Angewandte
Chemie
in CH2Cl2 at reflux or by employing microwave-assisted
acylation conditions, led to the degradation of 10 and/or 11.
Nevertheless, the two anomers of hexagalloylglucose 11 could
be individually subjected to a final hydrogenolysis of their
diphenylmethylene ketal and fifteen benzyl ethers under
classical palladium-mediated conditions in THF at room
temperature for 24 hours. The hexagalloyl-d-glucopyranoses
a-4a and b-4a were thus obtained in good yields (ca. 85%
each, 100 mg scale).
The NMR spectral data of these hexagalloylglucoses were
successfully compared with those previously reported for
isolated and enzymatically prepared b-4a.[6b,c,e] Most notably,
13C NMR analysis of our synthetic b-4a in [D6]acetone/D2O
(9:1) showed that the C3 carbon of the glucose resonates at
lower field (d =+ 1.6 ppm) than that of b-3, which is
indicative of the presence of the digalloyl motif on the C3
position of the sugar.[6c,e] Seven carbonyl carbon signals were
detected, five of which were assigned by HMBC NMR
experiments to the five galloyl carbonyl groups esterified to
the glucose core, and the other two signals were attributed to
the galloyl carbonyl groups esterified to the O3 galloyl unit of
the digalloyl depside, which is in meta/para equilibrium in
[D6]acetone/D2O. To confirm the operational effectiveness of
this equilibrium, which results from an intramolecular trans-
esterification,[6e,10] we prepared the meta- and para-depsidic
variants of 3-O-digalloyl-1,2:5,6-di-O-isopropylidene-a-d-
glucofuranose 22 (see the Supporting Information). Both
meta- and para-22 quickly equilibrated in [D6]acetone in the
course of their 13C NMR analysis, which afforded identical
spectra of the meta/para-depside mixtures.
We next moved to the synthesis of the decagalloylglucoses
14, whose elaboration requires the challenging simultaneous
installation of five digalloyl depsides. The pergalloylation of
commercial d-glucose (12) with 8a was successfully per-
formed in 88% yield (Scheme 3). A TBAF-mediated desily-
lation afforded a PGG analogue bearing one free phenolic
meta-hydroxy group on each of the five galloyl moieties. This
compound was next engaged in a second pentagalloylation
step, this time using 8b, to give a 1:1 a/b mixture of the fully
protected decagalloylglucose 13 (Scheme 3). Careful separa-
tion by column chromatography led to a-13 and b-13 in
relatively good yields (28 and 36%, respectively). The
removal of their five diphenylmethylene ketal and fifteen
benzyl ether groups again occurred smoothly by hydrogenol-
ysis, thus affording the desired 1,2,3,4,6-pentakis-O-digalloyl-
d-glucopyranoses a-14 and b-14 in high yields and conven-
iently on a scale of 50–100 mg. As expected, NMR character-
ization of these compounds, which are present as meta/para-
depsidic mixtures in solution, was difficult. Attempts to
visualize the separation of these mixtures by reverse-phase
HPLC analysis were unsuccessful, but electrospray ionization
(ESI) mass spectrometric analysis of each anomer gave the
correct m/z value of 1724 for the [M+Na+] species (see the
Supporting Information).
Scheme 3. Synthesis of the decagalloylglucoses a-14 and b-14.
very good yields according to previously reported procedures
(see the Supporting information).[9d] The synthesis of the
monogalloylglucoses a- and b-glucogallin (a-2 and b-2) from
their corresponding hepta-O-benzyl precursors 16 required
some modifications, as the final PdCl2-based hydrogenolytic
debenzylation described in the early 1960s[11a] only led to
degradation. We thus reconsidered this synthesis, and first
studied the anomeric galloylation of commercial 2,3,4,6-tetra-
O-benzyl-d-glucopyranose (15; see the Supporting Informa-
tion). High and reverse anomeric selectivities were obtained
under two sets of conditions using 3,4,5-tribenzyloxybenzoyl
chloride (8c)[9d] as the acylating agent (Scheme 4). After
a reaction in the presence of DMAP in MeCN at room
temperature for 24 hours (conditions A), 16 was isolated in
96% yield as a 92:8 a/b mixture. Interestingly, this ratio was
reversed to 8:92 when 15 was treated with 8c in the presence
of TMEDA in CH2Cl2 at reflux for 48 hours (conditions B).[9e]
Precipitation of this anomeric mixture (90% yield) using
EtOH afforded pure b-16 in 79% yield. Debenzylation of the
92:8 a/b mixture of 16 by hydrogenolysis using Pearlmanꢀs
catalyst in THF, followed by gel filtration chromatography on
Sephadex LH-20, afforded pure a-2 in 87% yield. Pure b-16
was also similarly debenzylated to give b-2 in 96% yield
(Scheme 4), typically on scales of 100 to 500 mg. This two-step
synthesis of b-glucogallin constitutes a facile alternative to
With the gallotannins 4a and 14 in both anomeric forms in
hand, we decided to complete the series with simpler
galloylglucoses in view of their evaluation as inhibitors of
Ab aggregation. The two anomers of pentagalloylglucose
(PGG, a-3 and b-3; see Scheme 1) were readily prepared in
Angew. Chem. Int. Ed. 2015, 54, 8217 –8221
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