Synthesis of all-methylated isorugosin B

Article abstract of DOI:10.1248/cpb.58.435

All-methylated isorugosin B was synthesized via two-step esterification between optically active valoneic acid and glucose derivatives.

Full text of DOI:10.1248/cpb.58.435

March 2010
Communications to the Editor
Chem. Pharm. Bull. 58(3) 435—437 (2010)
435
ucts, we postulated that the formyl compound 1027) could be
used in the same reaction. Based on this, the desired ether
compound 9 was obtained successfully. The reduction of the
formyl group and deprotection of the benzyl group afforded
the benzyl alcohol 11 (Chart 2).
Protection of the benzylic hydroxyl group of 11 using the
tert-butyldimethylsilyl chloride (TBSCl)-imidazole system
was effective for preparing the phenol fragment 5. The sim-
ple esterification between 5 and the corresponding benzoic
Synthesis of All-Methylated Isorugosin B
Kazuma SHIOE,a,b Yasuo TAKEUCHI,a
Takashi HARAYAMA, and Hitoshi ABE
c
,b
*
a Graduate School of Medicine, Dentistry, and Pharmaceutical
Sciences, Okayama University; Okayama 700–8530, Japan:
b Graduate School of Science and Engineering, University of
Toyama; Toyama 930–8555, Japan: and c Faculty of Pharmaceu-
tical Sciences at Kagawa Campus, Tokushima Bunri University;
Kagawa 769–2193, Japan.
Received October 13, 2009; accepted December 1, 2009; published
online December 4, 2009
All-methylated isorugosin B was synthesized via two-step es-
terification between optically active valoneic acid and glucose
derivatives.
Key words ellagitannin; palladium; coupling reaction; natural product;
glucose derivative
Ellagitannins are a class of polyphenols that are suspected
of being useful medically, as they are strong antioxidants1—3)
;
however, compared to other polyphenols, few synthetic stud-
ies of ellagitannins4—8) have been conducted because of their
chemical instability and structural intricacy. Within the ellag-
itannin family, compounds that contain valoneoyl groups are
frequently found in natural products.9—13) Despite this, the
complete synthesis of an ellagitannin containing a valoneoyl
group has not yet been reported.
Recently, we reported the stereoselective synthesis of a
valoneic acid derivative, in which Bringmann’s “lactone con-
cept”14—18) was used to form its optically active biphenyl
moiety.19) In this paper, based on our previous work, we re-
port the synthesis of all-methylated isorugosin B (1)20—23)
(Fig. 1).
Chart 1. Synthetic Plan for 1
The retrosynthetic analysis of 1 is depicted in Chart 1. Two
ester functions would be formed in the final stage of the syn-
thetic scheme, leading to the valoneic acid derivative (2) and
sugar moiety (3).24) The optically active valoneoyl group 2
would be formed by Bringmann’s method4) which involves
the intramolecular biaryl coupling reaction25) of 4, followed
by enantioselective lactone ring opening. The key intermedi-
ate 4 would be derived from the corresponding phenol 5 and
carboxylic acid 6.
Initially, we attempted to prepare the biphenyl ether from
the Ullmann condensation reaction26) between methyl o-bro-
mobenzoate 7 and (siloxymethyl)phenol 8.27) Because the
only compound isolated in the reaction between 7 and 8 was
the unexpected aldehyde 9, accompanied by many by-prod-
Fig. 1. Structure of Isorugosin B and Its Related Compounds
Chart 2. Synthesis of 14
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: abeh@eng.u-toyama.ac.jp

