5Ј
= 3.1 Hz, 5Ј-H), 6.88 (d, 1 H, 3Ј-H), 4.64 (d, 1 H, J1,2 = 9.5 Hz, 1-
H), 3.80 (br. d, 1 H, J6a,6b = 12.0 Hz, 6a-H), 3.71 (dd, 1 H, J5,6b
=
4.7 Hz, 6b-H), 3.70 (s, 3 H, OMe), 3.61 (t, 1 H, J2,3 = 9.4 Hz, 2-
H), 3.55 (br. t, 1 H, J3,4 = 9.2 Hz, 3-H), 3.49 (m, 2 H, 4-H, 5-H)
ppm. 13C NMR (125.8 MHz, CD3OD): δ = 153.4 (C-4Ј), 144.5 (C-
1Ј), 127.9 (C-2Ј), 123.0 (C-6Ј), 115.9 (C-5Ј), 113.3 (C-3Ј), 80.6 (C-
5), 77.7 (C-3), 76.8 (C-1), 73.8 (C-2), 70.0 (C-4), 61.1 (C-6), 56.4
(OMe) ppm. MS (ESI–): m/z (%) = 321 (35), 319 (100) [M – H]–,
355, 357 [M + Cl]–, 639, 641 [2M – H]–.
1-Chloro-3-(β-D-galactopyranosyl)-2-hydroxy-5-methoxybenzene
(16): Galactosylbenzoquinone 14 (26 mg, 0.059 mmol) was treated
with acidic methanol (1.2 mL containing 1.42 equiv. of AcCl) pre-
pared by adding freshly distilled AcCl (25 µL) to dry methanol
(5 mL; 0.5% v/v solution). Upon stirring for 1 week at room tem-
perature, the starting material (Rf = ≈ 1, EtOAc/MeOH, 20:1) was
converted into a single compound (Rf = 0.18, EtOAc/MeOH, 20:1).
Concentration of the solution overnight under reduced pressure
afforded a residue (24 mg) which was purified by column
chromatography with silica gel and EtOAc/MeOH (20:1) as the elu-
ent. Concentration of homogeneous fractions afforded a yellow
gum (15 mg, 94% yield), identified as 16. [α]2D2 = +41 (c = 0.7,
(Et2O). [α]2D2 = –28 (c = 1, acetone). IR (KBr): ν = 1740 (C=O,
˜
acetyl), 1655 (C=O, quinone) cm–1. UV (CH2Cl2): λ (ε) = 222
(5130), 225.4 (4890), 248.2 (15110) nm. 1H NMR (200.13 MHz,
CDCl3): δ = 6.91 (d, 1 H, J = 1 Hz, 3Ј-H), 6.77 (d, 2 H, J = 1.2 Hz,
5Ј-H, 6Ј-H), 5.37 (t, 1 H, J3,4 = 9.4 Hz, 3-H), 5.15 (t, 1 H, J4,5
=
9.8 Hz, 4-H), 4.98 (t, 1 H, J2,3 = 9.5 Hz, 2-H), 4.64 (dd, 1 H, J1,3Ј
= 0.8 Hz, J1,2 = 9.7 Hz, 1-H), 4.26 (dd, 1 H, J5,6a = 4.6 Hz, J6a,6b
= 12.4 Hz, 6a-H), 4.14 (dd, 1 H, J5,6b = 2.2 Hz, 6b-H), 3.80 (ddd,
1 H, 5-H), 2.10, 2.06, 2.02, 1.91 (4s, 3 H each, acetyl) ppm. 13C
NMR (125.8 MHz, CDCl3): δ = 186.9, 185.5 (C=O, quinone),
170.6, 170.0, 169.7, 169.5 (C=O), 144.1 (C-2Ј), 136.5, 136.4 (C-5Ј,
C-6Ј), 133.7 (C-3Ј) (C-5Ј/C-6Ј, C-3Ј in this order from HSQC), 76.3
(C-5), 73.7 (C-3), 72.5 (C-2), 72.0 (C-1), 68.2 (C-4), 62.0 (C-6), 20.7,
20.6, 20.6, 20.5 (acetyl) ppm. MS (CI, isobutane): m/z (%) = 441.4
(100) [M +3 H]+, 439.3 (17) [M + H]+. HRMS: calcd. for
1
methanol). H NMR (500.13 MHz, D2O): δ = 7.02 (d, 1 H, J3Ј,5Ј
= 3.1 Hz, 5Ј-H), 6.98 (d, 1 H, 3Ј-H), 4.62 (d, 1 H, J1,2 = 9.6 Hz, 1-
H), 4.00 (d, 1 H, J3,4 = 3.3 Hz, J4,5 = 0 Hz, 4-H), 3.82 (t, 1 H, J2,3
= 9.6 Hz, 2-H), 3.77 (dd, 1 H, J5,6a = 6.4 Hz, J5,6b = 5.6 Hz, 5-H),
3.73 (s, 3 H, OMe), 3.72 (dd, 1 H, J6a,6b = 11.3 Hz, 6a-H), 3.70
(dd, 1 H, 3-H), 3.68 (dd, 1 H, 6b-H) ppm. 1H NMR (500.13 MHz,
CD3OD): δ = 6.99 (d, 1 H, J3Ј,5Ј = 3.1 Hz, 3Ј-H), 6.89 (d, 1 H, 5Ј-
H), 4.50 (d, 1 H, J1,2 = 9.4 Hz, 1-H), 4.00 (br. d, 1 H, J3,4 = 2.9 Hz,
J4,5 = 0 Hz, 4-H), 3.85 (t, 1 H, J2,3 = 9.4 Hz, 2-H), 3.82 (dd, 1 H,
J5,6a = 6.9 Hz, J6a,6b = 11.6 Hz, 6a-H), 3.76 (s, 3 H, OMe), 3.75
(dd, 1 H, J5,6b = 5.3 Hz, 6b-H), 3.69 (dd, 1 H, 5-H), 3.64 (dd, 1 H,
3-H) ppm. 13C NMR (75.5 MHz, D2O): δ = 153.5 (C-4Ј), 144.6 (C-
1Ј), 128.2 (C-2Ј), 122.9 (C-6Ј), 116.1 (C-5Ј), 113.2 (C-3Ј), 79.7 (C-
5), 77.1 (C-1), 74.5 (C-3), 71.4 (C-2), 69.6 (C-4), 61.6 (C-6), 56.5
(OMe) ppm. 13C NMR (125.8 MHz, CD3OD): δ = 153.5 (C-4Ј),
145.1 (C-1Ј), 128.9 (C-2Ј), 121.9 (C-6Ј), 114.7 (C-5Ј), 113.1 (C-3Ј),
79.8 (C-5), 78.8 (C-1), 75.4 (C-3), 72.1 (C-2), 69.8 (C-4), 61.9 (C-
6), 55.4 (OMe) ppm. MS (CI, isobutane): m/z = 321 [M + H]+. MS
(ESI–): m/z = 319 [M – H]–. HRMS (FAB, nitrobenzyl alcohol):
calcd. for C13H16O7Cl1 [M – H]– 319.0584; found 319.05876.
