Synthesis and antifungal activity of 7-methyl-7-hydroxy-2,3-benzo[c]octa-1, 6-olide

Article abstract of DOI:10.1080/10286020.2013.879121

The racemic 7-methyl-7-hydroxy-2,3-benzo[c]octa-1,6-olide, the analog of natural product (6R)-3,7-dimethyl-7-hydroxy-2-octen-1,6-olide, was totally synthesized using easily available (E)-2-(2-carboxyvinyl)benzoic acid as a raw material in nine-step reacti

Full text of DOI:10.1080/10286020.2013.879121

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Synthesis and antifungal activity
of 7-methyl-7-hydroxy-2,3-
benzo[c]octa-1,6-olide
Jin Zhaoa, Hong-Bo Donga, Ming-Yan Yanga, Juan Dua, Jia-Zheng
Jianga & Ming-An Wanga
a Department of Applied Chemistry, College of Sciences, China
Agricultural University, Beijing, 1000193, China
Published online: 23 Jan 2014.
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To cite this article: Jin Zhao, Hong-Bo Dong, Ming-Yan Yang, Juan Du, Jia-Zheng Jiang & Ming-An
Wang (2014) Synthesis and antifungal activity of 7-methyl-7-hydroxy-2,3-benzo[c]octa-1,6-olide,
Journal of Asian Natural Products Research, 16:3, 312-317, DOI: 10.1080/10286020.2013.879121
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Journal of Asian Natural Products Research, 2014
Vol. 16, No. 3, 312–317, http://dx.doi.org/10.1080/10286020.2013.879121
Synthesis and antifungal activity of 7-methyl-7-hydroxy-2,3-
benzo[c]octa-1,6-olide
Jin Zhao, Hong-Bo Dong, Ming-Yan Yang, Juan Du, Jia-Zheng Jiang and
Ming-An Wang*
Department of Applied Chemistry, College of Sciences, China Agricultural University, Beijing
1000193, China
(Received 20 October 2013; final version received 22 December 2013)
The racemic 7-methyl-7-hydroxy-2,3-benzo[c]octa-1,6-olide, the analog of natural
product (6R)-3,7-dimethyl-7-hydroxy-2-octen-1,6-olide, was totally synthesized using
easily available (E)-2-(2-carboxyvinyl)benzoic acid as a raw material in nine-step
reactions including three key steps of Wittig reaction, epoxidation, and cyclization,
with an overall yield of 10.3%. The bioassay results showed that (^)-2 exhibited
stronger antifungal activity than the natural product (^)-1 and (R)-1 against Alternaria
solani with an EC50 value of 27.36 mg/ml.
Keywords: 7-methyl-7-hydroxy-2,3-benzo[c]octa-1,6-olide; total synthesis; lactoni-
zation of epoxy carboxylic acid; antifungal activity
1. Introduction
pyrethroid insecticides. We hoped to
(6R)-3,7-Dimethyl-7-hydroxy-2-octen-6-
olide (1) was an unique natural product
with seven-membered lactone which was
first isolated from the honey bee fungal
entomopathogen Ascosphaera apis [1] as
well as the fruit of plant Litsea cubeba in
Tibet [2], and exhibited good antifungal
and antioxidant activities. In order to
compare the antifungal activity differ-
ences against phytopathogens, the race-
mate of 3,7-dimethyl-7-hydroxy-2-octen-
6-olide was totally synthesized via lacto-
nization of epoxy carboxylic acid as a
synthetic strategy [3], and (6R) and (6S)
isomers were totally synthesized via
Sharpless asymmetry dihydroxylation
and acid-catalyzed cyclization as the key
steps [4]. Their photostabilities were
problem due to the double bond in the
molecule, and the structure needs to be
modified to enhance the activity and
stability such as in the development of
replace the double bond with a benzene
ring, and the novel aromatic analog 2 was
designed and could meet the requirements,
and have more possibility to modify the
structure in the future. Due to target
molecule (2) having a very unique
structure of a seven-membered lactone
ring with an isopropanol side chain, the
several protocols including oxidative
lactonization (Scheme 1), Baeyer–Villi-
ger oxidation (Scheme 1), the palladium-
catalyzed carbonylative annulation of
internal alkynes, the ring-closing metath-
esis synthesis of unsaturated lactones, and
enzymatic synthesis were not suitable for
synthesis [5–11]. In this paper, we choose
easily available (E)-2-(2-carboxyvinyl)
benzoic acid as the starting material and
synthesized the racemic title compound 2
through nine-step reactions with overall
yields of 10.3% (Scheme 2), and its
antifungal activity was evaluated.
