we attempted double esterification,12 which is the forma-
tion of the bislactone starting from a diol (13 in this
work) and a diacid (diacid chloride (S)-15 in this work),
first through intermolecular but subsequently through
intramolecularesterifications. However,thisapproachpro-
duced a dimer (not isolated), of which the mass spectrum
indicated the production of a compound in which the
two sugar moieties were esterified to one HHDP group
(m/z 1541.5, M þ Na). Diol 13 was prepared by introduc-
tion of p-methoxybenzylidene acetal on the 4,6-diol of
known 12.13 Diacid chloride (S)-15 was obtained by
chlorination of the diacid (S)-14 (98% ee)4,14 using 4 equiv
of (COCl)2.
Scheme 5. Synthesis of the Proposed Structure of Roxbin
B (1)
To avoid the formation of the dimer, we applied the
corresponding acid anhydride (S)-16 as the third approach
(Scheme 4). The acid anhydride (S)-16 was obtained by
bridge through the double esterification strategy with
racemic 14 via kinetic resolution.16 In this transformation,
the unnecessary (R)-HHDP dicarboxylic acid also reacts
by producing oligomers, which wastes the diol, the base
of the bridge.17 Adoption of the chiral HHDP donor
removed this problem and improved the efficiency of the
double esterification step, including isolation of the desired
bislactone compounds. Finally, hydrogenolytic cleavage
of the 15 benzyl groups of 19 gave 1. The purification of 1
was performed by Sephadex LH-20 column chromato-
graphy. Toyopearl HW-40, which has often been used as a
column packing material for purification of many natural
ellagitannins,18 decomposed 1, suggesting the instability of
the 1,2-HHDP bridged ellagitannin.
Scheme 4. Construction of the 1,2-HHDP Bridge
The synthetically obtained 1 was not identical to the
naturally occurring roxbin B (see Supporting Information).
Thus, the proposed structure 1 must be revised.
In conclusion, we achieved the first total synthesis of the
proposed structure for roxbin B, but the synthesized com-
pound was not identical to the natural product. In these
synthetic studies, we newly obtained an effective strategy
for the synthesis of natural ellagitannins, which was
the stepwise construction of the HHDP-bridge with the
corresponding acid anhydride. This strategy was useful
when the desired double esterification was ineffective.
Application of the strategy would expand the range of
synthetically available ellagitannins. Structural reconsi-
deration of roxbin B including total synthesis is currently
underway.
treatment of diacid (S)-14 with 1.3 equiv of (COCl)2. The
arylꢀaryl bond of (S)-16 did not rotate at rt for a week,
maintaining the axial chirality.15 The 1,2-(S)-HHDP bridge
was constructed by stepwise diacylation. Specifically, re-
gioselective esterification of diol 3 with acid anhydride
(S)-16 in the presence of Et3N, followed by lactonization
of the furnished β-glycosyl ester 17, afforded the 1,2-
bridged 18 in 61% yield from 3 as an R/β = 7/93 mixture
of anomers. The high regioselectivity of the esterification
was due to the higher reactivity of the anomeric hydroxy
group compared to the sterically more hindered 2-OH.
The following three steps transformed 18 to the pro-
posed structure of roxbin B (1) (Scheme 5). Acid hydrolysis
of the p-methoxybenzylidene acetal of 18 provided the
corresponding 4,6-diol 2 in 78% yield. The double ester-
ification of the 4,6-diol of 2 was effectively possible with
(S)-HHDP dicarboxylic acid (S)-14, thus obtaining
1,2-(S)- and 4,6-(S)-bridged 19 in 83% yield. Khanbabaee
andco-workersreportedtheformationofthe4,6-(S)-HHDP
Acknowledgment. We thank Dr. Takashi Yoshida, and
Prof. Tsutomu Hatano and Prof. Hideyuki Ito (both
(16) (a) Khanbabaee, K.; Großer, M. Tetrahedron 2002, 58, 1159–
€
1163. (b) Khanbabaee, K.; Lotzerich, K.; Borges, M.; Großer, M.
J. Prakt. Chem. 1999, 341, 159–166.
€
(17) Khanbabaee, K.; Lotzerich, K. Eur. J. Org. Chem. 1999, 3079–
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