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dichotomy of
1
versus
2
and the diastereoselectivity expressed from
1
,
we decided to examine by molecular modeling the fine structural
characterictics of each epimer and the mechanistic implications of the
benzylic cation intermediate that could derive from them.
9.2.1.1
Refractory chemical behavior of castalagin
The first chemical reaction we investigated from vescalagin/castalagin
(
1
/
2
) was their condensation with (+)-catechin in order to hemisynthesize
the acutissimins A/B (
14
/
15
, see Fig. 9.4). All attempts to form these
flavano-ellagitannins using
2
instead of
1
under similar conditions (
i.e.
,
1.5% (v/v) TFA/THF, 60 °C, 5 h, see Section 9.2.2) were unsuccessful.
To the best of our knowledge, the only chemical hemisynthesis of an
acutissimin from castalagin (
2
) was achieved using (+)-catechin under
more drastic conditions in refluxing anhydrous dioxane in the presence
of
p
-toluenesulfonic acid for 24 h. Only acutissimin A (
14
) could be
isolated in less than 4% yield (Ishimaru
et al.
, 1987).
Molecular-mechanics calculations performed using Macromodel
(MM3* force field) indicated that the minimum-energy conformer of
castalagin
(
2
, 501.6 kJ/mol) was slightly more stable than that of
1
(504.5 kJ/mol) (Quideau
et al.
, 2004). Admitedly, this energy difference
of 2.9 kJ (
ca.
0.7 kcal) is rather slim and the reactivity differences
observed between
1
and
2
cannot solely rely upon this figure. A closer
examination of the minimum-energy conformations reveals that the β-
oriented OH-1 group of
1
is
exo
-located relatively to the most crowded
face of the molecule, whereas the α-oriented OH-1 group in
2
is
endo
-
positioned (Fig. 9.8). As first observed by Okuda and co-workers
(Yoshida
et al.
, 1991), this
endo
-positioning of the α-oriented OH-1
group in
2
renders it more available to participate in an intramolecular
(stabilizing) hydrogen-bond between its oxygen atom and the hydrogen
atom of the phenolic OH-3' group of the galloyl-derived I-ring of the
NHTP unit (Fig. 9.8). This H-bond of 2.21 Å with an O-1
•••
H-O-3' angle
of 146° may be invoked to suggest that the basicity of the O-1 atom in
2
is consequently lower than that of the same oxygen atom in
1
, hence
rendering it less prone to protonation under mild acidic conditions.
Furthermore, departure of a protonated OH-1 group may be energetically