*Corresponding author. Email: wangma@cau.edu.cn
q 2014 Taylor & Francis

Journal of Asian Natural Products Research
313
O
O
O
O
O
O
OH
OH
O
[O]
O
B-V
+
O
O
O
[O]
O
OH
OH
O
+
OH
1
Scheme 1. Synthetic methods of benzoxepinone isomers [10,11] and structure of 1.
2. Results and discussion
give alcohol 6, which was further
esterified with methanol in the presence
of concentrated H2SO4 at reflux tempera-
ture to afford alcohol 7 in 68% yield
along with 10% byproduct of lactone 7a
(Scheme 2). Then alcohol 7 was con-
verted into bromide 7b, which could not
be efficiently transferred into the Wittig
reagent 7c in various conditions due to
the hindrance of ortho ester group in the
benzene ring (Scheme 3), so our work of
trying to prepare olefin 9 via the Wittig
reaction of acetone and the Wittig
reagent 7c was unsuccessful.
After that, the alcohol 7 was oxidized
into aldehyde 8, which could react with
the Wittig reagent 8a to produce olefin 9
in 62% yield. The olefin 9 was readily
hydrolyzed into the benzoic acid 10. The
benzoic acid 10 was epoxidized with
Lactonization of epoxy carboxylic acid
was selected as the synthetic strategy as
we did in the previous paper [3], and the
olefins 9 or 10 were the key intermedi-
ates. Based on the retro-synthesis anal-
ysis and the protocol in the reference
[12], the (E)-2-(2-carboxyvinyl) benzoic
acid was selected as the starting material
and transferred into compound 4 in
PdCl2 –HCO2H–NaOH system in 95%
yield, and the catalyst PdCl2 was
recovered and re-used five times without
yield decreasing. The monoester 5 could
be prepared via 4 and methanol in the
presence of concentrated H2SO4 at
ambient temperature in 87% yield with
about 8% byproduct of diester 5a
(Scheme 2). The monoester 5 was
selectively reduced by LiBH4 to
CO2R
CH2OH
R = H
7 R = CH3
O2CH3C
CHO
CO2H
CO2H
c
e
a
CO2R
6
CO2H
8
d
4
R = H
b
3
5 R = CH3
O
CO2R
CO2H
O
f
h
i
OH
O
9
R = CH3
10 R = H
g
11
(+/–) –2
Scheme 2. Synthetic route of racemic compound 2. Reaction conditions: (a) PdCl2, HCO2H,
NaOH, 658C; (b) CH3OH, H2SO4, r.t.; (c) N2, LiBH4,1008C; (d) CH3OH, H2SO4; (e) PCC, CH2Cl2,
r.t.; (f) N2, n-BuLi, Ph3PCH(CH3)2Br; (g) NaOH, reflux; (h) AcO2H, r.t.; (i) CSA, r.t.

314
J. Zhao et al.
O
CO2CH3
CO2CH3
CH2PPh3
CO2CH3
CO2CH3
O
PPh3
8a
CH2Br
5a
7a
7b
7c
Scheme 3. The byproducts and intermediates mentioned in synthesis of compound 2.
peracetic acid to give epoxy benzoic acid
11 without further purification, and it
could be cyclized into the racemic lactone
2 in the presence of catalytic quantity of
camphorsulfonic acid by the novel syn-
thetic strategy of lactonization of epoxy
carboxylic acid [3] (Scheme 2). After the
synthesis of 2 was successfully completed
in this paper, we found that the synthetic
route is still too long and more efficient
approaches were required and used in the
syntheses of the other substituted aromatic
analogs, and the progress was made in our
laboratory.