C20H23O11 [M + H]+ 439.12404; found 439.12392. C20H22O11
calcd. C 54.79, H 5.02, O 40.18; found C 54.37, H 5.00, O 40.68.
:
2-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-1,4-benzoquinone
(14): Galactopyranosyl 11β (280 mg, 0.6 mmol) was oxidized with
CAN as described previously for 10β. After workup, the residue
was purified by chromatography with EtOAc/petroleum ether (4:6)
as the eluent to afford pure 14 (208 mg, 80%) as a yellow foam,
[α]2D2 = –11.2 (c = 0.95, acetone). IR (KBr): ν = 1740 (C=O, acetyl),
˜
1655 (C=O, quinone) cm–1. UV (CH2Cl2): λ (ε) = 220.4 (4920),
1
225.6 (4090), 248.2 (15180) nm. H NMR (200.13 MHz, CDCl3):
δ = 6.98 (d, 1 H, J = 0.8 Hz, 3Ј-H), 6.76 (d, 2 H, J = 1 Hz, 5Ј-H,
6Ј-H), 5.50 (dd, 1 H, J4,5 = 0.7 Hz, J3,4 = 3.1 Hz, 4-H), 5.20 (dd, 1
H, J2,3 = 10.0 Hz, 3-H), 5.11 (t, 1 H, J1,2 = 8.6 Hz, 2-H), 4.63 (d,
1 H, 1-H), 4.21–3.99 (m, 3 H, 5-H, 6a-H, 6b-H), 2.18, 2.04, 1.99,
1.91 (4s, 3 H each, acetyl) ppm. In the 1H NMR spectrum recorded
2-(β-
D-Glucopyranosyl)-1,4-dimethoxybenzene (17): Deacetylation
with MeONa in MeOH: Upon stirring, 10β (94 mg, 0.2 mmol) was
602
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 596–606

Synthesis of C--Glycopyranosylbenzo(hydro)quinones
FULL PAPER
dissolved at room temperature into a 0.1  solution of MeONa in
MeOH (4 mL, prepared from commercial MeONa). After 2 h, the
starting material (Rf = 0.57, EtOAc/petroleum ether, 2:3, as violet
spot under 312 nm) was converted to a polar product (Rf = ≈ 0, as
violet spot under 312 nm). Exchange resin IR-120 (H+) was added
to the mixture. After stirring for a few minutes, filtration and con-
centration led to a residue which was applied to a short column
eluted with EtOAc/EtOH, (5:1) to afford 17 (59.2 mg, 98% yield)
as a white solid. Deacetylation with MeOH/Et3N/H2O (8:1:1): On
stirring overnight a MeOH/Et3N/H2O (8:1:1) mixture containing
10β, deacetylation was almost complete by TLC (vide infra prepa-
ration of 18 from 11β) and the product was purified by chromatog-
raphy to afford 17 (94.5% yield) as a white foam. [α]2D0 = –28.8 (c
ids were removed by filtration through a bed of Celite and rinsed
with 2-propanol (3ϫ10 mL). The volatiles were evaporated under
reduced pressure and the residue was applied to a short column
eluted with 2-propanol/EtOAc (1:5) to afford 19 as a dark red solid
(77% yield). Prepared from 23 upon oxidation with PhI(OAc)2: Glu-
cosylhydroquinone 23 (100 mg, 0.367 mmol) was dissolved in
MeOH (2 mL). While stirring at room temperature, PhI(OAc)2
(179 mg, 0.55 mmol, 1.5 equiv.) was added portionwise to the mix-
ture. The reaction was found to be complete within 40 min (TLC).
