5-(2,2-Dimethyl-4H-1,3-benzodioxin) methanol: The synthetic precursor to o-formylm- hydroxycinnamic acid, the most oxidized salicylaldehyde-type phytotoxin isolated from rice blast fungus, Magnaporthe grisea

Article abstract of DOI:10.1515/hc-2014-0053

o-Formyl-m-hydroxycinnamic acid, the most oxidized salicylaldehyde-type phytotoxin isolated from rice blast fungus, Magnaporthe grisea, was synthesized for the first time using 5-(2,2-dimethyl-4H-1,3-benzodioxin) methanol as the starting material, and the

Full text of DOI:10.1515/hc-2014-0053

Heterocycl. Commun. 2014; 20(3): 185–188
Akihito Saito, Konosuke Hiramatsu, Hai-Qun Cao, Yuta Nagashima, Koji Tanaka,
A5y-a(ka2S,a2sa-kDi, TiemikoeYatmhadyal,-S4higHef-um1,i K3u-wbahearna,zMoandabiuoNxukiinna)and Hiromasa Kiyota*
methanol: the synthetic precursor to o-formyl-
m-hydroxycinnamic acid, the most oxidized
salicylaldehyde-type phytotoxin isolated from
rice blast fungus, Magnaporthe grisea
Abstract: o-Formyl-m-hydroxycinnamic acid, the most (3) [3], pyriculone (4) [4], and pyricuol (5) [5], have been
oxidized salicylaldehyde-type phytotoxin isolated from isolated from the fungus as suspicious compounds
rice blast fungus, Magnaporthe grisea, was synthesized responsible for the disease; they induce dark necrotic
for the first time using 5-(2,2-dimethyl-4H-1,3-benzodi- spot, when being applied to wounded rice leaves. In
oxin)methanol as the starting material, and the proposed addition, o-formyl-m-hydroxycinnamic acid (6), prob-
structure was confirmed.
ably further oxidized compound derived from 4, has
also been found in the culture extract of the fungus [6]
Keywords: Magnaporthe grisea; phytotoxins; pyriculone; (Scheme 1). We have reported the synthesis of the deriv-
rice blast fungus; synthesis.
atives 1–3, 5 using a common intermediate, 5-(2,2-dime-
thyl-4H-1,3-benzodioxin)methanol (7) (Scheme 2) [7–10].
In continuation of our synthetic studies of these com-
pounds [7–13], the most oxidized derivative 6 was pre-
pared for the first time from 7. Isolation and synthesis
of o-carboxy-m-hydroxycinnamic acid, the related phy-
totoxin from other sources, has been reported [14–16].
Details of the synthesis are described in this report.
DOI 10.1515/hc-2014-0053
Received March 24, 2014; accepted March 31, 2014; previously pub-
lished online May 12, 2014
Introduction
Rice blast disease, caused by infection of rice blast
fungus, Magnaporthe grisea (Hebert) Barr, is one of the Results and discussion
most harmful diseases for rice [1]. Several salicylalde-
hyde derivatives, such as pyriculol (2) [2], pyriculariol We have already reported the preparation of compounds
with the same carbon skeleton as 6, as intermediates
towards the synthesis of pyricuol (5) [9, 10]. Thus, we
chose the intermediate 7 as the starting material. Partial
*Corresponding author: Hiromasa Kiyota, Graduate School
of Environmental and Life Science, Okayama University, 1-1-1
Tsushima-Naka, Kita, Okayama 700-8530, Japan,
oxidation of 7 and the Horner-Wadsworth-Emmons reac-
tion afforded ester 8, which was then reduced to give
aldehyde 9 according to our procedure [10] (Scheme 3).
At first, the aldehyde 9 was oxidized with Jones reagent
to give acid 10, and then the acetonide protecting group
was removed under acidic conditions. However, the
resulting dihydroxy acid 11 could barely be purified
because of its high hydrophilicity. Thus, we restarted
the synthesis from the ester 8, and the acetonide group
was removed under acidic conditions. The desired diol
12 was obtained as a colorless oil after silica gel purifi-
cation in 45% yield. Then, the alcoholic hydroxy group
e-mail: kiyota@okayama-u.ac.jp
Akihito Saito, Konosuke Hiramatsu, Yuta Nagashima, Koji Tanaka,
Ayaka Sasaki, Teiko Yamada and Shigefumi Kuwahara: Graduate
School of Agricultural Science, Tohoku University, Tohoku, Japan
Hai-Qun Cao: Graduate School of Agricultural Science, Tohoku
University, Tohoku, Japan; Graduate School of Environmental
and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita,
Okayama 700-8530, Japan; and School of Plant Protection, Anhui
Agricultural University, Hefei, Anhui Province, 230036, P.R. China
Manabu Nukina: Faculty of Agriculture, Yamagata University,
Yamagata, Japan