3.2 General procedure for title
compound 7-methyl-7-hydroxy-2,3-
benzo[c]octa-1,6-olide
3.2.1 Synthesis of 2-(2-carboxyethyl)
benzoic acid (4)
About 484 mg (2.6 mmol, 10 mol%)
of PdCl2, 5.01 g (E)-2-(2-carboxyvinyl)
of benzoic acid 3 (26.1 mmol), 300 ml of
2.5 mol/l NaOH solution, and 4.0 ml of
formic acid (104mmol, 4.0 equiv.) were
added into a 500-ml flask, stirred, and
heated to 658C for 24h. After removal of
the catalyst, the mother liquid was
extracted with diethyl ether. The water
phase was acidified carefully with HCl to
pH 1–2, and the precipitate was filtered.
The mother liquid was re-extracted with
AcOEt and the solvent was removed in
vacuo. The solid was combined and
re-crystallized with alcohol to give a white
solid 4.91g, yield 95%, m.p. 164–1668C
(167–1698C [12]). 1H NMR (300MHz,
DMSO-d6) d: 2.54 (t, J ¼ 6.9 Hz, 2H), 3.12
(t, J ¼ 6.9 Hz, 2H), 7.28–7.35 (m, 2H),
7.44–7.45 (m, 1H), 7.79–7.81 (m, 1H),
12.50 (br, 2H).
The preliminary bioassay showed that
the (^)-2, (^)-1, and (R)-1 exhibited
good antifungal activity against Alternaria
solani with EC50 values of 27.36, 50.48,
and 42.20 mg/ml [13], respectively. These
results indicated that compound 2 had
stronger antifungal activity than the
natural compound 1.
3. Experimental
3.1 General experimental procedures
Melting points were measured on a
Yanagimoto apparatus (Yanagimoto MFG
Co., Kyoto, Japan) and are uncorrected.
1H and 13C NMR spectra were
recorded on a Bru¨ker DPX 300 NMR
Spectrometer (Bru¨ker Biospin Co., Stutt-
gart, Germany) with CDCl3 as the solvent
and tetramethylsilane as the internal
standard. HR-MS were obtained on a
Bru¨ker Apex II mass spectrometer
(Bru¨ker Co., Bremen, Germany) using
nitrobenzoyl alcohol and sodium
chloride as matrices. The solvents were
analytical grade and newly distilled
before usage.
3.2.2 Synthesis of 2-(2-carboxyethyl)
benzoic acid monoester (5)
About 10.01 g (51.6 mmol) of 4, 150 ml of
MeOH, and 2 ml of 98% H2SO4 were added
into a 250-ml flask and stirred for 2 h at
ambient temperature. Then the solvent was
removed, and 20ml of water and 40 ml of
1.0 mol/l NaOH solution were added. The
obtained mixture was stirred and adjusted
to pH 8–9 with the saturated NaHCO3
solution. The solution was extracted with
diethyl ether, and the organic phase was

Journal of Asian Natural Products Research
315
dried. The byproduct 5a was obtained as a
1
little yellow liquid in 8% yield. H NMR
stirred and heated to reflux for 36h. Cooling
to room temperature, the solvent was
removed, and 20ml of water and 40ml of
1.0 mol/l NaOH solution were added. The
solution was stirred and adjusted to pH 8–9
with the saturated NaHCO3 solution. Then
the solution was extracted with AcOEt, the
organic phase was dried over MgSO4, and
the solvent was removed. The residue was
chromatographed on a silica gel column and
washed with petroleum ether–AcOEt (20:1,
0.8% AcOH) to give a colorless oily liquid
7a (0.89 g), yield 18%. 1H NMR (300MHz,
CDCl3) d: 2.04–2.17 (m, 2H), 2.90 (t,
J ¼ 7.2 Hz, 2H), 4.16 (t, J ¼ 6.3 Hz, 2H),
7.20–7.27 (m, 1H), 7.34–7.39 (m, 1H),
7.46–7.51 (m, 1H), 7.71–7.73 (m, 1H). The
residue was continued to wash and afforded
a colorless oily liquid 7 (3.78 g), yield 68%.