After evaporation of MeOH under reduced pressure, the residue
was dissolved in water (4 mL). The aqueous phase was washed with
CH2Cl2 (2ϫ8 mL) and evaporated to afford a residue that was
purified by chromatography (EtOAc/MeOH, 8:1) to afford 19 in
= 0.6, EtOH). 1H NMR (500.13 MHz, D2O): δ = 7.02 (m, 2 H), 76.3% yield. M.p. 104–106 °C, [α]2D5 = –28 (c = 0.8, EtOH). IR
6.96 (m, 1 H), 4.75 (d, 1 H, J1,2 = 9.2 Hz, 1-H), 3.76 (br. s, 6 H,
(KBr): ν = 3397 (OH), 2894 (w), 1657 (CO), 1601 (m), 1384 (s),
˜
OMe), 3.82–3.50 (m, 6 H) ppm. 13C NMR (50.3 MHz, D2O): δ =
1283 (m), 1083 (s), 1031 (s), 918 (s), 833 (m) cm–1. UV (EtOH): λ
153.8, 152.6 (C-1Ј, C-4Ј), 127.6 (C-2Ј), 115.8, 114.5, 114.5 (C-3Ј, C- (ε) = 203.6 (4660), 213.2 (2640), 245.4 (5730) nm. 1H NMR
5Ј, C-6Ј), 80.7, 78.0, 75.7, 74.0, 70.3 (C-1 to C-5), 61.3 (C-6), 57.4,
(500.13 MHz, D2O): δ = 6.98 (d, 1 H, J3Ј,5Ј = 2.5 Hz, 3Ј-H), 6.90
56.4 (OMe) ppm. MS (EI): m/z (%) = 300, (75) [M]+, 167 (100), (d, 1 H, J5Ј,6Ј = 10.4 Hz, 6Ј-H), 6.86 (dd, 1 H, 5Ј-H), 4.48 (d, 1 H,
151 (54).
2-(β- -Galactopyranosyl)-1,4-dimethoxybenzene (18): Deacetylation
J1,2 = 9.5 Hz, 1-H), 3.87 (dd, 1 H, J5,6a = 1.6 Hz, J6a,6b = 12.6 Hz,
6a-H), 3.74 (dd, 1 H, J5,6b = 5.0 Hz, 6b-H), 3.59 (t, 1 H, J2,3 = J3,4
= 8.8 Hz, 3-H), 3.52 to 3.46 (m, 3 H, 2-H, 4-H, 5-H) ppm. 13C
NMR (125.8 MHz, D2O): δ = 189.9 (C-4Ј), 187.6 (C-1Ј), 145.9 (C-
2Ј), 137.6 (C-6Ј), 136.8 (C-5Ј), 134.7 (C-3Ј), 80.6 (C-5), 77.5 (C-3),
74.7 (C-2), 74.0 (C-1), 70.1 (C-4), 61.2 (C-6) ppm. HRMS (ESI):
calcd. for C12H14O7 [M + H]+ 271.0818; found 271.08252.
D
with MeONa in MeOH: Galactopyranosyl 11β was treated with
MeONa in MeOH (vide supra preparation of 17 from 10β) to af-
ford 18 (99%), visible on TLC plates after H2SO4 spray and upon
charring first as brown reddish spots. Deacetylation with MeOH/
Et3N/H2O (8:1:1): 11β (702 mg, 1.5 mmol) dissolved in a MeOH/
Et3N/H2O, (8:1:1, 10 mL) was kept for 5 d at room temperature.
TLC showed the complete transformation of the substrate into a
single polar product (Rf = 0.35, EtOAc/MeOH, 20:3). The volatiles
were removed under vacuum and the clear residue (quantitative
yield) was crystallized from MeOH with successive addition of
EtOAc, Et2O, and petroleum ether, to afford 18 (372 mg, 83%) as
colourless prisms. M.p. 128–129.5 °C (MeOH/EtOAc/petroleum
2-(β-D-Galactopyranosyl)-1,4-benzoquinone (20): Prepared from 18
upon oxidation with CAN: CAN-oxidation of 18 (80 mg,
0.266 mmol), as described for 17 led to impure 20 (170 mg). Ana-
lytically pure samples were obtained as dark red solids by other
methods. Prepared from 24 upon oxidation with Ag2O: Oxidation of
24, carried out with Ag2O (360 mg, 1.5 mmol, 3 equiv.) as described
for 23, was found incomplete (5% of unreacted 24, based on NMR,
due to use of a smaller amount of Ag2O) and yielded 20 in 76%
yield. Prepared from 24 upon oxidation with PhI(OAc)2: Galactos-
1
ether). [α]2D0 = –13 (c = 0.6, EtOH). H NMR (500.13 MHz, D2O):
δ = 7.11 (d, 1 H, J3Ј,5Ј = 3.1 Hz, 3Ј-H), 7.01 (d, 1 H, J5Ј,6Ј = 9.0 Hz,
6Ј-H), 6.94 (dd, 1 H, 5Ј-H), 4.65 (d, 1 H, J1,2 = 9.7 Hz, 1-H), 4.00 ylbenzoquinone 20 was obtained from 24 upon oxidation with
(br. d, 1 H, J3,4 = 3.4 Hz, J4,5 = ≈ 0 Hz, 4-H), 3.84 (t, 1 H, J2,3
9.7 Hz, 2-H), ≈ 3.77 (overlapping signal, 5-H), 3.76 (s, 3 H, OMe),
=
PhI(OAc)2, as described for 23, in 79% yield, as a dark red solid.
M.p. 102–104 °C. [α]2D5 = –18 (c = 0.85, EtOH). IR (KBr): ν = 3413
˜
3.75 (s, 3 H, OMe), 3.71 (dd, 1 H, 3-H), 3.68 (d, 2 H, J = 6.2 Hz, (OH), 2970 (s), 2904 (s), 1660 (CO), 1601 (m), 1432 (m), 1313 (s),
6a-H, 6b-H) ppm. 13C NMR (50.3 MHz, D2O): δ = 153.8, 152.6 1078 (s), 914 (s) cm–1. UV (EtOH): λ (ε) = 204.6 (7240), 212.2
1
(C-1Ј, C-4Ј), 127.9 (C-2Ј), 115.9, 114.5, 114.2 (C-3Ј, C-5Ј, C-6Ј), (5020), 245.2 (15630) nm. H NMR (500.13 MHz, D2O): δ = 7.01
79.7, 75.6, 74.8, 71.7, 69.7 (C-1 to C-5), 61.5 (C-6), 57.4, 56.4 (d, 1 H, J3Ј,5Ј = 1.9 Hz, 3Ј-H), 6.88 (d, 1 H, J5Ј,6Ј = 10.4 Hz, 6Ј-H),
(OMe) ppm. MS (EI): m/z (%) = 300 (69) [M]+, 167 (100), 151 (76).
