Concise Synthesis of Natural Phenylphenalenone Phytoalexins and a Regioisomer

Article abstract of DOI:10.1021/acs.jnatprod.7b00709

Concise total syntheses of the natural phytoalexins 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1), 2-hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2), and hydroxyanigorufone (4), together with regioisomer 3 are accomplished in 11 or 12 steps. The synthetic strategy features a Friedel-Crafts acylation to construct the 1H-phenalen-1-one tricyclic core followed by a Suzuki cross-coupling to obtain the target compounds.

Full text of DOI:10.1021/acs.jnatprod.7b00709

Article
pubs.acs.org/jnp
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Concise Synthesis of Natural Phenylphenalenone Phytoalexins and
a Regioisomer
Ming-Zhong Wang,*,†,‡ Chuen-Fai Ku,‡ Tong-Xu Si,† Siu-Wai Tsang,‡ Xiao-Meng Lv,† Xiao-Wan Li,†
Zheng-Ming Li,§ Hong-Jie Zhang,*,‡ and Albert S. C. Chan*,†
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China
‡School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, People’s
Republic of China
§State Key Laboratory of Elemento-organic Chemistry, Research Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: Concise total syntheses of the natural phytoalexins 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1), 2-
hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2), and hydroxyanigorufone (4), together with regioisomer 3 are
accomplished in 11 or 12 steps. The synthetic strategy features a Friedel−Crafts acylation to construct the 1H-phenalen-1-
one tricyclic core followed by a Suzuki cross-coupling to obtain the target compounds.
yield was less than 1.5%, and the final product needed
purification by repeated preparative TLC. This limits the
potential applications of 8-phenylphenalenones in agricultural
or clinical use. In order to provide sufficient amounts of
phenylphenalenones for pharmacological studies as well as for
further structure−activity relationship (SAR) assessments, the
8-phenylphenalenones 1 and 2 with unusual substituted
positions, the 5-phenylphenalenone (3),7 and a 9-phenyl-
phenalenone (4) were selected to develop an efficient synthetic
strategy for phenylphenalenone-type phytoalexins. Herein, we
describe concise and efficient syntheses of 2-hydroxy-8-(4-
hydroxyphenyl)phenalen-1-one (1) and hydroxyanigorufone
(4), the first total synthesis of 2-hydroxy-8-(3,4-
dihydroxyphenyl)phenalen-1-one (2), and a synthesis of the
originally proposed structure of emenolone (3).
hytoalexins are natural antibiotics, and some of them are
Pused as fungicides or templates for the production of new
pesticides involving unique modes of action.1 Phenylphenale-
nones are a class of phytoalexins mainly produced by plants of
the Hemodoraceae, Pontederiaceae, Strelitziaceae, and Musa-
ceae families in response to chemical, physical, or microbial
stress factors.2 Phenylphenalenones are mainly composed of 4-,
6-, 7-, and 9-phenylphenalenones,3 but two 8-phenylphenale-
nones, 1 and 2 (Figure 1), have been isolated from Eichhornia
crassipes by Holscher and Schneider.4
Research by others has led to the synthesis of 4- and 9-
phenylphenalenones2a,5 and 2-hydroxy-8-(4-hydroxyphenyl)-
1H-phenalen-1-one (1).6 The latter synthesis was achieved in
6
̊
11 steps by Otalvaro and co-workers in 2015, but the overall
RESULTS AND DISCUSSION
■
2-Hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1) and 2-
hydroxy-8-(3, 4-dihydroxyphenyl)phenalen-1-one (2) were
synthesized from 8-bromo-2-hydroxy-1H-phenalen-1-one (5)
by Suzuki cross-coupling with their corresponding aryl boronic
acids, while the proposed structure of emenolone (3) was
Received: August 19, 2017
Figure 1. Selected phenylphenalenone compounds of 1−4.
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
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synthesized from cross-coupling of 5-bromo-2-hydroxy-1H-
phenalen-1-one (6) with an arylboronic acid. The intermedi-
ates 5 and 6 were derived from enones 7 and 8 via a Yang−
Finnegan epoxidation/ring-opening/proton migration process
between C-2 and C-3.
Inspired by Echeverri’s work on the syntheses of
perinaphthenone,2a compounds 7−9 were prepared directly
from 10−12 in one pot using the Friedel−Crafts acylation
reaction. The (E)-3-(naphthalen-1-yl)acrylic acid derivatives
10−12 were synthesized by reaction of naphthaldehydes 13−
15 with carbethoxymethyl-triphenylphosphonium bromide in a
Wittig reaction, followed by hydrolysis and acidification
(Figure 2). Although 6-bromo-1-naphthaldehyde (13) is a
by oxidation with Dess-Martin periodinane to afford 13 in 79%
yield (33% overall yield from 13a).
Compound 13 was converted to the key intermediate 10 by
reaction with carbethoxymethyl-triphenylphosphonium bro-
mide, followed by hydrolysis and acidification. With a sufficient
amount of 10, the focus was turned to the key Friedel−Crafts
acylation reaction to construct the phenalenone tricyclic core
of 8-bromo-1H-phenalen-1-one (7). Successive treatment of
10 with oxalyl chloride/DMF/CH2Cl2 and AlCl3/CH2Cl2 gave
7 in 61% yield, which underwent a Δ2(3) Yang−Finnegan
epoxidation/ring-opening/proton migration reaction to afford
8-bromo-2-hydroxy-1H-phenalen-1-one (5, Scheme 2).
Finally, the reaction of 5 with potassium 4-hydroxyphenyl-
trifluoroborate10 through a Suzuki cross-coupling reaction
afforded 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1) in
78% yield (Scheme 3). Using the same procedure, 2-hydroxy-
8-(3,4-dihydroxyphenyl)phenalen-1-one (2) was synthesized
in 70% yield (two steps) via reaction of 5 with (3,4-
dimethoxyphenyl)boronic acid followed by deprotection of
the methoxy groups (Scheme 3). The physical and
spectroscopic data of the synthesized compounds 1 and 2
were identical to the reported data.4
The synthesis of 3 was carried out using benzo[de]-
isochromene-1,3-dione11 as starting material. The tricyclic
core of 5-bromo-1H-phenalen-1-one (8) was synthesized via
the Friedel−Crafts acylation of 11 in a one-pot reaction
1
(Scheme 4). Unsurprisingly, the H NMR spectroscopic data
of 3 in CDCl3 were different from those of hydroxyanigorufone
(4).
Hydroxyanigorufone (4), the structure of emenolone
established by Luis and co-worker, was also synthesized.7b
Although hydroxyanigorufone (4) was first obtained via a
synthetic study in 1978,12 the total yield was low and a 60 h
refluxing under nitrogen protection was required in the final
step. Here, compound 4 was conveniently synthesized starting
from 15 (Scheme 4) or 9 (Scheme 5) by adopting the same
reaction procedure that was used for the synthesis of 3.
