Synthesis of kojic acid derivatives containing phenolic hydroxy groups

Article abstract of DOI:10.1081/SCC-120017129

Two kojic acid derivatives (2a and 2b) containing phenolic hydroxy groups were synthesized. The preparation was carried out by the reaction of a kojic acid derivative (3) having a chloromethyl group with phenol derivatives (4 and 7), followed by the subse

Full text of DOI:10.1081/SCC-120017129

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Synthesis of Kojic Acid Derivatives Containing Phenolic
Hydroxy Groups
J. Kadokawa a c , T. Nishikura a , R. Muraoka a , H. Tagaya a & N. Fukuoka b
a Department of Chemistry and Chemical Engineering , Faculty of Engineering , Yamagata
University , Yonezawa, Japan
b Chemipro Kasei Kaisha Ltd. , Chuo-ku, Kobe, Japan
c Department of Materials Chemistry , Graduate School of Engineering , Tohoku University ,
Aoba 07, Aoba-ku, Sendai 980-8579, Japan Fax: E-mail:
Published online: 21 Aug 2006.
To cite this article: J. Kadokawa , T. Nishikura , R. Muraoka , H. Tagaya & N. Fukuoka (2003) Synthesis of Kojic Acid
Derivatives Containing Phenolic Hydroxy Groups, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:7, 1081-1086, DOI: 10.1081/SCC-120017129
To link to this article: http://dx.doi.org/10.1081/SCC-120017129
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1081–1086, 2003
Synthesis of Kojic Acid Derivatives Containing
Phenolic Hydroxy Groups
1
1
J. Kadokawa,1, T. Nishikura, R. Muraoka,
*
H. Tagaya,1 and N. Fukuoka2
1Department of Chemistry and Chemical Engineering,
Faculty of Engineering, Yamagata University,
Yonezawa, Japan
2Chemipro Kasei Kaisha Ltd., Chuo-ku, Kobe, Japan
ABSTRACT
Two kojic acid derivatives (2a and 2b) containing phenolic hydroxy
groups were synthesized. The preparation was carried out by the reac-
tion of a kojic acid derivative (3) having a chloromethyl group with
phenol derivatives (4 and 7), followed by the subsequent deprotection
steps. The first reaction proceeded smoothly in the presence of potas-
sium carbonate in DMF at room temperature. Then, the appropriate
deprotection reactions gave the desired compounds 2a and 2b. The
structures of 2a and 2b were confirmed by the 1H NMR spectra.
*Correspondence: J. Kadokawa, Department of Materials Chemistry, Graduate
School of Engineering, Tohoku University, Aoba 07, Aoba-ku, Sendai 980-8579,
Japan; Fax: 481-22-2188231; E-mail: kadokawa@poly.che.tohoku.ac.jp.
1081
DOI: 10.1081/SCC-120017129
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1082
Kadokawa et al.
Key Words: Kojic acid; Phenolic hydroxy group; Tylosinase
inhibitor; Deprotection.
INTRODUCTION
Kojic acid (l), isolated from fermentative products of Aspergillus spe-
cies, inhibits tyrosinase due to chelation of its copper, which is indispens-
able for tyrosinase activity.[1] The acid, therefore, had been used as a
whitening agent for cosmetics and an antibrowning agent for food because
of its inhibitory effects on melanin synthesis, which was resulted by tyr-
osinase activity.[2] On the other hand, the degree of inhibition by 1 is not
sufficient enough for use in the above mentioned applications. On the
other hand, it is well known that some natural compounds containing
phenolic hydroxy groups, such as vitamin E and arbutin also act as tyr-
osinase inhibitors.[3,4]
Based on these viewpoints, we designed and synthesized new kojic
acid derivatives containing phenolic hydroxy groups, which can be
expected to have stronger inhibitory potency against tyrosinase than
that of 1. Two compounds have been synthesized here, which are 3-
hydroxy-6-[(4-hydroxyphenoxy)methyl]-4H-pyran-4-one (2a) and 3-
hydroxy-6-[(3,4-dihydroxyphenoxy)methyl]-4H-pyran-4-one (2b) having
one and two phenolic hydroxy groups, respectively (Fig. 1).
Figure 1. Structures of kojic acid derivatives.

