Asymmetric syntheses of daedalin A and quercinol and their tyrosinase inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2009.12.034

Stereoselective syntheses of daedalin A and quercinol, an enantiomer of daedalin A, is described. The tyrosinase inhibitory activities of daedalin A and quercinol were examined. The activity of quercinol was weaker than that of daedalin A at high concentration.

Full text of DOI:10.1016/j.bmcl.2009.12.034

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1063–1064
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Asymmetric syntheses of daedalin A and quercinol and their tyrosinase
inhibitory activity
Mitsuo Sekimoto a, Yasunao Hattori b, Keiji Morimura c, Mitsuru Hirota d, Hidefumi Makabe a,
*
a Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304, Minami-minowa, Kami-ina, Nagano 399-4598, Japan
b Department of Chemistry, Graduate School of Medicinal Science, Kyoto Prefectural University of Medicine, Kita-ku, Kyoto 603-8334, Japan
c Geol Cosmetics. Co., Ltd, 111-1, Shinmura, Katsuragi, Nara 639-2121, Japan
d Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304, Minami-minowa, Kami-ina, Nagano 399-4598, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective syntheses of daedalin A and quercinol, an enantiomer of daedalin A, is described. The
tyrosinase inhibitory activities of daedalin A and quercinol were examined. The activity of quercinol
was weaker than that of daedalin A at high concentration.
Received 14 October 2009
Revised 16 November 2009
Accepted 7 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chromene
Tyrosinase
Dermal hyper-pigmentation, caused by the accumulation of
melanin, is initiated by oxidation of tyrosine by tyrosinase, a key
enzyme of melanin biosynthesis.1 Tyrosinase inhibitors such as
arbutin, kojic acid, ellagic acid, and rucinol have been used as phar-
maceutical constituents of cosmetics in order to prevent hyper-
pigmentation. In an effort to find new types of tyrosinase inhibi-
tors, we have screened culture broths from mushroom mycelia
for tyrosinase inhibitory activity, and found that the mycelial cul-
ture of Daedalea dickinsii showed significant activity. Based on
the spectroscopic data, the bioactive compound was elucidated
as (2R)-6-hydroxymethyl-2-methyl-2H-chromene, named daeda-
lin A (1).2,3 We have synthesized racemic 1 and it showed weaker
activity than 1.3 Quercinol (2), an enantiomer of daedalin A (1), was
also isolated from the fungus of Daedalea quercina by Hertweck and
co-workers.4 They reported that compound 2 showed anti-inflam-
matory activity.4 It is very difficult to obtain enough amount of
daedalin A (1) and quercinol (2) for the biological study because
the mycelia cultures of D. dickinsii and/or D. quercina are limited.
Thus, syntheses of 1, 2, and their analogues are important for the
biological study. Especially, synthesis of 2 is required because the
tyrosinase inhibitory activity of 2 has not been reported yet. Here-
in, we wish to describe an asymmetric syntheses of 1 and 2 and
their tyrosinase inhibitory activity (Fig. 1).
modification.5 In this reaction Kirschleger used 1.5 mol % of
Pd(PPh3)4 at room temperature, however, sometimes the yield of
desired product was low. Thus, we used 1 mol % of Pd(PPh3)4 at
0 °C to give desired product in high yield. Acetylation, Claisen rear-
rangement followed by Sharpless asymmetric epoxidation gave
9.5,6 Reduction with LiAlH4 followed by protecting 1,2-diol with
2,2-dimethoxypropane afforded 11. Oxidative demethylation of
11 with ceric ammonium nitrate (CAN) afforded 12 only in 21%
yield with complex mixture.7 Probably the product was decom-
posed under acidic medium. Thus, we used silver(II) dipicolinate
{Ag(DPAH)2} in the presence of AcONa as an oxidant to give 12
in 96% yield.8 This method is useful for oxidizing acid sensitive
substrate because oxidation can be proceeded under neutral med-
ium. Transformation from 12 to 14 was achieved using Kirschleg-
er’s method.6 Protection of the hydroxy groups of 14 with TBSCl
and imidazole afforded 15. Treatment of 15 with DDQ afforded
16.9 Finally, deprotection of the TBS ether of 16 with TBAF fur-
nished daedalin A (1) in good yield. Recrystallization (CHCl3) gave
colourless solid whose melting point was 136–138 °C. The specific
rotation value of synthetic 1 was much higher than that of
The synthesis of daedalin A (1) is described as follows. Com-
pound 4 was synthesized from 4-methoxyphenol and vinyloxirane
using Pd-catalyzed O-alkylation using Kirschleger’s method with
* Corresponding author. Tel.: +81 265 77 1630; fax +81 265 77 1700.
E-mail address: makabeh@shinshu-u.ac.jp (H. Makabe).
Figure 1. The structure of daedalin A (1) and quercinol (2).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.034