ꢀꢀꢀꢁ
186ꢀ
ꢀA. Saito et al.: Synthesis of o-formyl-m-hydroxycinnamic acid
acetyl CoA
biogenetic
precursor 1
OH
O
OH
OH
OH
OH
OH
( )-pyriculariol (3)
(+)-pyriculol (2)
(-)-pyricuol (5)
O
OH
O
OH
OH
O
oxidation
O
O
oxidation
OH
O
o-formyl-m-hydroxycinnamic
acid (6)
pyriculone (4)
OH
O
OH
O
Scheme 1ꢂBiogenetic pathways of salicylaldehyde-type phytotoxin isolated from rice blast fungus.
OH
was oxidized using MnO2 in DMSO/CHCl3 [10] to give
aldehyde 13 in 97% yield. The alkaline hydrolysis of the
ester group was examined. The use of K2CO3 or KOH in
EtOH/H2O resulted in a complex mixture. Finally, we
found that LiOH in EtOH/H2O was the best choice that
afforded the target compound 6 as colorless needles
(mp 132–133°C) in 59% yield. The overall yield was 26%
from 8. The 1H NMR spectra of the natural product 6 and
synthetic compound 6 were virtually identical.
ref. [7]
O
O
OH
2,3-dimethylphenol
5-(2,2-dimethyl-4H-1,3-
benzodioxin)methanol (7)
Refs. [7–10]
1, 2, 3, 5
Scheme 2ꢂ5-(2,2-Dimethyl-4H-1,3-benzodioxin)methanol (7) as the
key synthetic intermediate for the synthesis of the phytotoxins.
OH
O
O
O
O
Jones
OH
OEt
Refs. [7, 10]
Refs. [10]
oxidation
7
8
9
10
O
O
O
O
O
O
O
TsOH, THF/H2O
rt, 3 d (45%)
hydrolysis
O
O
OH
OEt
12
11
OH OH
OH OH
MnO2, CHCl3/DMSO
rt, 5 h (97%)
O
O
LiOH, THF/H2O
0°C, 5 h (59%)
OEt
OH
13
OH
O
OH O
o-formyl-m-hydroxycinnamic
acid (6)
Scheme 3ꢂSynthesis of o-formyl-m-hydroxycinnamic acid (6).