Intermediate 17 was synthesized according to a literature
procedure.2a The deprotection step of the methoxy group of
18 was carried out under mild conditions, and a 23.8% overall
yield of hydroxyanigorufone (4) was achieved (from 15,
Schemes 4 and 5).
Figure 2. Retro-synthetic protocol toward 1−3.
known compound, no synthetic method has been reported. We
thus used ethyl 2-(4-bromophenyl)acetate (13a) as the
starting material to synthesize 13. Compound 13a could be
converted to 13b by reacting with tert-butyl acrylate via a
Michael annulation (35 g scale, Scheme 1).
The physical and spectroscopic data (1H NMR, methanol-
1
d4; H NMR, acetone-d6) of synthesized hydroxyanigorufone
(4) are identical to the reported data of hydroxyanigorufo-
ne.3e,13 Furthermore, the 1H NMR spectroscopic data
(CDCl3) of synthesized hydroxyanigorufone (4) were identical
to those reported for emenolone (1H NMR, CDCl3; see
Supporting Information).7a This confirms that emenolone and
hydroxyanigorufone are the same compound.
The synthesized phenylphenalenones were evaluated for
their biological activities against five phytofungal strains,
namely, Alternaria solani, Cercospora arachidicola, Fusarium
omysporum, Gibberella zeae, and Physalospora piricola, and
tobacco mosaic virus (TMV, Nicotiana tabacum L.), and four
human cancer cell lines (HCT-116, HT-29, PANC-1, and PC-
3). Compounds 1−4 and 16−18 did not show significant
antifungal activity. However, compounds 1 and 3 exhibited
more potent antiviral activity than the commercial virucidal
agent ribavirin (Table 1). Analogue 16 was cytotoxic to the
p53-wild-type HCT-116 colon cancer cells (IC50, 5.3 μM) and
PC-3 prostate cancer cells (IC50, 7.8 μM), but not the p53-
mutated HT-29 colon cancer cells or PANC-1 pancreatic
Deprotection of the tert-butyl group of 13b gave the free
acid 13c, which was treated with oxalyl chloride/dimethylfor-
mamide (DMF)/CH2Cl2 and AlCl3/CH2Cl2 to produce
tetrahydronaphthalene 13d in 75% yield. Compound 13d
was subsequently reduced to 13e followed by dehydration to
give 13f and 13g as byproducts (p-Toluenesulfonic acid
(PTSA), catalysis). As previously reported by Tagat,8 several
PTSA conditions were screened for the best yield of 13f.
However, the yields under all tested conditions were less than
13% (a). The Burgess reagent was then utilized, and 13e was
fully consumed to form 13f and a complex mixture (b, no 13g
produced). However, the yields were still low (<22%). Based
on Juby’s work in the synthesis of 1,2,3,4-tetrahydro-1-
naphthoic acids,9 the reduction of 13d with NaBH4 under
basic conditions and acidification afforded 13h, which was
dehydrated with PTSA to give dihydronaphthalene 13i in 74%
yield (Scheme 2). Compound 13i was further dehydrogenated
with DDQ to afford 13j, which was reduced with BH3 followed
B
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Scheme 1. Synthesis of Ethyl 6-Bromo-1,2-dihydronaphthalene-1-carboxylate (13f)
Scheme 2. Synthesis of 8-Bromo-2-hydroxy-1H-phenalen-1-one (5)
cancer cells. The IC50 values of compounds 1−4, 17, and 18
against the four human cell lines were higher than 10 μM.
In summary, a concise and efficient strategy for the total
synthesis of 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one
(1), 2-hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2),
the originally proposed structure of emenolone (3), and
hydroxyanigorufone (4) was developed by starting from their
corresponding naphthaldehydes (13−15) with the application
of Friedel−Crafts acylation and Suzuki cross-coupling as the
key reactions. The observed overall yield of 1 (11%) is much
higher than the reported yield (1.43%).6 This is the first report
of the total synthesis of compounds 2 and 3. The synthetic
protocol is also appropriate for the preparation of other
phenylphenalenone analogues.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Unless otherwise noted,
commercially available reagents were used without further purifica-
tion. All reactions were conducted in oven-dried (120 °C) or flame-
dried glassware under a N2 atmosphere and at ambient temperature
(20 to 25 °C) unless otherwise stated. All solvents were distilled prior
to use: Toluene, tetrahydrofuran (THF), and benzene were distilled
C
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Scheme 3. Synthesis of 2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1) and 2-Hydroxy-8-(3,4-
dihydroxyphenyl)phenalen-1-one (2)
Scheme 4. Synthesis of the Originally Proposed Structure of Emenolone (3)
Scheme 5. Synthesis of Hydroxyanigorufone (4)
from Na/benzophenone, and CH2Cl2, DMF, and Et3N from CaH2.
All nonaqueous reactions were performed under an atmosphere of
nitrogen or argon using oven-dried glassware and standard syringe in
septa techniques. Evaporation and concentration under reduced
pressure was performed at 10−500 mbar. Melting points were
measured with a Stanford Research System (OptiMelt-100). UV
spectra were recorded on a Shimadzu UV-2450 spectrophotometer.
1H NMR spectra were recorded in CDCl3 (unless stated otherwise)
on a Bruker Avance 400 at 400 MHz (13C NMR spectra at 100 MHz).
Chemical shifts are reported as δ values referenced to either
tetramethylsilane or the solvent residual. Mass spectra were measured
on an ABI Q-star Elite. The reaction progress was checked on
precoated TLC plates. TLC was carried out using precoated sheets
(Qingdao silica gel 60-F250, 0.2 mm), which, after development, were
D
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J = 8.2 Hz, 1H, H-7), 7.24 (d, J = 8.2 Hz, 1H, H-6), 4.20 (q, J = 7.2
Hz, 2H, 11-OEt), 3.92 (t, J = 4.8 Hz, 1H, H-4), 2.99−2.86 (m, 1H,
H-3), 2.66−2.60 (m, 1H, H-2), 2.54−2.39 (m, 1H, H-2), 2.39−2.31
(m, 1H, H-3), 1.26 (t, J = 7.2 Hz, 3H, 11-OEt); 13C NMR (100 MHz,
CDCl3) δ 195.7 (C-1), 172.0 (C-11), 139.0 (C-5), 136.3 (C-7), 133.7
(C-10), 131.0 (C-9), 130.3 (C-6), 122.2 (C-8), 61.5 (11-OEt), 44.0
(C-4), 35.3 (C-2), 25.5 (C-3), 14.2 (11-OEt); HRESIMS m/z
318.9935 [M + Na]+, calcd for C13H13BrO3Na, 318.9940.
Table 1. Inactivation, Curative, and Protection Effects of
Compounds 1−4 and Ribavirin against TMV in Vivo at a
Dose of 500 μg/mL
a
b
b
b
compd.
inactivation (%)
curative (%)
protection (%)
1
2
3
4
47.6
31.8
45.4
40.2
39.1
43.1
26.5
42.0
33.5
37.5
49.0
34.2
35.5
36.8
36.0
Ethyl 6-Bromo-1,2-dihydronaphthalene-1-carboxylate
(13f). NaBH4 (1.9 g, 50.0 mmol) was added to a solution of 13d
(5.0 g, 16.9 mmol) in a mixture of H2O (30 mL) and EtOH (30 mL)
in batches within 50 min at 25 °C. The mixture was stirred for 2 h.