1H NMR (300MHz, CDCl3) d: 1.85–1.94
(m, 2H), 2.71 (s, 1H), 3.05 (t, J ¼ 7.2 Hz,
2H), 3.61 (t, J ¼ 6.0 Hz, 2H), 3.88 (s, 3H),
7.21–7.28 (m, 2H), 7.39–7.45 (m, 1H),
7.85–7.88 (m, 1H), identical to those in Ref.
[14].
(300 MHz, CDCl3) d: 2.68 (t, J ¼ 6.9 Hz,
2H), 3.26 (t, J ¼ 6.9 Hz, 2H), 3.65 (s,
3H), 3.89 (s, 3H), 7.24–7.29 (m, 2H),
7.40–7.45 (m, 1H), 7.89–7.92 (m, 1H).
Then the water phase was acidified
carefully with HCl to pH 1–2, and the
precipitate appeared and was filtered. The
solid was dried to give a white solid 5
(9.37 g), yield 87%, m.p. 79–828C (79–
1
818C [12]). H NMR (300 MHz, CDCl3)
d: 2.72 (t, J ¼ 7.5 Hz, 2H), 3.36
(t, J ¼ 7.5 Hz, 2H), 3.68 (s, 3H), 7.26–
7.32 (m, 2H), 7.47–7.52 (m, 1H), 8.07–
8.10 (m, 1H), 12.00 (br, 1H).
3.2.3 Synthesis of 2-(3-hydroxypropyl)
benzoic acid (6)
Under the N2 atmosphere, 75 ml of 1,4-
dioxane and 2.36 g of LiBH4 were added
into a 250-ml flask, stirred 2 h at ambient
temperature, and then 7.45 g (35.8 mmol) of
5 solution in 1,4-dioxane was dropped in
30 min. After this, the flask was heated to
1008C for 6 h in an oil bath. Then the solvent
was removed and the residue was poured
into 100 g of ice water. The solution was
carefully adjusted to pH 9–10 with the
saturated NaOH solution. The solution was
extracted with diethyl ether and the organic
phase was casted out. The water phase was
acidified carefully with HCl to pH 1–2. The
solution was re-extracted with AcOEt, and
the organic phase was dried over MgSO4
and the solvent was removed in vacuo to
afford a white solid 6 (5.17 g), yield 80%,
3.2.5 Synthesis of methyl 2-(3-
bromopropyl) benzoate (7b)
About 300 mg (1.4mmol) of 7, 570 mg
(2.1mmol, 1.5 equiv.) of PBr3, 25ml of
diethyl ether, and five drops of pyridine
were added into a 50-ml flask. The solution
was stirred and heated to reflux for 24h.
The solid was filtered and the solvent was
removed, then 50ml of CH2Cl2 was added
and the solution was washed with saturated
NaHCO3 and NaCl solutions. The organic
phase was dried over MgSO4 and evapor-
ated under reduced pressure. The residue
was chromatographed on a silica gel
column and washed with petroleum
ether–AcOEt (15:1) to give a colorless
oily liquid 7b (250 mg), yield 52%. 1H
NMR (300MHz, CDCl3) d: 2.12–2.21 (m,
2H), 3.09 (t, J ¼ 7.5 Hz, 2H), 3.42 (t,
J ¼ 6.9 Hz, 2H), 3.87 (s, 3H), 7.22–7.28
(m, 2H), 7.39–7.44 (m, 1H), 7.88–7.91 (m,
1H), identical to those in Ref. [15].