ꢁꢀꢀꢀ
A. Saito et al.: Synthesis of o-formyl-m-hydroxycinnamic acidꢂ
ꢂ187
(1H, d, J ꢀ= ꢀ 15.8 Hz), 4.26 (2H, q, J ꢀ= ꢀ 7.2 Hz, CH2CH3), 1.34 (3H, t, J ꢀ= ꢀ 7. 2
Hz, CH2CH3). HR-EIMS. Calcd for C12H12O4 (M+.): m/z 220.0736. Found:
m/z 220.0736.
Conclusion
o-Formyl-m-hydroxycinnamic acid, the most oxidized
salicylaldehyde-type phytotoxin isolated from rice blast
fungus, Magnaporthe grisea, was successfully synthe-
sized for the first time using 5-(2,2-dimethyl-4H-1,3-benzo-
dioxin)methanol as the starting material.
(E)-3-(2′-Formyl-3′-hydroxyphenyl)ethenoic acid [(E)-o-
formyl-m-hydroxycinnnamic acid] 5
A solution of 13 (20.0 mg, 0.091 mmol) and LiOHꢀ× ꢀH2O (40.8 mg, 0.972
mmol) in THF/H2O (3:1, 2 mL) was stirred at 0°C for 5 h. The solu-
tion was neutralized with citric acid and the mixture extracted with
CH2Cl2. The combined organic layer was concentrated in vacuo. The
residue was chromatographed on silica gel (CHCl3/MeOH, 15:1) and
crystallized from hexane/EtOAc to give 6 (10.2 mg, 0.053 mmol, 59%)
as colorless needles; mp 132–133°C; Rf ꢀ= ꢀ 0.18 (CHCl3/MeOH, 15:1); IR:
ν 3400 (br. s, O–H), 2948 (m), 2833 (w), 1653 (w), 1449 (w), 1021 (s)
cm-1; 1H NMR (CD3OD, 400 MHz): δ 10.46 (1H, s, HCꢀ= ꢀO), 8.31 (1H, d, J ꢀ= ꢀ
15.7 Hz, H-2), 7.54 (1H, t, J ꢀ= ꢀ 8 Hz, H-5′), 7.17 (1H, d, J ꢀ= ꢀ 8 Hz), 6.99 (1H,
d, J ꢀ= ꢀ 8 Hz), 6.39 (1H, d, J ꢀ= ꢀ 15.7 Hz, H-3); 1H NMR (CDCl3, 400 MHz):
δ 11.92 (1H, s, HCꢀ= ꢀO), 10.39 (1H, s, OH), 8.31 (1H, d, J ꢀ= ꢀ 15.8 Hz, H-3′),
7.54 (1H, t, J ꢀ= ꢀ 8 Hz, H-5′), 7.09 (1H, d, J ꢀ= ꢀ 8 Hz), 7.05 (1H, d, J ꢀ= ꢀ 8 Hz),
6.40 (1H, d, J ꢀ= ꢀ 15.7 Hz). HR-FABMS. Calcd for C10H7O4 ([M–H]–): m/z
191.0344. Found: m/z 191.0341.
Experimental
General
Melting point was measured on a Yanako MP-J3 instrument and is
uncorrected. FT-IR spectra were recorded as films by a Jasco 4100
spectrometer (ATR, Zn-Se). 1H NMR spectra were recorded with a Var-
ian 400 MR (400 MHz) spectrometer in CDCl3 with CHCl3 (δH 7.26 ppm)
or CD3OD with CD3OH (δH 3.30 ppm) as internal standard. Mass spec-
tra were recorded with a Jeol JMS-700 spectrometer. Merck silica gel
60 (70–230 mesh) was used for column chromatography. Merck silica
gel 60 F254 (0.25 mm thickness) was used for TLC analysis.
Acknowledgments: Financial support by grant-in-aid from
Ethyl (E)-3-(3′-hydroxy-2′-hydroxymethylphenyl)ethenoate JSPS KAKENHI (numbers 17580092, 19580120, 22560112,
(12)
and 25450144), the Agricultural Chemical Research Foun-
dation, Intelligent Cosmos Foundation, and the Naito
Foundation are gratefully acknowledged.
A solution of 8 [9, 10] (82.0 mg, 0.31 mmol) and p-TsOHꢀ× ꢀH2O (21.0
mg, mmol) in THF/H2O (ca. 1 mL) was stirred at room temperature for
3 days and then treated with a saturated aqueous solution of NaHCO3.
The resulting mixture was extracted with EtOAc. The organic layer
was washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was chromatographed on silica gel (hexane/EtOAc, 3:1)
to give 12 (31.1 mg, 0.14 mmol, 45%) as a colorless oil; Rf ꢀ= ꢀ 0.16 (hex-
ane/EtOAc, 1:1); IR: ν 3450 (br. s, O–H), 2924 (m), 2854 (w), 1701 (w,
Cꢀ= ꢀO), 1640 (w), 1019 (s, C–O), 953 (m) cm-1; 1H NMR (CDCl3, 400 MHz):
δ 7.90 (1H, d, J ꢀ= ꢀ 15.6 Hz, H-3), 7.70 (1H, s, ArOH), 7.22 (1H, pseudo t,
J ꢀ= ꢀ 8.0 Hz, H-5′), 7.08 (1H, d, J ꢀ= ꢀ 8 Hz), 6.93 (1H, d, J ꢀ= ꢀ 8 Hz), 6.30
(1H, d, J ꢀ= ꢀ 15.6 Hz, H-2), 5.08 (2H, d, J ꢀ= ꢀ 5 Hz, CH2OH), 4.26 (2H, q, J ꢀ= ꢀ
7 Hz, CH2CH3), 2.24 (1H, br., CH2OH), 1.34 (3H, t, J ꢀ= ꢀ 7 Hz, CH2CH3).
HR-FABMS. Calcd for C12H12O4Na ([M+Na]+): m/z 245.0789. Found: m/z
245.0792.
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