The EtOH was removed under vacuum, and the residue extracted
with EtOAc (2 × 50 mL) and H2O (100 mL). The organic phase was
separated and concentrated under vacuum to afford crude 13e (5.1 g,
100% yield) as a colorless oil. PTSA (5.0 mg, 0.03 mmol) was added
to a solution of 13e (0.1 g, 0.3 mmol) in toluene (30 mL), and the
reaction mixture was heated at 80 °C for 2 h. After being cooled to
room temperature, the mixture was concentrated under vacuum and
the residue purified by chromatography (EtOAc/hexanes, 1:10) to
afford 13f (11.0 mg, 12% yield) as a colorless oil and 13g (25.0 mg,
30% yield) as a colorless oil. 13f: UV (MeOH) λmax (log ε) 221
(3.73) nm; 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 8.0, 2.0 Hz,
1H, H-7), 7.20 (d, J = 2.0 Hz, 1H, H-9), 7.05 (d, J = 8.0 Hz, 1H, H-
6), 6.39 (d, J = 9.6 Hz, 1H, H-1), 6.08−6.01 (m, 1H, H-2), 4.14 (q, J
= 7.2, Hz, 2H, 11-OEt), 3.78−3.62 (m, 1H, H-4), 2.91−2.74 (m, 1H,
H-3), 2.62−2.43 (m, 1H, H-3), 1.22 (t, J = 7.2 Hz, 3H, 11-OEt); 13C
NMR (100 MHz, CDCl3) δ 172.0 (C-11), 134.4 (C-10), 129.7 (C-5),
128.8 (C-6/7), 128.0 (C-9), 127.0 (C-2), 125.4 (C-1), 120.3 (C-8),
60.0 (11-OEt), 41.8 (C-4), 24.9 (C-3), 13.1 (11-OEt); HRESIMS m/
z 302.9982 [M + Na]+, calcd for C13H13BrO2Na, 302.9991.
ribavirin
a
The inactivation effects of compounds 16−18 are less than 30.0%,
b
and the curative and protection effects are not detected. The data are
the average of three individual experiments.
visualized under UV light at 254 nm. Flash column chromatography
was performed using the indicated solvents on Qingdao silica gel 60
(230−400 mesh ASTM). Yields refer to chromatographically purified
compounds, unless otherwise stated.
5-tert-Butyl 1-Ethyl 2-(4-bromophenyl)pentanedioate
(13b). To a solution of 13a (35.0 g, 144 mmol) and tert-butyl
acrylate (18.5 g, 144 mmol) in dry THF (100 mL) at 0 °C was added
NaOBut (2.77 g, 28.8 mmol) in batches within 30 min. The reaction
mixture was stirred at 5 °C for 4 h, and the solvent concentrated
under vacuum. The resulting mixture was extracted with EtOAc (2 ×
150 mL) and H2O (200 mL). After separation, the aqueous phase was
abandoned and the organic phase was concentrated under vacuum.
The residue was purified by flash chromatography (EtOAc/hexanes,
1:10) to afford 13b (52.2 g, 98%) as a colorless oil: UV (MeOH) λmax
1
(log ε) 203 (3.74), 224 (3.71) nm; H NMR (400 MHz, CDCl3) δ
7.45 (d, J = 8.0 Hz, 2H, H-7/9), 7.17 (d, J = 8.0 Hz, 2H, H-6/10),
4.17−4.07 (m, 2H, 11-OEt), 3.56 (t, J = 8.0 Hz, 1H, H-4), 2.32−2.25
(m, 1H, H-3), 2.16 (t, J = 8.0 Hz, 2H, H-2), 2.07−2.00 (m, 1H, H-3),
1.43 (s, 9H, 1-OtBu), 1.20 (t, J = 8.0 Hz, 3H, 11-OEt); 13C NMR
(100 MHz, CDCl3) δ 173.1 (C-11), 172.0 (C-1), 137.5 (C-5), 131.8
(C-7/9), 129.7 (C-6/10), 121.4 (C-8), 80.5 (1-OtBu), 61.0 (11-OEt),
50.0 (C-4), 32.9 (C-2), 28.5 (C-3), 28.1 (1-OtBu), 14.1 (11-OEt);
HRESIMS m/z 393.0674 [M + Na]+, calcd for C17H23BrO4Na,
393.0672.
7-Bromo-1,2,3,4-tetrahydro-1,4-(epoxymethano)-
naphthalen-9-one (13g). UV (MeOH) λmax (log ε) 204 (3.61),
1
220 (3.41) nm; H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz,
1H, H-7), 7.47 (s, 1H, H-9), 7.19 (d, J = 8.0 Hz, 1H, H-6), 5.59 (d, J
= 2.8 Hz, 1H, H-1), 3.93 (t, J = 2.8 Hz, 1H, H-4), 2.68−2.32 (m, 1H,
H-2), 2.31−2.03 (m, 1H, H-3), 1.87−1.58 (m, 1H, H-2; 1H, H-3);
13C NMR (100 MHz, CDCl3) δ 172.9 (C-11), 139.1 (C-10), 135.6
(C-5), 131.8 (C-9), 126.3 (C-6), 126.1 (C-7), 121.1 (C-8), 77.0 (C-
1), 43.8 (C-4), 25.8 (C-3), 21.0 (C-2); HRESIMS m/z 268.9820 [M
+ H2O − H]−, calcd for C11H10BrO3, 268.9819.14
4-(4-Bromophenyl)-5-ethoxy-5-oxopentanoic Acid (13c).
Trifluoroacetic acid (50 mL, 670 mmol) was added dropwise to a
solution of 13b (50.0 g, 135 mmol) in CH2Cl2 (100 mL) at 0 °C. The
reaction mixture was allowed to warm to 25 °C and stirred for 12 h,
concentrated under vacuum, and extracted with EtOAc (2 × 150 mL)
and H2O (200 mL). The combined organic phase was dried over
anhydrous Na2SO4 and concentrated under vacuum to give 13c (40.3
g, 95%) as a colorless oil. The residue was used for the next step
without purification. 13c: UV (MeOH) λmax (log ε) 203 (3.67), 224
6-Bromo-1,2-dihydronaphthalene-1-carboxylic Acid (13i).
Compound 13d (8.0 g, 27.0 mmol) was added to a solution of
THF (100 mL) and NaOH (100 mL, 1 mol/L), the mixture stirred
for 1 h at 25 °C, and NaBH4 added in batches over 4 h. Stirring was
continued for 2 h, the mixture cooled to 0 °C with ice water, and the
pH adjusted to <3 with HCl (1 mol/L). The mixture was extracted
with EtOAc (3 × 150 mL), and the combined organic layer dried over
Na2SO4 and concentrated under vacuum to give 13h (6.6 g, 90%).