6.84 (dd, 1 H, 5Ј-H), 4.41 (d, 1 H, J1,2 = 9.1 Hz, 1-H), 4.00 (d, 1
H, J = 2.8 Hz, 4-H), 3.76 to 3.69 (m, 4 H, 3-H, 5-H, 6a-H, 6b-H),
3.68 (t, 1 H, J2,3 = 9.5 Hz, 2-H) ppm. 13C NMR (125.8 MHz, D2O):
δ = 190.0 (C-4Ј), 187.7 (C-1Ј), 146.2 (C-2Ј), 137.6 (C-6Ј), 136.8 (C-
5Ј), 134.7 (C-3Ј), 79.9 (C-5), 74.2 (C-1), 74.2 (C-3), 72.0 (C-2), 69.5
(C-4), 61.6 (C-6) ppm. This substance contained a minor amount
of the corresponding hydroquinone. MS (CI, isobutane): m/z = 273
[M + 3H]+. HRMS (ESI): calcd. for C12H14O7 [M + H]+ 271.0818;
found 271.08236.
2-(β-D-Glucopyranosyl)-1,4-benzoquinone (19): Prepared from 17
upon oxidation with CAN: Glucopyranosyl 17 (100 mg, 0.33 mmol)
was dissolved in H2O (2 mL). A solution of CAN (548 mg, 1 mmol,
3 equiv.) in H2O (2 mL) was added slowly, while stirring at room
temperature. After ca. 30 min, TLC showed conversion of the start-
ing material (Rf = 0.35, MeOH/EtOAc, 1:8, violet spot/312 nm)
into a less polar product (Rf = 0.38, violet spot/312 nm, dark violet
spot/254 nm). Water was evaporated under reduced pressure and
the residue was applied to a column of silica gel (MeOH/EtOAc,
1:8 as mobile phase) to afford 19 as a dark red solid (190 mg) con-
taining inorganic impurities still present after another chromatog-
raphy. Analytically pure samples were obtained as dark red solids
by other methods. Prepared from 23 upon oxidation with Ag2O:
Glucosylhydroquinone 23 (136 mg, 0.5 mmol) was dissolved in 2-
propanol (1.5 mL) with the flask wrapped in aluminium foil.
Freshly prepared Ag2O (927 mg, 4 mmol, 8 equiv.) was added. Af-
ter the mixture was stirred at room temperature for 1.5 h, the reac-
tion was over and 23, well visible at 312 nm (Rf = ≈ 0.37, MeOH/
EtOAc, 1:8) was converted into a more mobile product (Rf = 0.40,
intense and visible spots at 254 and 312 nm, respectively). The sol-
2-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)hydroquinone (21):
Prepared from 13 upon reduction with NaBH4: Glucosylbenzoqui-
none 13 (380 mg, 0.87 mmol) was dissolved in EtOAc (2 mL).
Na2SO4 (about 60 mg) was then added followed by NaBH4 (66 mg,
1.74 mmol, 2 equiv.) added portionwise. The mixture was stirred at
room temperature for 30 min, whereby the starting compound (Rf
= 0.76, CH2Cl2/EtOAc, 4:1, violet spot under UV 312 nm, dark
spot under 254 nm) was converted into a polar product as seen on
TLC plates (Rf = 0.32, CH2Cl2/EtOAc, 4:1, violet spot under UV
312 nm). The reaction mixture was filtered, and the solids were
rinsed with EtOAc (3ϫ15 mL). The combined organic layers were
washed with brine and then dried with MgSO4. After filtration and
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J.-P. Praly et al.
FULL PAPER
concentration, the residue was applied to a silica gel column with
tration, the residue was applied to a column with EtOAc/CH3OH
CH2Cl2/EtOAc (4:1) as the mobile phase to afford 21 (336 mg, (8:1) as the eluent to afford compound 23 (38 mg, 0.14 mmol,
0.76 mmol, 88%). Prepared from 13 upon reduction with Na2S2O4:
Glucosylbenzoquinone 13 (380 mg, 0.87 mmol) dissolved in CHCl3
(3 mL) was treated with Na2S2O4 (906 mg, 5.2 mmol, 6 equiv.) dis-
solved in water (3 mL). The mixture was stirred vigorously at room
temperature for 8 min whereby the yellow colour of the organic
layer disappeared while 13 was transformed into a more polar com-
pound (TLC). The reaction mixture was extracted with CHCl3
(3 ϫ 15 mL), and processed as before to afford 21 (368.4 mg,
0.84 mmol, 96%), as a white foam. [α]2D5 = –23 (c = 0.9, chloro-
form). UV (CHCl3): λ (ε) = 241.6 (1130), 259.2 (70), 296.8 (3710)
93%). Prepared upon acid-catalyzed deacetylation: Glucosylhydro-
quinone 21 (100 mg, 0.23 mmol) was stirred under an argon atmo-
sphere in MeOH (3 mL) acidified with CH3COCl (1% v/v). After
the reaction mixture was kept at room temperature for 5 d, TLC
showed the presence of a more polar compound (Rf = 0.38, EtOAc/
CH3OH, 8:1, violet spot under 312 nm). Work up as before led to
compound 23 (52 mg, 0.19 mmol, 83%), as a yellowish solid. M.p.
