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zyl compounds have been isolated from extracts of several organ-
isms including liverwort, algae, and fern,19 which are known to be
possess various biological activities such as antifungal, phytotoxic
and anti-HIV effects.20–22 However, the bibenzyl glycoside having
significant tyrosinase inhibitory activity is a novel observation.
These structural and biological findings prompted us to further
investigate congeners 2–4 by a chemical approach.
most effective among all the bibenzyl xylosides synthesized. The
xylosyl site on the bibenzyl skeleton has obviously an influence
on tyrosinase inhibitory activity. The inhibitory activity of xyloside
2 was comparable to that of bibenzyl 4. Hence, this resorcinol moi-
ety could be easily to bind on the active site of the tyrosinase be-
cause of the absence of the bulky xylosyl substitution at 2-
position. The hydrophobic interaction occurred between the tyros-
inase inhibitor and the active site of tyrosinase would contribute to
the inhibitory activity.26,27 However, the effect of the hydrophilic
substituent on tyrosinase inhibitors had not been well docu-
mented. Since derivatives 1–3 were glucosides, they can be lead
compounds for the exploring tool of new hydrophilic interaction
between the enzyme and inhibitor as well as for the development
of water soluble tyrosinase inhibitors with efficiency.
Bibenzyl derivative 2 was synthesized as illustrated in Scheme
2. With the use of the similar synthetic pathway, derivative 3 could
be prepared, effectively. Firstly, both hydroxyl groups of 2,4-dihy-
droxybenzaldehyde as the same starting materiel of 1 were pro-
tected by using MOMCl under basic condition. Phosphonium salt
8 and aldehyde 14 obtained were coupled by Wittig reaction and
stilbene 15 yielded in 84%. Sixty percent of 15 were found as cis-
form, which was calculated by the 1H NMR experiment. Following
selective hydrogenation by using Pd(en)/C as a catalyst, 15 was
smoothly transformed to bibenzyl 16 in 72% yield. Bibenzyl 17, a
key intermediate was prepared from 16 in quantitative yield by
the removal of all MOM groups under acidic condition. In the next
reaction, the selectivity of products 2 or 3 was governed by the
amount of imidate 12. When 1.5 equivalent of 12 was used as a
glycosylation donor, b-xyloside 18 was obtained in 71% yield and
dixyloside 19 was not detected by TLC analyses. Successive re-
moval of the benzyl and acetyl moieties by hydrogenolysis and so-
dium methoxide, respectively, afforded xyloside 2, a regioisomer of
1 in 85% yield (two steps). In contrast, 19 was synthesized in 77%
by using 4.0 equiv of donor 12. Removal of all protective groups
in 19 gave dixyloside 3 in 84% yield (two steps). Consequently,
derivatives 2 and 3 were concisely synthesized from 14 via six
steps in 37% and 39% overall yields, respectively.23,24 Symmetric
bibenzyl 4 was readily prepared by the method as previously
reported.25
Acknowledgments
We are grateful to Dr. Noriyoshi Masuoka (Okayama University
of Science) and Dr. Yoichi Yamada (Utsunomiya University) for
obtaining the NMR and HRMS data. Thanks are also due to Drs.
Tadashi Yanagisawa and Masayuki Iigo (Utsunomiya University),
and Dr. Kimiko Hashimoto (Kyoto Pharmaceutical University) for
their invaluable discussions. This study was supported in part by
a Grant-in-Aid from Asahi Breweries Foundation.
References and notes
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Brain Res. 1997, 45, 159.
Although NMR data of 2 were not identical to that of the biben-
zyl reported as a constituent of C. arundinaceum, bibenzyls 2–4
show remarkable tyrosinase inhibitory activity (Table 3). Espe-
6. Prezioso, J. A.; Epperly, M. W.; Wang, N.; Bloomer, W. D. Cancer Lett. 1992, 63,
73.
7. Wiley, J. W.; Tyson, G. N.; Steller, J. S. J. Am. Chem. Soc. 1942, 64, 963.
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13. Kaushik, N. Phytochem. Rev. 2005, 4, 191.
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15. Matsushita, M.; Kanemura, T.; Hatakeyama, S.; Irie, H.; Toki, T.; Miyashita, M.
Tetrahedron 1995, 51, 10687.
cially, IC50 of 2 represented 0.43
lM, indicating that this compound
OBn
OMOM
OMOM
CHO
a
b
OBn
MOMO
MOMO
14
15
16. Sajiki, H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63, 7990.
17. Compound 1: colorless solid; a2D0 ꢀ10.6 (c 0.09, MeOH); IR (Nujol) mmax 3350,
R1O
O
1603, 1508 cmꢀ1 1H and 13C NMR, see Tables 1 and 2; ESIHRMS m/z 377.1240
;
[MꢀH]ꢀ (Calcd for C19H21O8, 377.1236).