1064
M. Sekimoto et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1063–1064
Scheme 1. Synthesis of daedalin A (1). Reagents and conditions: (a) 0.5 mol % of Pd(PPh3)4, CH2Cl2, 0 °C (93%); (b) Ac2O, Et3N, DMAP, AcOEt (quant.); (c) HCl (gas), CH2Cl2
(99%); (d) MOMCl, i-Pr2NEt, CH2Cl2 (99%); (e) K2CO3, MeOH (quant.); (f) TBHP, Ti(O-iPr)4, -(+)-DET, CH2Cl2 (78%); (g) LiAlH4, diethyl ether, (88%); (h) DMP, p-TsOH (quant.); (i)
L
Ag(DPAH)2, AcONa, MeCN–H2O (96%); (j) 1 N HCl, MeOH (90%); (k) Red-Al, THF, À78 °C (92%); (l) TBSCl, imidazole, DMF (quant.); (m) DDQ, benzene (81%); (n) TBAF, THF
(95%).
Scheme 2. Synthesis of quercinol (2). Reagent and condition: (a) TBHP, Ti(O-iPr)4,
D
-(À)-DET, CH2Cl2 (89%).
from that of daedalin (1) in the tyrosinase inhibitory activity (Table
1).3
In summary, asymmetric syntheses of daedalin A (1) and quer-
cinol (2) were achieved. The tyrosinase inhibitory activity of 2 was
weaker than that of 1 at high concentration. The study of the inhib-
itory mechanism of 2 is currently underway.
Table 1
Tyrosinase inhibitory activities of 1, 2 and daedalin A
Compound
Inhibition SDa (%)
400
100
l
M
200
lM
lM
IC50 (lmol/l)
Daedalin A (1)
Quercinol (2)
Daedalin A
28.6 5.0
30.7 6.7
23.7 5.7
48.4 1.1
43.9 1.2
45.5 3.1
61.6 1.0
48.1 1.7
55.6 1.1
208
490
289
Supplementary data
a
Each value is expressed as the means SD from three tests.
Supplementary data (spectroscopic and physical data of 1 and 2,
biological assays) associated with this article can be found, in the
online version, at doi:10.1016/j.bmcl.2009.12.034.
reported. All the spectral data of synthetic 1 were in good agree-
ment with those of natural 1 (Scheme 1).2
References
Synthesis of quercinol (2) was achieved as the same procedure
of daedalin A (1) except that
D
-(À)-DET was used in the Sharpless
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epoxidation. The melting point and specific rotation values were
higher than those reported. All the spectral data of synthetic 2
were in good agreement with those of natural 2 (Scheme 2).4
The HPLC analysis of the synthetic 1 and 2 using chiral column
showed more than 99% ee, respectively.
The tyrosinase inhibitory activities of 1 and 2 were examined.
Interestingly, the tyrosinase inhibitory activity of 2 was weaker
than that of 1 at higher concentration (400 lM). This result sug-
7. Kirschleger and co-workers reported that 9 was obtained in 90% yield using CAN
as an oxidant.6
gested that the mechanism of action of quercinol (2), which has
an opposite stereochemistry at C-2 position, might be different
8. Kloc, K.; Mlochowski, J.; Syper, L. Chem. Lett. 1980, 725.
9. Trost, B. M.; Shen, H. C.; Surivet, J.-P. Angew. Chem., Int. Ed. 2003, 42, 3943.