79.5–81.5 °C. [α]2D5 = +19 (c = 0.8, MeOH). UV (MeOH): λ (ε) =
205 (8930), 242.4 (1400), 291.6 (4760) nm. 1H NMR (500.13 MHz,
D2O): δ = 6.86 (d, 1 H, J3Ј,5Ј = 2.8 Hz, 3Ј-H), 6.82 (d, 1 H, J5Ј,6Ј
8.8 Hz, 6Ј-H), 6.77 (dd, 1 H, 5Ј-H), 4.59 (d, 1 H, J1,2 = 9.7 Hz, 1-
8.8 Hz, 6Ј-H), 6.68 (dd, 1 H, J3Ј,5Ј = 2.9 Hz, 5Ј-H), 6.57 (d, 1 H, H), 3.85 (d, 1 H, J6a,6b = 12.3 Hz, 6a-H), 3.74 (dd, 1 H, J5,6b
=
nm. 1H NMR (500.13 MHz, CDCl3): δ = 6.74 (d, 1 H, J5Ј,6Ј
=
=
3Ј-H), 6.50 (s, 1 H, OH), ≈ 5.8 (br. s, 1 H, OH), 5.36 (t, 1 H, J2,3 4.4 Hz, 6b-H), 3.70 (t, 1 H, J2,3 = J3,4 = 9.3 Hz, 2-H), 3.61 to 3.53
= J3,4 = 9.3 Hz, 3-H), 5.31 (t, 1 H, J1,2 = 9.8 Hz, 2-H), 5.27 (t, 1
H, J4,5 = 9.8 Hz, 4-H), 4.61 (d, 1 H, 1-H), 4.31 (dd, 1 H, J5,6a
4.0 Hz, J6a,6b = 12.5 Hz, 6a-H), 4.16 (dd, 1 H, J5,6b = 2.0 Hz, 6b-
H), 3.88 (ddd, 1 H, 5-H), 2.10, 2.07, 2.01, 1.86 (4 s, 3 H each, acetyl
at positions 6, 4, 3, 2) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
171.3, 171.0, 170.0, 169.6 (C=O at positions 6, 4, 3, 2), 149.5 (C-
(m, 3 H, 3-H, 5-H, 4-H in this order) ppm. 13C NMR (125.8 MHz,
D2O): δ = 149.5 (C-4Ј), 148.3 (C-1Ј), 125.5 (C-2Ј), 117.9 (C-6Ј),
117.3 (C-5Ј), 115.5 (C-3Ј), 80.6 (C-5), 77.9 (C-3), 76.6 (C-1), 73.6
(C-2), 70.1 (C-4), 61.2 (C-6) ppm. MS (CI, isobutane): m/z = 273
[M + H]+. MS (ESI–): m/z = 579 [2M + Cl]–, 307 [M + Cl]–, 271
[M – H]–. HRMS: calcd. for C12H17O7 [M + H]+ 273.0974; found
=
4Ј), 148.9 (C-1Ј), 121.9 (C-2Ј), 118.7 (C-6Ј), 117.6 (C-5Ј), 115.3 (C- 273.09759.
3Ј), 79.3 (C-1), 76.4 (C-5), 74.2 (C-3), 71.3 (C-2), 68.5 (C-4), 62.2
2-(β-D-Galactopyranosyl)hydroquinone (24): Prepared by Zemplén
(C-6), 21.1, 21.1, 21.0, 20.8 (acetyl) ppm. HRMS (ESI): calcd. for
C20H25O11 [M + H]+ 441.1319; found 441.12890. C20H24O11: calcd.
C 54.55, H 5.49, O 39.96; found C 53.11, H 5.48, O 39.96.
deacetylation: To 22 (110 mg, 0.25 mmol) dissolved in MeOH
(1 mL) under an argon atmosphere was added 0.1  NaOMe
(0.5 mL) in MeOH. After stirring for 3 h at room temperature un-
der an argon atmosphere, TLC showed complete transformation of
the starting material (Rf = 0.96) into a more polar product (Rf =
0.37, MeOH/EtOAc, 1:8), visible as a violet spot on TLC plates at
312 nm UV light. Resin IR-120 was added to the liquid, whose pH
was checked with litmus paper. After filtration and concentration,
the residue was applied to a short column of silica gel with
CH3OH/EtOAc (1:8) as the eluent to afford 24 as a white solid
(63.4 mg, 93%), which on standing at ca. –10 °C crystallized from
MeOH/AcOEt as a yellowish solid. M.p. 76–78 °C. Prepared by
acid-catalyzed deacetylation: Galactosylhydroquinone 22 (260 mg,
0.6 mmol) was dissolved in MeOH (5 mL) containing 50 µL AcCl
(1% AcCl solution in MeOH). After stirring at room temperature
under an argon atmosphere for 7 d, deacetylation was almost over
and the starting material (Rf = ≈ 0.95) was converted into a more
polar product (Rf = 0.37, MeOH/EtOAc, 1:8) visible as a violet
spot on TLC at 312 nm UV light. After the volatiles were removed
under reduced pressure, chromatography (MeOH/EtOAc, 1:8) af-
forded 24 (142.5 mg, 89% yield) as a solid which was recrystallized
from MeOH/EtOAc. M.p. 76–78 °C. [α]2D2 = +31.5 (c = 0.7,
MeOH). UV (MeOH): λ (ε) = 206 (8140), 248.6 (370), 294.4 (3700)
nm. 1H NMR (500.13 MHz, D2O): δ = 6.92 (d, 1 H, J3Ј,5Ј = 2.8 Hz,
3Ј-H), 6.82 (d, 1 H, J5Ј,6Ј = 8.8 Hz, 6Ј-H), 6.77 (dd, 1 H, 5Ј-H),
4.56 (d, 1 H, J1,2 = 9.8 Hz, 1-H), 4.03 (br. s, 1 H, 4-H), 3.91 (t, 1
H, J2,3 = 9.6 Hz, 2-H), 3.8 to 3.7 (m, 4 H, 5-H, 3-H, 6a-H, 6b-H)
ppm. 13C NMR (125.8 MHz, D2O): δ = 149.5 (C-4Ј), 148.3 (C-1Ј),
125.7 (C-2Ј), 117.9 (C-6Ј), 117.2 (C-5Ј), 115.3 (C-3Ј), 79.7 (C-5),
76.6 (C-1), 74.6 (C-3), 71.1 (C-2), 69.6 (C-4), 61.6 (C-6) ppm. MS
(CI, isobutane): m/z = 273 [M + H]+. HRMS: calcd. for C12H17O7
[M + H]+ 273.0974; found 273.09722.