1
m.p. 55–588C (55–658C [12]). H NMR
(300 MHz, CDCl3) d: 1.90–1.99 (m, 2H),
3.08–3.15 (m, 2H), 3.68 (t, J ¼ 6.0 Hz, 2H),
4.52 (s, 1H), 7.27–7.32 (m, 2H), 7.44–7.51
(m, 1H), 7.99–8.06 (m, 1H), 12.14 (br, 1H).
3.2.4 Synthesis of methyl 2-(3-
hydroxypropyl) benzoate (7)
About 5.17g (51.6 mmol) of 6, 100 ml of
MeOH, and 2 ml of 98% H2SO4 were added
into a 250-ml flask, and the mixture was

316
J. Zhao et al.
3.2.6 Synthesis of methyl 2-(3-
oxopropyl) benzoate (8)
130.4, 131.0, 131.7, 132.1, 143.9, 168.2.
HR-ESI-MS m/z: 219.1380 [M þ H]þ
(calcd for C14H19O2, 219.1379).
About 571 mg (2.65 mmol) of PCC, 1.5 g
of silica gel, and 20 ml of CH2Cl2 were
added into a 50-ml flask. The mixture was
stirred and the solution of 343 mg
(1.77 mmol) of 7 in 15 ml of CH2Cl2 was
dropped. After that, the solution was stirred
at ambient temperature overnight, the
solvent was removed, and the residue was
chromatographed on a silica gel column
and washed with petroleum ether–AcOEt
(20:1, 15:1, 10:1) to give a colorless oily
3.2.8 Synthesis of 2-(4-methyl-3-penten-
1-yl) benzoic acid (10)
About 280 mg (1.28 mmol) of 9, 0.5 g of
NaOH, 10 ml of water, and 15 ml of
methanol were added into a 50-ml flask.
The solution was stirred and heated to
reflux for 12 h, the solvent was removed
and 20 ml of water was added, and then
extracted with diethyl ether. The water
phase was adjusted to pH 1–2 with HCl
solution and extracted with AcOEt. The
organic phase was dried over MgSO4 and
the solvent was removed. The residue was
chromatographed on a silica gel column
and washed with petroleum ether–AcOEt
(100:1, 0.5% AcOH) to give a white solid
10 (165 mg), yield 85%, m.p. 61–638C.
IR vmax (cm21): 2924, 2641, 1694, 1269,
1
liquid 8 (285 mg), yield 84%. H NMR
(300 MHz, CDCl3) d: 2.78–2.84 (m, 2H),
3.27 (t, J ¼ 7.5 Hz, 2H), 3.89 (s, 3H),
7.25–7.31 (m, 2H), 7.41–7.44 (m, 1H),
7.91–7.94 (m, 1H), 9.82 (brs, 1H),
identical to those in Ref. [16].
3.2.7 Synthesis of methyl 2-(4-methyl-3-
penten-1-yl) benzoate (9)
1
920, 747, 702, 659. H NMR (300 MHz,
Under N2 atmosphere, 859 mg 8a
(2.25 mmol, 1.5 equiv.), which was pre-
pared following the procedure in Ref. [16],
was added into a 100-ml flask. The flask
was sealed, and 50 ml of diethyl ether
was injected. The mixture was cooled to
2108C. Then 0.75 ml of 2.5 mol/l n-BuLi
solution was injected, and the solution was
stirred 1 h at ambient temperature. The
solution of 286 mg (1.49 mmol) of 8 in
10 ml of diethyl ether was added by
injection, and the mixture was stirred 3 h
at ambient temperature. The solvent was
removed and the residue was chromato-
graphed on a silica gel column, washed
with petroleum ether–AcOEt (40:1, 30:1,
20:1) to give a colorless oily liquid 9
(135 mg), yield 62%. IR vmax (cm21):
2926, 1725, 1601, 1434, 1258, 1080, 752,
CDCl3) d: 1.54 (s, 3H), 1.69 (s, 3H),
2.28–2.35 (m, 2H), 3.06 (t, J ¼ 7.5 Hz,
3H), 5.21 (m, 1H), 7.26–7.31 (m, 2H),
7.44–7.50 (m, 1H), 8.02–8.05 (m, 1H).