436
Vol. 58, No. 3
Chart 3. Synthesis of All-Methylated Isorugosin B (1)
phys. Acta, 1158, 251—256 (1993).
3) Okuda T., Kimura Y., Yoshida T., Hatano T., Okuda H., Arichi S.,
Chem. Pharm. Bull., 31, 1625—1631 (1983).
4) Several total syntheses of simple ellagitannins have been reported:
Quideau S., Feldman K. S., Chem. Rev., 96, 475—503 (1996) and ref-
erences cited therein.
5) Khanbabaee K., van Ree T., Synthesis, 2001, 1585—1610 (2001).
6) Feldman K. S., Phytochemistry, 66, 1984—2000 (2005).
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Chem. Soc., 130, 7566—7567 (2008).
9) Hatano T., Yasuhara T., Matsuda M., Yazaki K., Yoshida T., Okuda T.,
Chem. Pharm. Bull., 37, 2269—2271 (1989).
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Bull., 37, 2083—2090 (1989).
11) Hatano T., Yasuhara T., Matsuda M., Yazaki K., Yoshida T., Okuda T.,
J. Chem. Soc., Perkin Trans. 1, 1990, 2735—2743 (1990).
12) Yoshida T., Hatano T., Ahmed A. F., Okonogi A., Okuda T., Tetrahe-
dron, 47, 3575—3584 (1991).
13) Santos S. C., Waterman P. G., Fitoterapia, 72, 95—97 (2001).
14) Bringmann G., Breuning M., Tasler S., Synthesis, 1999, 525—558
(1999).
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16) Bringmann G., Breuning M., Pfeifer R.-M., Schenk W. A., Kamikawa
K., Uemura M., J. Organomet. Chem., 661, 31—47 (2002).
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Chem., 661, 49—65 (2002).
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acid 12 successfully afforded the precursor 13 for the in-
tramolecular biaryl coupling reaction. The reaction of 13
with Pd(OAc)2, Ph3P, and NaOAc proceeded smoothly, re-
sulting in the lactone compound 14 in moderate yield.
The enantioselective lactone-opening reaction of 14 using
Bringmann’s method, the borane-CBS reagent system,28) pro-
ceeded efficiently to generate the biphenyl compound 1529) in
an enantioselective form.30) The methylation of the resulting
phenolic hydroxy group followed by two-step oxidation
(pyridinium dichromate (PDC) oxidation and Pinnick oxida-
tion31)) of the benzylic hydroxy group formed the optically
active valoneic acid derivative 2 (Chart 3).30)
To complete the synthesis of 1, we needed to form the
eleven-membered ring via double esterification between 2
and the glucose derivative 3. The first ester condensation be-
tween 2 and 3, and the selective desilylation of the primary
alcohol yielded the desired alcohol 17. This compound was
successively subjected to the usual manipulation involving
the two-step oxidation leading to the carboxylic acid 18. Fi-
nally, the silyl group on the sugar moiety was deprotected,
and this was followed by the second esterification32) of the
hydroxyl group at the 4-position of the sugar with the car-
boxylic acid of the valoneoyl group, resulting in the synthesis
of 1.20,33)
The NMR data of the synthetic 1 were identical with the
authentic chart.
In conclusion, we succeeded in the first synthesis of the
valoneoyl group-containing ellagitannin derivative 1. Based
on this work, our laboratory is attempting to synthesize natu- 21) Yoshida T., Chou T., Haba K., Okano Y., Shingu T., Miyamoto K.,
Koshiura R., Okuda T., Chem. Pharm. Bull., 37, 3174—3176 (1989).
22) Hatano T., Kira R., Yasuhara T., Okuda T., Heterocycles, 27, 2081—
ral isorugosin B.
2085 (1988).
Acknowledgment The authors are indebted to Professor T. Hatano and
Dr. H. Ito (Okayama University) for providing the authentic NMR data for 1.
We thank the SC-NMR Laboratory of Okayama University for performing
the NMR experiments.
23) Hatano T., Kira R., Yasuhara T., Okuda T., Chem. Pharm. Bull., 36,
3920—3927 (1988).
24) Compound 3 was prepared easily from the known compound: Nelson
T. D., Meyers A. I., J. Org. Chem., 59, 2577—2588 (1994).
25) Abe H., Harayama T., Heterocycles, 75, 1305—1320 (2008).
26) For a recent review on Ullmann condensation reaction, see; Ley S. V.,
Thomas A. W., Angew. Chem. Int. Ed., 42, 5400—5449 (2003).
27) Compounds 8 and 10 were obtained by two-step transformation from
methyl 3-benzyloxy-5-hydroxy-4-methoxybenzoate: Tanaka M., Ikeya
Y., Mitsuhashi H., Maruno M., Wakamatsu T., Tetrahedron, 51,
References and Notes
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March 2010
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437
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28) Cho B. T., Tetrahedron, 62, 7621—7643 (2006).
29) The S-configuration was confirmed by comparison of the optical rota-
tion of the known compound which has been synthesized in our labo-
latory.19)
30) The ee was determined by HPLC analysis using Daicel CHIRALPAK
AD or CHIRALCEL OD.
32) The low yield of this step may be due to the low reactivity of the sec-
ondary hydroxyl group.
33) The [a]D value of the synthetic sample did not match the reported
value (synthetic [a]D ꢀ28° (cꢁ1.52, acetone); reported [a]D ꢂ7°
(cꢁ0.3, acetone)20)). We speculate that this discrepancy was due to im-
purities in the reported sample, as many unidentified peaks are seen in
the authentic NMR data.
31) Bal B. S., Childers W. E. Jr., Pinnick H. W., Tetrahedron, 37, 2091—