2-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)hydroquinone (22):
Galactosylbenzoquinone 14 (438 mg, 1 mmol) was dissolved by
stirring at room temperature in dry EtOAc (2 mL) containing
Na2SO4 (76 mg). Upon portionwise addition of NaBH4 (76 mg,
2 mmol), the substrate (Rf = 0.74, CH2Cl2/EtOAc, 4:1) was trans-
formed within 30 min (TLC) into a new compound (Rf = 0.30).
Whereas the starting quinone was visible on the TLC plates under
UV light as dark violet and violet spots at 254 and 312 nm, respec-
tively, the product was visible as a violet spot at 312 nm. The solids
were filtered off and rinsed with Et2O (20 mL). The organic phase
was washed with brine (10 mL) and water. The aqueous phase was
re-extracted with CHCl3 (10 mL). After drying (MgSO4) the com-
bined organic layers and concentration of the solution, the residue
was applied to a column of silica gel with CH2Cl2/EtOAc (4:1) as
the eluent. Concentration of homogeneous fractions led to 22 as a
white foamy solid (400 mg, 91%). [α]2D2 = –0.6 (c = 0.7, CHCl3).
1
UV (CHCl3): λ (ε) = 241.4 (1620), 257.2 (580), 296 (4300) nm. H
NMR (500.13 MHz, CDCl3): δ = 6.77 (d, 1 H, J5Ј,6Ј = 8.5 Hz, 6Ј-
H), 6.69 (dd, 1 H, J3Ј,5Ј = 2.8 Hz, 5Ј-H), 6.63 (s, 1 H, OH), 6.55 (d,
1 H, 3Ј-H), ≈ 6.0 (br. s, 1 H, OH), 5.56 (t, 1 H, J2,3 = 10.1 Hz, 2-H),
5.54 (superimposed br. s, 1 H, 4-H), 5.16 (dd, 1 H, J3,4 = 2.8 Hz, 3-
H), 4.48 (d, 1 H, J1,2 = 9.8 Hz, 1-H), 4.18 (m, 2 H, 6a-H, 6b-H),
4.08 (t, 1 H, J5,6a = J5,6b ≈ 6.3 Hz, 5-H), 2.19, 2.04, 1.98, 1.85 (4s,
3 H each, acetyl at positions 6, 4, 3, 2) ppm. 13 C NMR
(125.8 MHz, CDCl3): δ = 171.0, 170.8, 170.5, 169.6 (C=O at posi-
tions 6, 4, 3, 2), 149.3, 149.1 (C-1Ј, C-4Ј), 122.1 (C-2Ј), 118.5 (C-
6Ј), 117.5 (C-5Ј), 115.5 (C-3Ј), 80.7 (C-1), 75.1 (C-5), 72.1 (C-3),
68.3, 68.0 (C-2, C-4), 61.9 (C-6), 20.8 (3C), 20.6 (acetyl) ppm.
HRMS (ESI): calcd. for C20H25O11 [M + H]+ 441.1319; found
441.12993. C20H24O11·0.5H2O: calcd. C 53.45, H 5.61, O 40.94;
found C 53.35, H 5.42, O 40.97.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and spectroscopic data for compounds 1, 4, 10β,
11β. Data collection, refinement statistics, hydrogen bonding inter-
actions and Van der Waals interactions for compounds 19 and 23.
2-(β-D-Glucopyranosyl)hydroquinone (23): Prepared by Zemplén de-
acetylation: Glucosylhydroquinone 21 (66 mg, 0.15 mmol), dis-
solved in MeOH (1 mL), was treated with a solution of NaOMe in
MeOH (0.1 , 0.5 mL) while stirring. After 2 h at room tempera-
ture under an argon atmosphere, TLC showed the almost complete
conversion of compound 21 into a polar compound. After concen-
Acknowledgments
Région Rhône-Alpes is warmly thanked for stipends (L. H., Y.-
Z. Z.) and generous financial support allocated in the frame of the
604
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Eur. J. Org. Chem. 2007, 596–606

Synthesis of C--Glycopyranosylbenzo(hydro)quinones
FULL PAPER
[14] S. Satoh, M. Shimojima, K. Ito, T. Kuribayashi, Annu. Rep.
Sankyo Res. Lab. 2002, 54, 85–104.
MIRA collaborative programme with Shanghai City (P. R. China).
Grants from the National Science Foundation of China (NSFC,
Grant No. 20576034) as well as financial support from CNRS
(France), University Claude-Bernard Lyon1 (co-tutored PhD), and
ARCUS-Chine are gratefully acknowledged. Tibor Docsa and Pál
Gergely (Department of Medical Chemistry, Medical and Health
Science Centre, University of Debrecen, Hungary) are thanked for
performing preliminary kinetic measurements of compounds 17,
19, and 23 with RMGPb. This work has benefited from the support
of Greek GSRT through PENED-204/2001 and ENTER-EP6/
2001, Scientific and Technological cooperation between Greece and
USA (2005–2006) and the EMBL-Hamburg outstation under FP6
“Structuring the European Research Area Programme” contract
no RII3/CT/2004/5060008.