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Kojic Acid Derivatives
1083
EXPERIMENTAL
General
Compounds 3, 4, and 7 were prepared according to the literature.[5–7]
Solvents were purified according to the usual manners. Other reagents
1
were used without further purification. H NMR spectra were recorded
on a Varian Mercury 200 spectrometer.
Synthesis of 2a
Under argon, a solution of 3 (1.49 g, 6.00 mmol), 4 (2.00 g,
10.0 mmol), and K2CO3 (1.38 g, 10.0 mmol) in DMF (15.0 mL) were stir-
red at room temperature for 9 h. After the reaction mixture was concen-
trated by evaporation, the residue was poured into water, extracted with
chloroform, washed successively with 1 mol/L H2SO4 aqueous, NaHCO3
aqueous, and water. The chloroform layer was dried over Na2SO4,
filtered, and evaporated. The residue was purified by recrystallization
from toluene to give 5 (1.44 g, 3.49 mmol) in 58.2% yield. Then, 5
(1.36 g, 3.30 mmol) was dissolved in THF (27.2 mL) and the solution
was stirred in the presence of 10% Pd-C (0.136 g) at room temperature
for 1.5 h under hydrogen atmosphere. After the filtration and evapora-
tion of the reaction mixture, the crude product of 6 (0.924 g, 2.88 mmol)
was obtained in 87.3% yield. A solution of 6 (0.841 g, 2.62 mmol) in
methanol (20.2 mL) was stirred in the presence of 10% Pd-C (0.126 g)
at room temperature for 1.5 h under hydrogen atmosphere. After the
filtration and evaporation of the reaction mixture, the residue was
washed with hot ethanol to give 2a (0.150 g, 0.651 mmol) in 24.8%
1
yield. H NMR (DMSO-d6) ꢀ 4.87 (s, CH2-O, 2H), 6.48 (s, CH-C¼O,
1H), 6.68, 6.84 (2d, J ¼ 8.8 Hz, C6H4, 4H), 8.10 (s, O-CH¼, 1H), 9.04,
9.20 (2s, OH, 2H).
Synthesis of 2b
Under argon, a solution of 3 (0.33 g, 1.31 mmol), 7 (0.27 g,
1.31 mmol), and K2CO3 (0.18 g, 1.31 mmol) in DMF (2.0 mL) were stir-
red at room temperature for 4 h. After the reaction mixture was concen-
trated by evaporation, the residue was poured into water and extracted
with chloroform. The chloroform layer was dried over Na2SO4, filtered,
and evaporated to give a crude 8 (0.46 g, 1.09 mml) in 83.5% yield. Then,