The residue was used in the next step without purification. PTSA (0.4
g, 2.2 mmol) was added to a solution of 13h (6.0 g, 22.0 mmol) in
toluene (200 mL). The mixture was stirred and refluxed with a
Dean−Stark trap for 12 h. After being cooled to room temperature,
the mixture was concentrated under vacuum, and the residue was
purified by chromatography (EtOAc/hexanes, 1:6) to produce 13i
(4.1 g, 74% yield) as a colorless solid: mp 100−102 °C; UV (MeOH)
λmax (log ε) 226 (2.84) nm; 1H NMR (400 MHz, CDCl3) δ 7.29 (dd,
J = 8.0, 1.6 Hz, 1H, H-7), 7.20 (d, J = 1.6 Hz, 1H, H-9), 7.08 (d, J =
8.0 Hz, 1H, H-6), 6.39 (d, J = 9.6 Hz, 1H, H-1), 6.21−5.85 (m, 1H,
H-2), 3.73 (dd, J = 17.2, 4.4 Hz, 1H, H-4), 2.83 (dt, J = 17.2, 4.4 Hz,
1H, H-3), 2.42−2.67 (m, 1H, H-3); 13C NMR (100 MHz, CDCl3) δ
179.0 (C-11), 135.4 (C-10), 130.2 (C-6), 130.0 (C-7), 129.7 (C-5),
129.1 (C-9), 127.7 (C-2), 126.5 (C-1), 121.8 (C-8), 42.4 (C-4), 25.6
(C-3); HRESIMS m/z 252.9857 [M + H]+, calcd for C11H10BrO2,
252.9859.14
1
(3.64) nm; H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 2H,
H-7/9), 7.17 (d, J = 8.0 Hz, 2H, H-6/10), 4.18−4.08 (m, 2H, 11-
OEt), 3.61−3.58 (m, 1H, H-4), 2.38−2.31 (m, 2H, H-2; 1H, H-3),
2.13−2.06 (m, 1H, H-3), 1.22 (t, J = 8.0 Hz, 3H, 11-OEt); 13C NMR
(100 MHz, CDCl3) δ 178.3 (C-1), 172.9 (C-11), 137.1 (C-5), 131.9
(C-7/9), 129.7 (C-6/10), 121.6 (C-8), 61.2 (11-OEt), 49.9 (C-4),
31.4 (C-2), 27.9 (C-3), 14.0 (11-OEt); HRESIMS m/z 337.0038 [M
+ Na]+, calcd for C13H15BrO4Na, 337.0046.
Ethyl 6-Bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-car-
boxylate (13d). Oxalyl chloride (27 mL, 320 mmol) was added to a
solution of 13c (20.0 g, 63.7 mmol) in CH2Cl2 (200 mL) at 25 °C.
After stirring for 30 min, two drops of DMF was added slowly and
stirring continued for 12 h. Volatiles were removed under vacuum,
and the residue was diluted with fresh CH2Cl2 (200 mL) and cooled
to 0 °C with ice. AlCl3 (17.0 g, 1.2 mmol) was added in batches
within 30 min, and the mixture stirred for 12 h at room temperature.
The mixture was poured slowly onto ice. The aqueous phase was
extracted with CH2Cl2 (2 × 150 mL). The organic phase was
combined and concentrated under vacuum. The residue was purified
by flash chromatography (EtOAc/hexanes, 1:12) to produce 13d
(14.0 g, 75% yield) as a light yellow oil: UV (MeOH) λmax (log ε) 219
(3.83) nm; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H, H-9), 7.63 (d,
6-Bromo-1-naphthoic Acid (13j). 2,3-Dicyano-5,6-dichloroben-
zoquinone (DDQ) (5.4 g, 24.0 mmol) was added to a solution of 13i
(4.0 g, 15.8 mmol) in toluene (15 mL). The mixture was stirred for
12 h at 80 °C and then concentrated under vacuum. The residue was
purified by chromatography (EtOAc/hexanes, 1:7) to afford
E
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compound 13j (3.5 g, 90%) as a gray solid: mp 187−189 °C; UV
purified by chromatography on silica gel (petroleum ether/EtOAc,
9:1) to afford 7 (orange solid, 1.2 g, 61%): mp 177−179 °C; UV
1
(MeOH) λmax (log ε) 229 (3.58), 287 (2.02) nm; H NMR (400
1
MHz, acetone-d6) δ 9.00 (d, J = 8.2 Hz, 1H, H-6), 8.35 (d, J = 7.6 Hz,
1H, H-3), 8.25 (d, J = 2.0 Hz, 1H, H-9), 8.16 (d, J = 8.2 Hz, 1H, H-
1), 7.76 (dd, J = 8.2, 2.0 Hz, 1H, H-7), 7.68 (dd, J = 8.2, 7.6 Hz, 1H,
H-2); 13C NMR (100 MHz, acetone-d6) δ 167.5 (C-11), 135.3 (C-5),
132.5 (C-1), 131.0 (C-7), 130.6 (C-9), 130.4 (C-3), 130.0 (C-10),
128.1 (C-2), 127.2 (C-4), 126.1 (C-6), 119.8 (C-8); HRESIMS m/z
248.9557 [M − H]−, calcd for C11H6BrO2, 248.9557.11
(MeOH) λmax (log ε) 204 (3.75), 255 (3.52), 378 (3.28) nm; H
NMR (400 MHz, CDCl3) δ 8.54 (d, J = 1.6 Hz, 1H, H-9), 8.24 (s,
1H, H-7), 7.85 (d, J = 8.4 Hz, 1H, H-3), 7.74−7.63 (m, 2H, H-4/6),
7.57 (dd, J = 8.0, 7.6 Hz, 1H, H-5), 6.64 (d, J = 8.4 Hz, 1H, H-2); 13C
NMR (100 MHz, CDCl3) δ 184.4 (C-1), 141.8 (C-3), 136.2 (C-4),
133.5 (C-3a), 132.9 (C-7), 131.5 (C-9), 130.8 (C-6), 130.5 (C-9a),
128.9 (C-5), 127.9 (C-6a), 127.7 (C-2), 125.9 (C-9b), 121.5 (C-8);
HRESIMS m/z 280.9574 [M + Na]+, calcd for C13H7BrONa,
280.9572.