[15] a) L. Mignon, C. Goichot, P. Ratel, G. Cagnin, M. Baudry, J.-
P. Praly, B. Boubia, V. Barberousse, Carbohydr. Res. 2003, 338,
1271–1282; b) M. Baudry, V. Barberousse, G. Descotes, J. Pires,
J.-P. Praly, Tetrahedron 1998, 54, 7447–7456; c) M. Baudry, V.
Barberousse, Y. Collette, G. Descotes, J. Pires, J.-P. Praly, S.
Samreth, Tetrahedron 1998, 54, 13783–13792.
[16] L. Kalvoda, Collect. Czech. Chem. Commun. 1973, 38, 1679–
1692.
[17] K. Briner, A. Vasella, Helv. Chim. Acta 1990, 73, 1764–1778.
[18] T. Kuribayashi, N. Ohkawa, S. Satoh, Tetrahedron Lett. 1998,
39, 4537–4540.
[19] T. Kuribayashi, Y. Mizumo, S. Gohya, S. Satoh, J. Carbohydr.
Chem. 1999, 18, 371–382.
[20] a) for 4-hydroxyphenyl 2,3,4,6-tetra-O-acetyl-α--glucopyrano-
side (tetraacetyl α-arbutin), see: T. Kariyone, M. Takahashi, K.
Takaishi, J. Pharm. Soc. Jpn. 1952, 72, 13–16 [Chem. Abstr.
46, 1952, 11114g]; b) for arbutin and α-arbutin, see: K. Sugim-
oto, T. Nishimura, K. Nomura, K. Sugimoto, T. Kuriki, Chem.
Pharm. Bull. 2003, 51, 798–801; c) for 4-hydroxyphenyl 2,3,4,6-
tetra-O-acetyl-α--galactopyranoside, see: S. Yamago, M.
Hashidume, J.-i. Yoshida, Tetrahedron 2002, 58, 6805–6813; d)
for 4-hydroxyphenyl 2,3,4,6-tetra-O-acetyl-β--galactopyrano-
side, see: A. Robertson, J. Chem. Soc. 1929, 1820–1823; e) for
4-hydroxyphenyl 2,3,5-tri-O-benzoyl-β--ribofuranoside, see
[1]
[2]
a) Y. Chapleur (Ed.) Carbohydrate Mimics: Concepts and Meth-
ods, Wiley-VCH, Weinheim, 1998; b) R. Roy (Ed.) Glycomimet-
ics: Modern Synthetic Methodologies, ACS Symposium Series
896, 2005.
a) M. H. D. Postema, Tetrahedron 1992, 48, 8545–8599; b)
M. H. D. Postema, C-Glycosides Synthesis, CRC Press Inc.,
Boca Raton, 1995; c) D. E. Levy, C. Tang, The Chemistry of
C-Glycosides, Pergamon, Elsevier Science Ltd, Oxford, 1995;
d) Y. Du, R. J. Linhardt, I. R. Vlahov, Tetrahedron 1998, 54,
9913–9959; e) Z. Györgydeák, I. F. Pelyvás in Glycoscience:
Chemistry and Chemical Biology (Eds.: B. Fraser-Reid, K. Tat-
suta, J. Thiem), Springer, Berlin, 2001, vol. 1, pp. 691–747.
C. Bertozzi, M. Bednarski in Modern Methods in Carbohydrate
Synthesis (Eds.: S. H. Khan, R. A. O’Neill), Harwood Aca-
demic Publishers, Amsterdam, 1996, pp. 316–351.
F. Nicotra in Topics in Current Chemistry Vol. 187: Glycosci-
ence – Synthesis of Substrate Analogs and Mimetics (Eds.: H.
Driguez, J. Thiem), Berlin, 1997, pp. 55–83.
a) P. Meo, H. M. I. Osborn in Carbohydrates (Ed.: H. M. I.
Osborn), Academic Press, Oxford, 2003, pp. 337–384; b) P. Vo-
gel, R. Ferritto, K. Kraehenbuehl, A. Baudat in Carbohydrate
Mimics: Concepts and Methods (Ed.: Y. Chapleur), Wiley-
VCH, Weinheim, 1998, pp. 19–48; c) O. R. Martin in Carbo-
hydrate Mimics: Concepts and Methods (Ed.: Y. Chapleur),
Wiley-VCH, Weinheim, 1998, pp. 259–282.
a) B. Giese, H.-G. Zeitz in Preparative Carbohydrate Chemistry
(Ed.: S. Hanessian), Marcel Dekker, Inc. New York, 1997, pp.
507–525; b) J.-P. Praly, G.-R. Chen, J. Gola, G. Hetzer, Eur. J.
Org. Chem. 2000, 2831–2838; c) J.-P. Praly, A. S. Ardakani, I.
Bruyère, C. Marie-Luce, B. B. Qin, Carbohydr. Res. 2002, 337,
1623–1632.
J.-M. Beau, T. Gallagher in Topics in Current Chemistry Vol.
187: Glycoscience – Synthesis of Substrate Analogs and Mi-
metics (Eds.: H. Driguez, J. Thiem), Springer, Berlin, 1997, pp.
1–54.
ref.[16]
.
[21]
[22]
[23]
M. Schnabelrauch, A. Vasella, S. G. Withers, Helv. Chim. Acta
1994, 77, 778–799.
J.-P. Praly, L. He, B. B. Qin, M. Tanoh, G.-R. Chen, Tetrahe-
dron Lett. 2005, 46, 7081–7085.
N. G. Oikonomakos, M. Kosmopoulou, S. E. Zographos, D. D.
Leonidas, E. D. Chrysina, L. Somsak, V. Nagy, J.-P. Praly, T.
Docsa, B. Toth, P. Gergely, Eur. J. Biochem. 2002, 269, 1684–
1696.
[3]
[4]
[5]
[24]
[25]
S. A. Ross, E. A. Gulve, M. Wang, Chem. Rev. 2004, 104, 1255–
1282.
a) J. G. McCormack, N. Westergaard, M. Kristiansen, C. L.
