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protecting group from the O-4 and O-6 centers, the released hydroxyl
groups were then again acylated with the gallic acid derivative
8
.
Subsequent desilylation was again followed by oxidative coupling of the
two galloyl units at C-4 and C-6 to give the second (
S
)-configured biaryl
unit, thus leading to the formation of the 2,3,4,6-coupled product
86
.
Pedunculagin (
87
) is finally obtained in a 2.9% overall yield after
hydrogenolytic cleavage of all benzyl protecting groups of the precursor
86
(Fig. 5.17, Feldman and Smith, 1996).
As mentioned before, the majority of naturally occurring 2,3- and
4,6-HHDP-containing ellagitannins displays the (
S
)-configuration.
According to the postulate first proposed by Schmidt (Schmidt
et al.
,
1965) and later by Haslam (Gupta
et al.
, 1982), enzymes would not be
responsible for such a strong diastereoselectivity in the biosynthesis of
ellagitannins, but the chirality of the
D
-glucopyranosyl scaffold on which
biaryl coupling occurs would induce this remarkable stereoselectivity.
Even though the exact reaction sequence of galloyl-galloyl couplings is
still unknown
in vivo
(Feldman and Smith, 1996), the stereoselectivity
observed in Feldman's oxidative 2,3- and 4,6-phenolic coupling reaction
is in agreement with ellagitannin stereochemistry, strongly favouring the
(
S
)-configuration.
5.2.3.3
Total synthesis of pedunculagin via the double esterification
strategy
For this total synthesis of pedunculagin (
87
), the 4,6-positions of the
sugar derivative
88
were first protected as a benzylidene acetal and the
resulting diol
2
was subsequently acylated with the enantiomerically pure
(
S
)-configured hexabenzyloxydiphenic acid (
S
)-
16
. The benzylidene
acetal protection was then hydrolytically removed to furnish diol
89
in a
quantitative yield. This diol was then also acylated with (
S
)-
16
to give an
unpolar product, which could be identified as the desired tetraester
90
by
NMR analysis (Fig. 5.18). Finally, to complete the total synthesis of
pedunculagin (
87
), the tetraester
90
was exposed to hydrogenolysis
under standard conditions using H
2
-Pd/C to cleave off all benzylic
protective groups. From this reaction, the natural pedunculagin (
87
)
could be isolated as a brownish solid after purification by preparative