6-Bromo-1-naphthaldehyde (13). BH3 (27 mL, 1 mol/L) was
added to a solution of 13j (3.4 g, 13.6 mmol) in dry THF (30 mL) at
0 °C, and the mixture stirred at room temperature for 4 h. The
reaction was quenched with a saturated aqueous solution of NH4Cl
and concentrated under vacuum. The aqueous residue was extracted
with EtOAc (3 × 100.0 mL). The combined organic layers were dried
over Na2SO4 and concentrated under vacuum. The residue was used
in the next step without purification. Dess-Martin reagent (5.9 g, 14.0
mmol) and NaHCO3 (3.4 g, 40.0 mmol) were added to a solution of
the residue in CH2Cl2 (50 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 3 h, H2O (50 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 50.0 mL). The combined organic layer
was concentrated under vacuum. The residue was purified by
chromatography (EtOAc/hexanes, 1:15) to afford compound 13
(2.5 g, 80%) as a colorless solid: mp 75−77 °C; UV (MeOH) λmax
8-Bromo-2-hydroxy-1H-phenalen-1-one (5). A solution of
compound 7 (1.0 g, 3.8 mmol) in toluene (30 mL) was cooled to −5
°C and treated with Triton B (0.8 mL, 40 wt % in MeOH) and
aqueous tert-butylhydroperoxide (0.8 mL, 70 wt %). The solution was
stirred for 1 h before a second batch of Triton B and tert-
butylhydroperoxide was added. Formation of the epoxide was
observed by TLC during a period of 4 h. The reaction was quenched
with saturated Na2S2O3 solution, the mixture extracted with EtOAc (2
× 50 mL) and H2O (100 mL), and the organic layer concentrated to
give a residue. The residue was diluted in toluene, p-toluenesulfonic
acid monohydrate (0.72 g, 3.8 mmol) added, and the mixture stirred
overnight. The mixture was concentrated and extracted with EtOAc
(2 × 50 mL) and H2O (100 mL). The organic layer was evaporated
under vacuum, and the residue purified by column chromatography
on silica gel (petroleum ether/EtOAc, 7:1) to afford 5 (0.85 g, 80%)
as a red solid: mp 264−266 °C; UV (MeOH) λmax (log ε) 204 (3.89),
1
(log ε) 230 (3.54), 308 (2.70) nm; H NMR (400 MHz, CDCl3) δ
10.31 (s, 1H, 1-CHO), 9.11 (d, J = 9.2 Hz, 1H, H-6), 8.02 (d, J = 2.0
Hz, 1H, H-9), 7.98−7.90 (m, 2H, H-1/3), 7.70 (dd, J = 9.2, 2.0 Hz,
1H, H-7), 7.62 (dd, J = 8.0, 7.2 Hz, 1H, H-2); 13C NMR (100 MHz,
CDCl3) δ 193.2 (C-11), 137.0 (C-3), 134.9 (C-4), 134.0 (C-1), 132.2
(C-7), 131.4 (C-10), 130.3 (C-9), 128.8 (C-5), 126.8 (C-2), 126.0
(C-6), 121.3 (C-8); HRESIMS m/z 250.9710 [M + H2O − H]−,
calcd for C11H8BrO2, 250.9713.15
1
266 (3.47), 379 (3.07) nm; H NMR (400 MHz, DMSO-d6) δ 9.83
(s, 1H, 2-OH), 8.68 (d, J = 2.0 Hz, 1H, H-9), 8.48 (d, J = 2.0 Hz, 1H,
H-7), 7.99 (d, J = 8.0 Hz, 1H, H-6), 7.81 (d, J = 7.2 Hz, 1H, H-4),
7.73−7.61 (m, 1H, H-5), 7.16 (s, 1H, H-3); 13C NMR (100 MHz,
DMSO-d6) δ 179.4 (C-1), 150.9 (C-2), 137.6 (C-7), 133.7 (C-6a),
132.1 (C-9), 130.3 (C-4), 130.2 (C-3a), 129.2 (C-9a), 129.0 (C-6),
128.5 (C-5), 122.6 (C-9b), 120.5 (C-8), 115.5 (C-3); HRESIMS m/z
296.9516 [M + Na]+, calcd for C13H7BrO2Na, 296.9522.
(E)-Ethyl 3-(6-Bromonaphthalen-1-yl)acrylate (10 Ethyl
Ester). To a solution of (carbethoxymethy1)triphenylphosphonium
bromide (6.9 g, 15 mmol) in 50 mL of THF was added tBuOK(1.7 g,
15 mmol). The solution was stirred for 1 h, compound 13 (2.4 g, 10.0
mmol) was added, and stirring continued for 12 h. The mixture was
evaporated under reduced pressure, the residue was extracted with
EtOAc (2 × 50 mL) and H2O (100 mL), and the organic layer was
concentrated and purified by chromatography (EtOAc/hexanes, 1:10)
to afford (E)-ethyl 3-(6-bromonaphthalen-1-yl)acrylate as a colorless
oil (2.6 g, 88%): UV (MeOH) λmax (log ε) 203 (3.39), 231 (3.65),
317 (2.79) nm; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 15.6 Hz,
1H, H-3), 7.98 (d, J = 9.2, 1H, H-10), 7.96 (d, J = 2.0 Hz, 1H, H-7),
7.72 (d, J = 8.4 Hz, 1H, H-6), 7.70 (d, J = 7.6 Hz, 1H, H-4), 7.58 (dd,
J = 9.2, 2.0 Hz, 1H, H-9), 7.45 (dd, J = 8.4, 7.6 Hz, 1H, H-5), 6.48 (d,
J = 15.6 Hz, 1H, H-2), 4.32 (q, J = 7.2 Hz, 2H, 1-OEt, 1.38 (t, J = 7.2
Hz, 3H, 1-OEt); 13C NMR (100 MHz, CDCl3) δ 166.6 (C-1), 140.8
(C-3), 134.7 (C-3a), 132.0 (C-10a), 130.5 (C-7), 130.0 (C-9), 129.8
(C-5), 129.3 (C-6a), 126.6 (C-6), 125.2 (C-10), 125.2 (C-4), 121.5
(C-2), 120.3 (C-8), 60.7 (1-OEt), 14.4 (1-OEt); HRESIMS m/z
326.9987 [M + Na]+, calcd for C15H13BrO2Na, 326.9991.