13C NMR (75 MHz, CDCl3) d: 17.4,
25.7, 30.3, 34.7, 123.7, 125.9, 128.3,
131.4, 131.6, 132.4, 132.8, 145.2, 173.4.
HR-ESI-MS m/z: 205.1222 [M þ H]þ
(calcd for C13H17O2, 205.1223).
3.2.9 Synthesis of racemic 7-methyl-7-
hydroxy-2,3-benzo[c]octa-1,6-olide (R,S-2)
About 3.06g (15 mmol) of 10 and 75ml of
CH2Cl2 were added into a 250-ml flask. The
solution was stirred and 10ml of peracetic
acid solution was added, and 3.3g of
Na2CO3 was added three times in 15min
interval. After 2 h, the solution was adjusted
to pH 5–6 with the diluted HCl solution and
extracted with CH2Cl2. The organic phase
was dried over MgSO4 and the solvent was
removed to afford 11 without further
purification. Then acid 11 was dissolved in
75mlofCH2Cl2 ina150-mlflask,200 mgof
camphorsulfonic acid was added, and the
1
710. H NMR (300 MHz, CDCl3) d: 1.51
(s, 3H), 1.67 (s, 3H), 2.24–2.32 (m, 2H),
2.97 (t, J ¼ 7.5 Hz, 2H), 3.88 (s, 3H), 5.18
(t, J ¼ 7.0 Hz, 1H), 7.20–7.25 (m, 2H),
7.37–7.43 (m, 1H), 7.83–7.86 (m, 1H).
13C NMR (75 MHz, CDCl3) d: 17.5, 25.6,
30.2, 34.4, 51.8, 123.7, 125.7, 129.7,

Journal of Asian Natural Products Research
mixture was stirred overnight at ambient References
317
temperature. The solution was washed with
saturated NaHCO3 and NaCl solutions. The
organic phase was dried over MgSO4 and
the solvent was removed. The residue was
chromatographed on a silica gel column and
washed with petroleum ether–AcOEt (20:1,
12:1, 8:1) to afford a colorless oily liquid 2
(1.72 g), yield 52% for two steps. IR vmax
(cm21): 3417, 2973, 1715, 1455, 1299, 942,
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1
757, 641. H NMR (300MHz, CDCl3) d:
1.25 (s, 6H), 1.92–2.01 (m, 1H), 2.25–2.36
(m, 1H), 2.77–2.84 (m, 1H), 2.89–2.96 (m,
1H), 3.87 (dd, J ¼ 13.5, 4.8 Hz, 1H), 7.21–
7.28(m, 1H),7.35–7.40(m, 1H),7.46–7.52
(m, 1H), 7.71–7.74 (m, 1H). 13C NMR
(75 MHz, CDCl3) d: 24.3, 26.2, 28.5, 29.5,
71.6, 84.2, 127.3,128.6, 130.1, 131.3,132.7,
138.2, 171.2. HR-ESI-MS m/z: 221.1172
[M þ H]þ (calcd for C13H17O3, 221.1172).
In summary, the racemic 7-methyl-7-
hydroxy-2,3-benzo[c]octa-1,6-olide (2)
was synthesized through nine-step reac-
tions with an overall yield of 10.3%.
The (^)-2 exhibited stronger antifungal
activity against A. solani with an EC50
value of 27.36 mg/ml than the natural
product (^)-1 and (R)-1 with EC50 values
of 50.48 and 42.20 mg/ml, respectively.
[14] T. Morimoto, M. Fujioka, K. Fuji, K.
Tsutsumi, and K. Kakiuchi, J. Organomet.
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Acknowledgments
This project was co-founded by the National
Key Technologies R&D Program (No.
2011BAE06B04), Natural Science Foundation
of China (No. 21172254), National Hi-Tech
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