Isolation, synthesis, and antifungal activity of kojic acid and its derivatives

Full text of DOI:10.1007/s10600-016-1565-z

DOI 10.1007/s10600-016-1565-z
Chemistry of Natural Compounds, Vol. 52, No. 1, January, 2016
ISOLATION, SYNTHESIS, AND ANTIFUNGAL ACTIVITY
OF KOJIC ACID AND ITS DERIVATIVES
Shaopeng Wei and Zhiqin Ji*
Microorganisms produce a vast number of secondary metabolites with useful biological activities for both the medicine
and agricultural industries, including antibiotics, immunosuppressive and antitumor agents, as well as herbicides, insecticides,
and antiparasitic agents [1–3]. In the process of screening of new antibiotics from microbial products, an endophytic fungus
F52 was isolated from Vigna unguiculata, and it was identified as Aspergillus flavus F52 according to morphological
characteristics and ITS region of rDNA.
In the present paper, 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one (kojic acid) was isolated from the fermentation
broth of Aspergillus flavus F52 by extracted with ethyl acetate and recrystallized with ethanol. Furthermore, seven derivatives
of kojic acid, including five new compounds (2, 3, 5, 6, and 7), were synthesized by acylation with corresponding acyl
1
chlorides (Scheme 1). Their structures were confirmed by H NMR and elemental analysis. Antifungal activity tests
indicated that the derivatives exhibited obvious inhibitory activities against the mycelial growth of Glomerella cingulata
and Botrytis cinerea (Table 1).
O
O
O
HO
HO
HO
O
b
a
3
5
OR
O
OH
O
Cl
O
O
O
1'
2 - 7
1
8
O
O
O
Cl
O
4'
6'
6'
R =
4'
7'
2
3
5
4
6
7
Cl
a. RCOCl; b. SOCl
2
Scheme 1
5-Hydroxy-2-hydroxymethyl-4H-pyran-4-one (1). White crystals, mp 151.2–152.3ꢀC (ref. 151.5–152.3ꢀC [4]).
–1
IR spectrum (KBr, ꢁ, cm ): 3200 (OH), 2927 (CH), 1700 (C=O), 1625 (C=C), 1600, 1482 (CH), 1077 (CO). Mass spectrum
+
1
(HR-ESI-MS), m/z 143.0342 [M + H] (calcd for C H O , 143.0344). H NMR (400 MHz, CD OD, ꢂ, ppm): 4.41 (2H, s,
6
7
4
3
13
CH O), 6.50 (1H, s, H-3), 7.94 (1H, s, H-6). C NMR (100 MHz, CD OD, ꢂ, ppm): 59.8 (C-1ꢃ), 109.4 (C-3), 139.6 (C-6),
2
3
145.9 (C-5), 169.0 (C-2), 175.5 (C-4).
1
(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl Pentanoate (2). White wax. C H O . H NMR (500 MHz, CDCl ,
11 14
5
3
ꢂ, ppm, J/Hz): 0.93 (3H, t, J = 7.5, 6ꢃ-CH ), 1.34–1.39 (2H, m, 5ꢃ-CH ), 1.63–1.67 (2H, m, 4ꢃ-CH ), 2.41 (2H, t, J = 7.5, 3ꢃ-CH ),
3
2
2
2
4.94 (2H, s, CH O), 6.51 (1H, s, H-3), 7.86 (1H, s, H-6).
2
1
(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl Isobutyl Carbonate (3). White wax. C H O . H NMR (500 MHz, CDCl ,
11 14
6
3
ꢂ, ppm, J/Hz): 0.96 (6H, d, J = 7.5, 6ꢃ, 7ꢃ-CH ), 1.97–2.04 (1H, m, H-5ꢃ), 3.98 (2H, d, J = 6.5, 4ꢃ-CH ), 4.97 (2H, s, CH O),
3
2
2
6.54 (1H, s, H-3), 7.86 (1H, s, H-6).
College of Plant Protection, Northwest A&F University, Yangling, 712100, Shaanxi, P. R. China, fax: +86 29 870 939 87,
e-mail: 358486867@qq.com. Published in Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2016, pp. 109–110.
Original article submitted January 27, 2014.
0009-3130/16/5201-0123 02016 Springer Science+Business Media New York
123

TABLE 1. Antifungal Activity of Target Compounds against G. cingulata and B. cinerea
Inhibition ratio, %
Inhibition ratio, %
Compound
Compound
G. cingulata
B. cinerea
G. cingulata
B. cinerea
11.2
55.2
55.2
44.8
86.2
–
44.8
62.07
48.3
50.0
50.0
56.7
35.7
1
2
3
5
6
7
8
63.3
50.0
56.7
46.7
23.5
4
Azoxystrobin
(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl Benzoate (4). White crystals, C H O , mp 173.2–174.9ꢀC (ref. 174–175ꢀC
13 10
5
1
[5]). H NMR (500 MHz, CDCl , ꢂ, ppm, J/Hz): 5.22 (2H, s, CH O), 6.67 (1H, s, H-3), 7.48–7.52 (2H, m, Ar-H), 7.62–7.64
3
2
(1H, m, Ar-H), 8.01 (1H, s, H-6), 8.08 (2H, d, J = 7.0, Ar-H).
(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 3-Methylbenzoate (5). White crystals, C H O , mp 99.7–101.2ꢀC.
14 12
5
1
H NMR (500 MHz, CDCl , ꢂ, ppm, J/Hz): 2.42 (3H, s, Ar-CH ), 5.17 (2H, s, CH O), 6.61 (1H, s, H-3), 7.36–7.44 (2H, m,
3
3
2
Ar-H), 7.86 (2H, d, J = 8.0, Ar-H), 7.87 (1H, s, H-6).
(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 2-Chlorobenzoate (6). White crystals, C H ClO , mp 142.3–144.1ꢀC.
13
9
5
1
H NMR (500 MHz, CDCl , ꢂ, ppm, J/Hz): 5.19 (2H, s, CH O), 6.64 (1H, s, H-3), 7.34–7.38 (1H, m, Ar-H), 7.46–7.51 (2H,
3
2
m, Ar-H), 7.89 (1H, s, H-6), 7.91 (1H, d, J = 8.0, Ar-H).
(5-Hydroxy-4-oxo-4H-pyran-2-yl)methyl 3-Chlorobenzoate (7). White crystals, C H ClO , mp 145.3–147.1ꢀC.
13
9
5
1
H NMR (500 MHz, CDCl , ꢂ, ppm): 5.19 (2H, s, CH O), 6.60 (1H, s, H-3), 7.38–7.42 (1H, m, Ar-H), 7.49–7.52 (2H, m, Ar-H),
3
2
7.89 (1H, s, H-6), 7.92–7.97 (1H, m, Ar-H).
2-(Chloromethyl)-5-hydroxy-4H-pyran-4-one (8). Yellow crystals, mp 165.3–168.1ꢀC [6–9].
ACKNOWLEDGMENT
This study was supported in part by the grants of the National Natural Science Foundation of China (31371973 and
31301700), the Natural Science Foundation of Shaanxi Province (No. 2013JQ3003), and the Fundamental Research Funds for
the Central Universities (QN2013009).
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