8-Bromo-1H-phenalen-1-one (7). NaOH (30 mL, 1 mol/L)
was added to (E)-ethyl 3-(6-bromonaphthalen-1-yl)acrylate (3.0 g,
10.0 mmoL) that was diluted with THF (30 mL). The mixture was
stirred at 40 °C for 12 h. The THF was removed under vacuum, the
residue was extracted with CH2Cl2 (50 mL) and H2O (100 mL), and
the aqueous phase was acidified with concentrated HCl to give 10
(2.4 g, 86%) as a white solid, which was collected by filtration and
dried under reduced pressure. To a solution of compound 10 (2.2 g,
8.0 mmol) in dry CH2Cl2 (50 mL) was added oxalyl choride (3.5 mL,
40.0 mmol), and the mixture stirred for 10 min when two drops of dry
DMF were added. The mixture was stirred overnight at room
temperature. The light yellow solution was evaporated under vacuum
to afford 3-(6-bromonaphthalen-1-yl)acryloyl chloride, which was
rapidly dissolved in dry CH2Cl2 (50 mL). AlCl3 (2.1 g, 16 mmol) was
added at 0 °C, and the solution stirred overnight at room
temperature. The mixture was poured slowly onto ice, and the
aqueous phase was extracted with CH2Cl2 (2 × 100 mL). The organic
phase was combined and concentrated under vacuum, and the residue
2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1). To
a 100 mL three-necked flask equipped with a condenser was added 5
(150 mg, 0.55 mmol), Pd(PPh3)4 (130.0 mg, 0.11 mmol), and THF
(15 mL). The clear yellow solution was stirred for 15 min under an
atmosphere of nitrogen. Potassium 4-hydroxyphenyltrifluoroborate
(140.0 mg, 0.7 mmol) in THF (10 mL) was added dropwise followed
by Cs2CO3 (1 mL, 1 mol/L, aq), and the mixture was refluxed for 3 h
under an atmosphere of nitrogen. The THF was removed under
vacuum, and the residue was diluted with H2O and extracted with
CH2Cl2 (2 × 50 mL). The separated organic layer was concentrated
under vacuum and purified by chromatography on silica gel
(petroleum ether/EtOAc, 7:1) to afford 1 (red solid, 120 mg,
78%): mp 233−235 °C; UV (MeOH) λmax (log ε) 200 (3.62), 276
(2.48), 339 (2.02) nm; 1H NMR (400 MHz, acetone-d6) δ 8.86 (d, J
= 2.0 Hz, 1H, H-9), 8.68 (s, 1H, 2-OH), 8.62 (d, J = 2.0 Hz, 1H, H-
7), 8.20 (s, 1H, 4′-OH), 8.11 (d, J = 8.0 Hz, 1H, H-6), 7.82 (d, J = 8.0
Hz, 1H, H-4), 7.79 (d, J = 8.4 Hz, 2H, H-2′/6′), 7.71−7.63 (m, 1H,
H-5), 7.21 (s, 1H, H-3), 7.05 (d, J = 8.4 Hz, 2H, H-3′/5′); 13C NMR
(100 MHz, acetone-d6) δ 181.2 (C-1), 159.0 (C-4′), 151.5 (C-2),
140.6 (C-8), 133.9 (C-6a), 133.7 (C-7), 131.7 (C-1′), 130.6 (C-4),
130.5 (C-6), 129.7 (C-3a), 129.6 (C-2′/6′), 129.5 (C-9), 129.4 (C-
9a), 128.7 (C-5), 124.0 (C-9b), 117.2 (C-3′/5′), 114.7 (C-3);
HRESIMS m/z 311.0670 [M + Na]+, calcd for C19H12O3Na,
311.0679.4
8-(3,4-Dimethoxyphenyl)-2-hydroxy-1H-phenalen-1-one
(16). Compound 16 (red solid, 128 mg, 76%) was prepared from 5
(140 mg, 0.5 mmol) with (3,4-dimethoxyphenyl)boronic acid under
the same conditions described for 1: mp 195−197 °C; UV (MeOH)
1
λmax (log ε) 207 (3.79), 276 (3.63), 418 (3.01) nm; H NMR (400
MHz, CDCl3) δ 8.93 (d, J = 2.0 Hz, 1H, H-9), 8.38 (d, J = 2.0 Hz,
1H, H-7), 7.95 (d, J = 8.0 Hz, 1H, H-6), 7.67 (d, J = 7.2 Hz, 1H, H-
4), 7.62−7.56 (m, 1H, H-5), 7.34 (dd, J = 8.0, 2.0 Hz, 1H, H-6′), 7.30
(d, J = 2.0 Hz, 1H, H-2′), 7.15 (s, 1H, 1-OH), 7.03 (s, 1H, H-3), 7.01
(d, J = 8.0 Hz, 1H, H-5′), 4.02 (s, 3H, 3′-OMe), 3.97 (s, 3H, 4′-
OMe); 13C NMR (100 MHz, CDCl3) δ 180.5 (C-1), 149.5 (C-2),
F
DOI: 10.1021/acs.jnatprod.7b00709
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
149.5 (C-3′), 149.3 (C-4′), 139.7 (C-8), 133.5 (C-7), 132.5 (C-6a),
132.2 (C-1′), 130.2 (C-4), 130.0 (C-6), 129.9 (C-9), 128.2 (C-3a),
127.7 (C-9a), 127.5 (C-5), 123.2 (C-9b), 120.0 (C-6′), 113.8 (C-5′),
111.6 (C-2′), 110.4 (C-3), 56.1 (3′-OMe), 56.0 (4′-OMe);
HRESIMS m/z 355.0931 [M + Na]+, calcd for C21H16O4Na,
355.0941.
129.2 (C-8), 128.4 (C-3a), 128.3 (C-9a), 127.0 (C-2), 125.0 (C-9b),
119.3 (C-5); HRESIMS m/z 258.9751 [M + H]+, calcd for
C13H8BrO, 258.9753.
5-Bromo-2-hydroxy-1H-phenalen-1-one (6). Compound 6
(red solid, 0.6 g, 81%) was prepared from 8 (0.7 g, 3.5 mmol)
under the same conditions as for 5: mp 243−245 °C; UV (MeOH)
1
8-(3,4-Dihydroxyphenyl)-2-hydroxy-1H-phenalen-1-one (2).
To a solution of 16 (120 mg, 0.36 mmol) dissolved in CH2Cl2 (50
mL) at 0 °C was added BBr3 (0.4 mL, 1 mol/L CH2Cl2 solution).
The mixture was stirred for 1 h at 0 °C under an atmosphere of
nitrogen. NaHCO3 (10 mL, saturated solution) was added slowly at 0
°C, the CH2Cl2 was evaporated and H2O (50 mL) was added. The
water phase was extracted with EtOAc (2 × 50 mL). The organic
layer was concentrated under vacuum and purified by chromatog-
raphy on silica gel (petroleum ether/EtOAc, 5:1) to afford 2 (red
solid, 100 mg, 92%): mp 245−247 °C; UV (MeOH) λmax (log ε) 198
(3.27), 276 (2.12) nm; 1H NMR (400 MHz, acetone-d6) δ 8.83 (d, J
= 1.6 Hz, 1H, H-9), 8.58 (d, J = 1.6 Hz, 1H, H-7), 8.26 (s, 1H, 3′-
OH), 8.20 (s, 1H, 4′-OH), 8.10 (d, J = 8.0 Hz, 1H, H-6), 7.80 (d, J =
7.2 Hz, 1H, H-4), 7.70−7.62 (m, 1H, H-5), 7.40 (d, J = 2.0 Hz, 1H,
H-2′), 7.28 (dd, J = 8.0, 2.0 Hz, 1H, H-6′), 7.20 (s, 1H, H-3), 7.03 (d,
J = 8.0 Hz, 1H, H-5′); 13C NMR (100 MHz, acetone-d6) δ 181.2 (C-
1), 151.5 (C-2), 146.9 (C-3′), 146.7 (C-4′), 140.7 (C-8), 133.9 (C-
6a), 133.7 (C-7), 132.4 (C-1′), 130.6 (C-4), 130.5 (C-6), 129.7 (C-
9), 129.6 (C-3a), 128.7 (C-5), 124.0 (C-9a), 120.0 (C-6′), 120.0 (C-
9b), 117.1 (C-5′), 115.3 (C-2′), 114.7 (C-3); HRESIMS m/z
305.0804 [M + H]+, calcd for C19H13O4, 305.0808.4
λmax (log ε) 205 (3.87), 246 (3.48), 366 (3.17) nm; H NMR (400
MHz, DMSO-d6) δ 9.94 (brs, 1H, 2-OH), 8.55 (d, J = 7.6 Hz, 1H, H-
9), 8.40 (d, J = 8.0 Hz, 1H, H-7), 8.33 (s, 1H, H-6), 8.00 (s, 1H, H-
4), 7.91 (dd, J = 8.0, 7.6 Hz, 1H, H-8), 7.16 (s, 1H, H-3); 13C NMR
(100 MHz, DMSO-d6) δ 180.2 (C-1), 151.8 (C-2), 135.6 (C-6a),
133.1 (C-3a), 131.5 (C-4/6), 130.8 (C-7), 130.4 (C-9), 128.7 (C-9a),
128.5 (C-8), 122.7 (C-9b), 120.8 (C-5), 113.9 (C-3); HRESIMS m/z
274.9699 [M + H]+, calcd for C13H8BrO2, 274.9702.
