First synthesis of astilbin, biologically active glycosyl flavonoid isolated from Chinese folk medicine

Article abstract of DOI:10.1016/S0040-4039(00)00826-1

A synthetic route to a biologically active glycosyl flavonoid, astilbin (1), was developed. The tetra-benzyl ether 4, derived from (+)-catechin, was glycosylated with the L-rhamnosyl donor 10 by using Cp₂HfCl₂-AgClO₄, and subsequent oxidation of the C(4)position of the flavan skeleton followed by deprotection gave 1. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00826-1

Tetrahedron Letters 41 (2000) 5537±5541
First synthesis of astilbin, biologically active glycosyl
¯avonoid isolated from Chinese folk medicine
Ken Ohmori, Hiroki Ohrui and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science and Technology (JST),
O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received 27 April 2000; accepted 11 May 2000
Abstract
A synthetic route to a biologically active glycosyl ¯avonoid, astilbin (1), was developed. The tetra-benzyl
ether 4, derived from (+)-catechin, was glycosylated with the l-rhamnosyl donor 10 by using Cp2HfCl2±
AgClO4, and subsequent oxidation of the C(4) position of the ¯avan skeleton followed by deprotection
gave 1. # 2000 Elsevier Science Ltd. All rights reserved.
Astilbin (1) is a glycosyl ¯avonoid isolated from the root of Astilbe odontophylla Miquel,1
which has recently been proven to exhibit some important bioactivities including antioxidant and
aldose reductase inhibitory e€ects.2 Such bioactivities, as well as the lack of synthetic routes,
attracted our interest in this compound. Herein, we describe the ®rst synthetic route to 1 starting
from readily available (+)-catechin (2) and l-rhamnose (3). Scheme 1 shows our retrosynthetic
analysis with three issues to be considered: (1) choice of the protecting group (R) that could be
detached under mild conditions to cope with the acid- and base-labile nature of 1; (2) oxidation
of the C(4) position of the ¯avan skeleton, i.e. the viability and the timing; and (3) introduction of
the sugar moiety.
Our initial attention was focused on the oxidation of the C(4) position of the ¯avan skeleton.
As a model reaction to address this issue, the tetra-benzyl catechin 43 was treated with DDQ and
MeOH (CHCl3, 4 h)4 to give the methyl ether 6 in 79% yield as a single diastereomer.5 Under the
similar conditions, the silyl ether 5, derived from 4 [t-BuMe2SiCl (TBSCl), imidazole, CH2Cl2,
90% yield], was treated with DDQ in CH2Cl2±H2O, thereby giving the alcohol 7 in 76% yield
again as a single diastereomer. Oxidation of the alcohol 7 with TPAP6 (NMO, CH2Cl2, 16 h)
a€orded the ketone 8 in 32% yield. Attempts to improve the yield of this step, unfortunately,
were unfruitful. Desilylation with PPTS in EtOH (25ꢀC, 66 h) gave the ketol 9 in 60% yield.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00826-1

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Scheme 1.
With these data in hand, we next examined the introduction of the rhamnoside moiety. The
rhamnosyl acetate 10 was used as the glycosyl donor, and three compounds, 4, 6 and 9 were tested
as the glycosyl acceptor. Attempts were made by using Cp2HfCl2 and AgClO4 as the promoter7,8
in CH2Cl2 with the reaction temperature starting from ^78ꢀC followed by warming up to ^20 or
0ꢀC. The results are summarized in Table 1.
It turned out that the glycosyl acceptors with a C(4)-oxygen function, 9 and 6, gave only poor
results. In the case of 9, none of the glycosylated product was obtained, although the donor 10
was completely consumed (run 1). Partial recovery of the glycosyl acceptor 9 suggests the low
reactivity of its C(3)-hydroxyl group due to the internal hydrogen bonding to the C(4) carbonyl.
In the case of 6, decomposition of the glycosyl acceptor 6 was the main event observed, which
could be rationalized by the Lewis acid-induced departure of the C(4)-methoxy group to generate
a p-quinonemethide A, which might undergo various side reactions (run 2, Table 1). Formation
of the methyl glycoside 11, albeit in 12% yield, is consistent with this rationalization. On the
other hand, we were pleased to ®nd that the alcohol 4, without an oxygen function at C(4),
underwent the glycosylation under these conditions, thereby giving the corresponding a-rhamno-
side (a-12) in 68% yield (run 3, Table 1). Further optimization of the glycosylation of the acceptor
4 is summarized in Table 2.
Notable features are the following: (1) the yield was improved by carrying out the reaction at a
lower temperature (run 1, Table 2); (2) the use of Cp2ZrCl2 and AgClO4 also gave a good yield
for a-12 (run 2), whereas other promoters gave poor yields (runs 3±5); and (3) substantial

5539
Table 1
Table 2
amounts of the anomeric product b-12 were produced by the reaction with TMSOTf or SnCl4
(runs 4 and 5),9 which were even prominent when the ¯uoride 13 was used as the glycosyl donor
under the hafnocene-promoted conditions (runs 6 and 7).
With the requisite glycoside a-12 in hand, we focused on the ®nal stages of the synthesis. Thus,
we attempted at oxidation of the C(4) position of the ¯avan skeleton of a-12, which was nicely

5540
e€ected in the following two steps. Upon treatment with DDQ (H2O, CH2Cl2, 25ꢀC, 5 h), the
alcohol 14 was obtained in 68% yield as a single diastereomer,5 which was then treated with PDC
(CH2Cl2, 25ꢀC, 19 h) to give the ketone 15 in 85% yield (Scheme 2). It was pleasing for us that
the latter step (14!15) proceeded far more cleanly than the reaction of the non-glycosidic
counterpart (cf. 7!8; vide supra). Final removal of the seven benzyl-protecting groups in 15
required some experimentation, which eventually went nicely. Initial attempts, when using Pd±C
as the catalyst, resulted in a slow reaction and a very low yield of the desired product. The poor
material balance suggested that the deprotected products were strongly absorbed to the charcoal.
Addition of an acid (0.01 M HCl aq.) accelerated the deprotection process, which, however,
produced an unidenti®ed side product. Eventually, the best result was attained by employing Pd-
black as the catalyst, and the target 1 was obtained in 91% yield. All the physical data of 1 (1H
and 13C NMR, IR, [ꢀ]D, mp) were fully identical with those of the authentic specimen10 by direct
18
D
25
D
comparison, ‰ꢀŠ ^11 (c 0.52, EtOH) [lit. ‰ꢀŠ ^13.6 (c 0.52, EtOH)],1d mp 179±182ꢀC [lit. mp
179±180ꢀC].1b
Scheme 2. Reagents and conditions: (a) DDQ, H2O, CH2Cl2 (66%); (b) PDC, CH2Cl2 (85%); (c) H2, Pd-black, MeOH
(91%)
Acknowledgements
We thank Suntory for bringing this topic to our attention and providing partial ®nancial
support.
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5541
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