Brand, J. Lau, Curr. Pharm. Des. 2001, 7, 1451–1474; b) J. L.
Treadway, P. Mendys, D. J. Hoover, Expert Opin. Invest. Drugs
2001, 10, 439–454.
[26]
[27]
D. J. Baker, J. A. Timmons, P. L. Greenhaff, Diabetes 2005, 54,
2453–2459, and references therein.
[6]
[7]
a) N. G. Oikonomakos, Curr. Protein Pept. Sci. 2002, 3, 561–
586; b) L. Somsák, V. Nagy, Z. Hadady, T. Docsa, P. Gergely,
Curr. Pharm. Des. 2003, 9, 1177–1189; c) L. Somsák, V. Nagy,
Z. Hadady, N. Felföldi, T. Docsa, P. Gergely in Frontiers in
Medicinal Chemistry (Eds.: A. B. Reitz, C. P. Kordik, M. I.
Choudhary, Atta-ur-Rahman), Bentham Science Publishers,
2005, vol. 2, pp. 253–272.
[28]
[29]
a) B. Giese in Radicals in Organic Synthesis: Formation of Car-
bon–Carbon Bonds, Pergamon Press, Oxford, 1986; b) J.-P.
Praly, Adv. Carbohydr. Chem. Biochem. 2001, 56, 65–151.
L. Cipolla, M. Guerrini, F. Nicotra, G. Torri, E. Vismara,
Chem. Commun. 1997, 1617–1618.
[8]
[9]
L. Somsák, Chem. Rev. 2001, 101, 81–135.
P. S. Belica, A. Berthold, N. Charles, G. Chen, A. Parhi, P.
Pasetto, J. Pu, C. Yang, R. W. Franck in Glycomimetics: Mod-
ern Synthetic Methodologies (Ed.: R. Roy), ACS Symposium
Series 896, 2005, pp. 107–119.
[30]
[31]
S. Knapp, D. S. Myers, J. Org. Chem. 2002, 67, 2995–2999.
A. Ghosez, T. Göbel, B. Giese, Chem. Ber. 1988, 121, 1807–
1811.
[10]
[11]
C. Taillefumier, Y. Chapleur, Chem. Rev. 2004, 104, 263–292.
A. M. Gómez, C. Uriel, S. Jarosz, S. Valverde, J.
Cristóbal López, Eur. J. Org. Chem. 2003, 4830–4837.
M. Jay in The Flavonoids: Advances in Research Since 1986
(Ed.: J. B. Harborne), Chapman & Hall, London, 1994, pp. 57–
93.
a) C. Jaramillo, S. Knapp, Synthesis 1994, 1–20; b) K. Suzuki,
T. Matsumoto in Preparative Carbohydrate Chemistry (Ed.: S.
Hanessian), Marcel Dekker, Inc. New York, 1997, pp. 527–542;
c) K. A. Parker in Glycomimetics: Modern Synthetic Methodol-
ogies (Ed.: R. Roy), ACS Symposium Series 896, 2005, pp. 93–
105.
[32]
[33]
W. M. Owton, J. Chem. Soc., Perkin Trans. 1 1999, 2409–2420.
A. Dargelos, J. Migliaccio, M. Chaillet, Tetrahedron 1971, 27,
5673–5681.
N. G. Oikonomakos, M. Kontou, S. E. Zographos, K. A. Wat-
son, L. N. Johnson, C. J. F. Bichard, G. W. J. Fleet, K. R. Ach-
arya, Protein Sci. 1995, 4, 2469–2477.
N. G. Oikonomakos, A. E. Melpidou, L. N. Johnson, Biochim.
Biophys. Acta 1985, 832, 248–256.
Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307–
326.
[34]
[12]
[13]
[35]
[36]
[37]
A. T. Brünger, P. D. Adams, G. M. Clore, W. L. DeLano, P.
Gros, R. W. Grosse-Kunstleve, J.-S. Jiang, J. Kuszewski, M.
Eur. J. Org. Chem. 2007, 596–606
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
605

J.-P. Praly et al.
FULL PAPER
Nilges, N. S. Pannu, R. J. Read, L. M. Rice, T. Simonson, G. L.
Warren, Acta Crystallogr., Sect. D 1998, 54, 905–921.
[38] N. G. Oikonomakos et al., unpublished results.
[39] T. A. Jones, J. Y. Zou, S. W. Cowan, M. Kjeldgaard, Acta Crys-
tallogr., Sect. A 1991, 47, 110–119.
[40] R. A. Laskowski, M. W. MacArthur, D. S. Moss, J. M. Thorn-
ton, J. Appl. Crystallogr. 1993, 26, 283–291.
[44] R. M. Esnouf, J. Mol. Graphics Modell. 1997, 15, 132–134.
[45] E. A. Merritt, D. J. Bacon, Methods Enzymol. 1997, 277, 505–
524.
[46] J. L. Martin, K. Veluraja, L. N. Johnson, G. W. J. Fleet, N. G.
Ramsden, I. Bruce, N. G. Oikonomakos, A. C. Papageorgiou,
D. D. Leonidas, H. S. Tsitoura, Biochemistry 1991, 30, 10101–
10116.
[41] Collaborative Computational Project No 4. The CCP4 suite:
Programmes for Protein Crystallography, Acta Crystallogr.,
Sect. D 1994, 50, 760–763.
[42] V. Luzatti, Acta Crystallogr. 1952, 5, 802–810.
[43] P. Kraulis, J. Appl. Crystallogr. 1991, 24, 946–950.
[47] P. Jacob III, P. S. Callery, A. T. Shulgin, N. Castagnoli Jr, J.
Org. Chem. 1976, 41, 3627–3629.
Received: June 26, 2006
Published Online: November 27, 2006
606
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 596–606