2-Hydroxy-5-(4-hydroxyphenyl)-1H-phenalen-1-one (3).
Compound 3 (red solid, 50 mg, 76%) was prepared from 6 (64
mg, 0.23 mmol) under the same conditions as for 1: mp 279−281 °C;
UV (MeOH) λmax (log ε) 205 (3.81), 278 (3.61), 379 (3.01) nm; 1H
NMR (400 MHz, acetone-d6) δ 8.64 (s, 1H, 2-OH), 8.60 (d, J = 7.6
Hz, 1H, H-9), 8.47 (d, J = 8.0 Hz, 1H, H-7), 8.24 (s, 1H, H-6), 8.20
(s, 1H, 4′-OH), 8.16 (s, 1H, H-4), 7.90 (dd, J = 8.0, 7.6 Hz, 1H, H-8),
7.75 (d, J = 8.4 Hz, 2H, H-2′/6′), 7.30 (s, 1H, H-3), 7.03 (d, J = 8.4
Hz, 2H, H-3′/5′); 13C NMR (100 MHz, acetone-d6) δ 180.0 (C-1),
157.8 (C-4′), 150.5 (C-2), 139.9 (C-5), 136.2 (C-6), 132.8 (C-6a),
130.9 (C-1′), 129.5 (C-7), 129.3 (C-3a), 129.1 (C-4), 128.3 (C-2′/
6′), 127.8 (C-9a), 127.2 (C-9), 125.4 (C-8), 123.1 (C-9b), 115.9 (C-
3′/5′), 113.7 (C-3); HRESIMS m/z 311.0688 [M + Na]+, calcd for
C19H12O3Na, 311.0684.
3-Bromo-1-naphthaldehyde (14). Compound 14 (gray solid,
2.0 g, 80%) was prepared from 14a (gray solid, 2.8 g, 11.2 mmol)
under the same conditions as for 13. Compound 14a: mp 227−229
(E)-3-(Naphthalen-1-yl)acrylic Acid (12). Compound 12
(colorless solid, 1.5 g, 78%) was prepared from 15 (1.6 g, 10.0
mmol) under the same conditions as for 10: mp 212−214 °C; UV
1
°C; UV (MeOH) λmax (log ε) 230 (3.93), 287 (2.78) nm; H NMR
1
(MeOH) λmax (log ε) 202 (3.10), 228 (3.39), 311 (2.79) nm; H
(400 MHz, DMSO-d6) δ 8.81 (d, J = 8.4 Hz, 1H, H-8), 8.46 (d, J =
2.0 Hz, 1H, H-4), 8.16 (d, J = 2.0 Hz, 1H, H-2), 8.02 (dd, J = 8.0, 2.0
Hz, 1H, H-5), 7.76−7.57 (m, 2H, H-6/7); 13C NMR (100 MHz,
DMSO-d6) δ 167.7 (C-1), 135.2 (C-8a), 134.8 (C-4), 132.4 (C-2),
130.5 (C-4a), 129.6 (C-1a), 128.5 (C-7), 128.3 (C-6), 127.8 (C-5),
126.1 (C-8), 118.0 (C-3); HRESIMS m/z 248.9557 [M − H]−, calcd
for C11H6BrO2, 248.9557.13 Compound 14: mp 54−56 °C; UV
NMR (400 MHz, DMSO-d6) δ 12.61 (brs, 1H, −COOH), 8.40 (d, J
= 15.6 Hz, 1H, H-3), 8.21 (d, J = 8.4 Hz, 1H, H-7), 8.04−7.95 (m,
3H, H-4/6/10), 7.66−7.55 (m, 3H, H-5/8/9), 6.63 (d, J = 15.6 Hz,
1H, H-2); 13C NMR (100 MHz, DMSO-d6) δ 167.4 (C-1), 140.1 (C-
3), 133.2 (C-3a), 130.9 (C-6a), 130.7 (C-10a), 130.3 (C-7), 128.6
(C-6), 127.1 (C-5), 126.2 (C-9), 125.6 (C-8), 125.1 (C-10), 122.9
(C-4), 121.8 (C-2); HRESIMS m/z 221.0571 [M + Na]+, calcd for
C13H10O2Na, 221.0573.17
1
(MeOH) λmax (log ε) 202 (2.70), 230 (2.93) nm; H NMR (400
MHz, CDCl3) δ 10.35 (s, 1H, 1-CHO), 9.15 (d, J = 8.0 Hz, 1H, H-8),
8.24 (d, J = 2.0 Hz, 1H, H-4), 8.04 (d, J = 2.0 Hz, 1H, H-2), 7.83 (d, J
= 8.0 Hz, 1H, H-5), 7.73−7.66 (m, 1H, H-7), 7.61 (dd, J = 8.0, 7.6
Hz, 1H, H-6); 13C NMR (100 MHz, CDCl3) δ 192.0 (C-1), 138.7
(C-2), 136.8 (C-4), 135.1 (C-1a), 132.8 (C-4a), 129.3 (C-7), 129.0
(C-8a), 128.0 (C-6), 127.6 (C-5), 124.9 (C-8), 118.5 (C-3);
HRESIMS m/z 250.9704 [M + H2O − H]−, calcd for C11H8BrO2,
250.9713.16
1H-Phenalen-1-one (9). Compound 9 (orange solid, 0.75 g,
60%) was prepared from 12 (1.4 g, 7.0 mmol) under the same
conditions as for 7: mp 155−157 °C; UV (MeOH) λmax (log ε) 204
1
(3.57), 248 (3.44), 361 (3.12) nm; H NMR (400 MHz, CDCl3) δ
8.53 (d, J = 7.6 Hz, 1H, H-9), 8.08 (d, J = 8.0 Hz, 1H, H-7), 7.91 (d, J
= 8.4 Hz, 1H, H-6), 7.69−7.62 (m, 3H, H-3/4/8), 7.49 (dd, J = 8.0,
7.6 Hz, 1H, H-5), 6.65 (d, J = 8.4 Hz, 1H, H-2); 13C NMR (100
MHz, CDCl3) δ 185.5 (C-1), 141.7 (C-3), 134.8 (C-3a), 132.0 (C-
9a), 131.9 (C-9), 131.4 (C-4), 130.2 (C-6a), 129.2 (C-7), 129.0 (C-
6), 127.6 (C-5), 127.3 (C-8), 126.9 (C-9b), 126.5 (C-2); HRESIMS
m/z 181.0650 [M + H]+, calcd for C13H9O, 181.0648.2a
(E)-Ethyl 3-(3-Bromonaphthalen-1-yl)acrylate (11 Ethyl
Ester). The ethyl ester of compound 11 (colorless oil, 2.0 g, 89%)
was prepared from 14 (1.8 g, 7.6 mmol) under the same conditions as
for the ethyl ester of 10: UV (MeOH) λmax (log ε) 204 (3.07), 227
1
(3.37), 310 (2.09) nm; H NMR (400 MHz, CDCl3) δ 8.34 (d, J =
9-(4-Methoxyphenyl)-1H-phenalen-1-one (17). A solution of
9 (135 mg, 0.75 mmol) in dry THF (20 mL) was added slowly to the