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1084
Kadokawa et al.
8 (0.20 g, 0.47 mmol) was dissolved in methanol (4.0 mL) and the solution
was stirred in the presence of 10% Pd-C (0.020 g) at 40ꢀC for 1.5 h under
hydrogen atmosphere. After the filtration and evaporation of the reaction
mixture, the crude product of 9 (0.070 g, 0.21 mmol) was obtained in
44.5% yield. To a mixed solution of concentrated hydrochloric acid
(1.32 mL) and ethanol (5.30 mL), which was preheated at 70ꢀC for
1.5 h, 9 (0.070 g, 0.21 mmol) and water (13.2 mL) was added. The mixture
was heated at 70ꢀC for 1.5 h and cooled to room temperature. The reac-
tion mixture was concentrated and dried under reduced pressure to give
1
2b (0.030 g, 0.12 mmol) in 56.6% yield. H NMR (DMSO-d6) ꢀ 4.83 (s,
CH2-O, 2H), 6.27–6.63 (m, aromatic protons, 3H), 6.46 (s, CH-C¼O,
1H), 8.10 (s, O-CH¼, 1H), 8.53, 8.97, 9.21 (3s, OH, 3H).
RESULTS AND DISCUSSION
As the synthetic design, the desired compounds 2a and 2b would be
obtained by the reaction of a kojic acid derivative (3-benzyloxy-6-chloro-
methyl-4H-pyran-4-one, 3) having the electrophilic moiety of a chloro-
methyl group with the corresponding phenol derivatives 4 and 7,
followed by several deprotection steps (Schs. 1 and 2). These three sub-
strates were prepared according to the literature.[5–7] The nucleophilic
substitution of 3 with 4 or 7 was carried outin the presence of potassium
carbonate and the reaction was monitored by thin layer chromatography
(TLC) on silica gel. Both the reactions from 4 and 7 took place smoothly
at room temperature, which were completed for several hours. After the
general work-up procedures, 5 was purified by recrystallization from
toluene (58.2% yield from 3), whereas 8 was obtained with enough
purity for the subsequent reaction steps without further purification
Scheme 1. (a) K2CO3, DMF, r.t., 9 h; (b) H2, Pd-C, THF, r.t., 1.5 h; (c) H2,
Pd-C,MeOH, r.t., 1.5 h.

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Kojic Acid Derivatives
1085
Scheme 2. (a) K2CO3, DMF, r.t., 4 h; (b) H2, Pd-C, MeOH, 40ꢀC, 1.5 h; (c) HCl,
EtOH/H2O, 70ꢀC, 1.5 h.
(83.5% yield from 3). Then, we attempted to carry out the simultaneous
deprotection of two benzyl groups in 5 by catalytic hydrogenation. The
attempt, however, was not successful, probably due to the different natures
of the two benzyl groups. Therefore, the deprotection of the benzyl
groups was carried out by the step-by-step manner as shown in Sch. 1.
First, the benzyl group of the kojic acid side was successfully cleaved in
the presence of 10% Pd-C in THF solvent at room temperature under
hydrogen atmosphere, giving rise to 6. Then, cleavage of the other benzyl
group took place by the similar hydrogenation in methanol solvent to
give 2a, which was purified by washing with hot ethanol. The structure of
1
the product was confirmed by the H NMR measurement. On the other
hand, the deprotection of 8 was demonstrated as follows. First, the
benzyl group was cleaved by the catalytic hydrogenation in methanol
solventot produce 9. Then, an acidic hydrolysis of the cyclohexylidene
1
acetal proceeded, leading to 2b. The H NMR data of the product fully
supported the structure of 2b.
In conclusion, we presently synthesized kojic acid derivatives (2a and
2b) containing phenolic hydroxy groups. These novel compounds can be
expected for the application as a whitening agent for cosmetics as well as
an antibrowning agent for food. The evaluation of inhibitory effects of 2a
and 2b on tyrosinase activity is now in progress.
ACKNOWLEDGMENT
We are indebted to Ms. Masa Karasu of our research group for her
technical assistance.

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1086
Kadokawa et al.
REFERENCES
1. Izumida, H. Fragrance J. 1989, 109.
2. Ohyama Y.; Mishima, Y. Fragrance J. 1990, 53.
3. Mukai, K.; Nishimura, M.; Kikuchi, S. J. Biol. Chem. 1991, 266, 274.
4. Akiu, S.; Suzuki, Y.; Fujinuma, Y.; Asahara, T.; Fukuda, M. Proc.
Jpn. Soc. Invest. Dermatol. 1988, 12, 138.
5. Morisaki K.; Ozaki, S. Chem. Pharm. Bull. 1996, 44, 1647.
6. Kawamura M.; Mizuno, K. Japanese Patent 6251635; Chem. Abstr.
1987, 107, 96429y.
7. Cole, E.R.; Crank, G.; Minh, H.T.H. Aust. J. Chem. 1980, 33, 527.
Received in Japan February 11, 2002