OR2
18. The assay was performed as previously reported.28 The commercial mushroom
tyrosinase purchased from Sigma (St. Louis, Mo) was purified by the procedure
OBn
OR
R1O
O
R1O
as previously reported.29
.
g
19. Asakawa, Y. Phytochemistry 2001, 56, 297.
OBn
OR2
20. Lorimer, S. D.; Perry, N. B. J. Nat. Prod. 1993, 56, 1444.
21. Hernández-Romero, Y.; Acevedo, L.; Sánchez, M. L. Á.; Shier, W. T.; Abbas, H. K.;
Mata, R. J. Agric. Food Chem. 2005, 53, 6276.
RO
c
O
O
OR1
OR1
16: R = MOM
17: R = H
22. Manfredi, K. P.; Vallurupalli, V.; Demidova, M.; Kindscher, K.; Pannell, L. K.
Phytochemistry 2001, 58, 153.
23. Compound 2: colorless solid; a2D0 ꢀ5.9 (c 0.17, MeOH); IR (Nujol) mmax 3520,
d
OR1
3350, 1595, 1510 cmꢀ1 1H and 13C NMR, see Tables 1 and 2; ESIHRMS m/z
;
OR2
19: R1 = Ac, R2 = Bn
3: R1 = R2 = H
377.1234 [MꢀH]- (Calcd for C19H21O8, 377.1236).
OH
h, i
24. Compound 3: colorless solid; a2D0 ꢀ48.0 (c 0.05, MeOH); IR (Nujol) mmax 3350,
R1O
R1O
1508 cmꢀ1 1H NMR (pyridine-d5, 400 MHz) d 7.49 (1H, br s), 7.31 (1H, d,
;
O
O
OR1
J = 8.3 Hz), 7.28 (1H, d, J = 8.3 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.02 (1H, br s), 6.72
(1H, d, J = 8.3 Hz), 5.52 (1H, d, J = 5.4 Hz), 5.38 (1H, d, J = 7.3 Hz), 4.28 (8H, m),
3.85 (1H, t, J = 9.8 Hz), 3.67 (1H, dd, J = 8.8, 11.2 Hz), 3.43 (2H, m), 3.30 (2H, m);
13C NMR (pyridine-d5, 100 MHz) d 157.6, 157.2, 156.8, 156.7, 130.8, 130.1,
126.0, 119.9, 109.6, 106.7, 105.3, 103.2, 103.1, 102.7, 77.8, 77.6, 74.2, 70.3, 70.2,
OR2
18: R1 = Ac, R2 = Bn
2: R1 = R2 = H
e, f
66.6, 66.5, 30.90, 30.86; ESIHRMS m/z 509.1649 [MꢀH]ꢀ (Calcd for C24H29O12
,
509.1659).
Scheme 2. Syntheses of bibenzyl xylosides 2 and 3. Reagents and conditions: (a) 8,
LiHMDS, THF, 0 °C to rt, 1 h, 84%; (b) H2-Pd(en)/C, rt, 12 h, 72%; (c) TsOH, THF,
MeOH, reflux, 2 h, 100%; (d) 12, TMSOTf, CH2Cl2, 0 °C, 5 min, 71%; (e) H2-Pd(OH)2/C,
rt, 12 h, 96%; (f) NaOMe, MeOH, 0 °C, 0.5 h, then H+, 89%; (g) 12 (excess), TMSOTf,
CH2Cl2, 0 °C, 5 min, 77%; (h) H2-Pd(OH)2/C, rt, 12 h, 87%; (i) NaOMe, MeOH, 0 °C,
0.5 h, then H+, 97%.
25. Silcoff, E. R.; Sheradsky, T. New J. Chem. 1999, 23, 1187.
26. Kubo, I.; Kinst-Hori, I. J. Agric. Food Chem. 1998, 49, 5338.
27. Mastuda, T.; Odaka, Y.; Ogawa, N.; Nakamoto, K.; Kuninaga, H. J. Agric. Food
Chem. 2008, 46, 597.
28. Nihei, K.; Kubo, I. Bioorg. Med. Chem. Lett. 2003, 13, 2409.
29. Espín, J. C.; Wichers, H. J. J. Agric. Food Chem. 1999, 47, 2638.