appropriate Grignard reagent [1.5 mmol, prepared from 1-bromo-4-
methoxybenzene and Mg in dry THF (10 mL)] under a nitrogen
atmosphere. After stirring for 20 min at −10 °C, the mixture was
allowed to warm to room temperature and stirred for 30 min. The
mixture was quenched with HCl solution (5.0%), the THF removed
under vacuum, the aqueous phase extracted with EtOAc (2 × 50 mL),
and the combined organic extract washed with H2O and evaporated
to dryness. The crude material was dissolved in CH2Cl2 (100 mL)
and treated with DDQ (2.0 equiv), refluxed for 3 h, and cooled to
room temperature. After addition of H2O (100 mL), the CH2Cl2
phase was separated and purified by chromatography on silica gel
(petroleum ether/EtOAc, 9:1) to afford 17 (orange solid, 150 mg,
70%): mp 183−185 °C; UV (MeOH) λmax (log ε) 204 (3.69), 257
15.6 Hz, 1H, H-3), 8.06 (d, J = 8.0 Hz, 1H, H-10), 7.96 (d, J = 1.6
Hz, 1H, H-6), 7.81 (d, J = 1.6 Hz, 1H, H-4), 7.77 (d, J = 8.4 Hz, 1H,
H-7), 7.57−7.40 (m, 2H, H-8/9), 6.44 (d, J = 15.6 Hz, 1H, H-2),
4.25 (q, J = 7.2 Hz, 2H, 1-OEt), 1.30 (t, J = 7.2 Hz, 3H, 1-OEt); 13C
NMR (100 MHz, CDCl3) δ 165.4 (C-1), 139.0 (C-3), 133.7 (C-3a),
132.9 (C-10a), 130.9 (C-6), 128.8 (C-6a), 126.9 (C-7), 126.8 (C-8),
126.2 (C-9), 126.1 (C-4), 122.6 (C-10), 121.3 (C-2), 118.3 (C-5),
59.7 (1-OEt), 13.3 (1-OEt); HRESIMS m/z 305.0170 [M + H]+,
calcd for C15H14BrO2, 305.0172.
5-Bromo-1H-phenalen-1-one (8). Compound 8 (orange solid,
0.83 g, 58%) was prepared from 11 (1.7 g, 6.1 mmol) under the same
conditions as for 7: mp 173−175 °C; UV (MeOH) λmax (log ε) 203
1
(3.47), 258 (3.55), 360 (3.05) nm; H NMR (400 MHz, CDCl3) δ
8.55 (dd, J = 7.4, 1.6 Hz, 1H, H-9), 8.11 (d, J = 1.6 Hz, 1H, H-6),
8.05 (dd, J = 8.0, 0.8 Hz, 1H, H-7), 7.81 (d, J = 1.6 Hz, 1H, H-4),
7.76 (m, 1H, H-8), 7.62 (d, J = 9.6 Hz, 1H, H-3), 6.71 (d, J = 9.6 Hz,
1H, H-2); 13C NMR (100 MHz, CDCl3) δ 184.0 (C-1), 139.3 (C-3),
132.7 (C-4), 132.5 (C-6), 132.1 (C-6a), 132.0 (C-7), 129.3 (C-9),
1
(3.43), 368 (3.13) nm; H NMR (400 MHz, CDCl3) δ 8.15 (d, J =
8.0 Hz, 1H, H-7), 8.03 (d, J = 8.0 Hz, 1H, H-6), 7.77 (d, J = 6.8 Hz,
1H, H-4), 7.69 (d, J = 9.6 Hz, 1H, H-3), 7.63−7.59 (m, 2H, H-5/8),
7.37 (d, J = 8.8 Hz, 2H, H-2′/6′), 7.03 (d, J = 8.8 Hz, 2H, H-3′/5′),
G
DOI: 10.1021/acs.jnatprod.7b00709
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Journal of Natural Products
Article
6.63 (d, J = 9.6 Hz, 1H, H-2), 3.90 (s, 3H, 4′-OMe); 13C NMR (100
MHz, CDCl3) δ 185.9 (C-1), 159.0 (C-4′), 147.5 (C-9), 140.3 (C-3),
134.9 (C-1′), 133.7 (C-7), 131.9 (C-6), 131.7 (C-8), 131.6 (C-9a),
131.4 (C-4), 130.6 (C-2), 129.4 (C-2′/6′), 128.5 (C-3a), 128.4 (C-
9b), 126.2 (C-5), 125.9 (C-6a), 113.8 (C-3′/5′), 55.3 (4′-OMe);
HRESIMS m/z 287.1063 [M + H]+, calcd for C20H15O2, 287.1067.2a
2-Hydroxy-9-(4-methoxyphenyl)-1H-phenalen-1-one (18).
Compound 18 (red solid, 117 mg, 79%) was prepared from 17
(140 mg, 0.49 mmol) under the same conditions as for 5: mp 186−
188 °C; UV (MeOH) λmax (log ε) 204 (3.73), 254 (3.27), 369 (2.79)
Province (A2016090); the Science and Technology Planning
Project of Guangzhou City (201707010189), Hong Kong
Scholars Program (XJ2013025), China; and the Interdiscipli-
nary Research Matching Scheme (RC-IRMS/15-16/02) of
Hong Kong Baptist University, Hong Kong SAR, China.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00709.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: mzwang2000@163.com. Tel: +86-(0)20-39943043.
Fax: +86-(0)20-39943043.
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*E-mail: zhanghj@hkbu.edu.hk.
*E-mail: chenxz3@mail.sysu.edu.cn.
ORCID
Ming-Zhong Wang: 0000-0003-2498-5222
Hong-Jie Zhang: 0000-0002-7175-5166
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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(16) Dastan, A.; Yildiz, Y. K.; Kazaz, C.; Balci, M. Turk. J. Chem.
2002, 26, 143−151.
This work was financially supported by the Research
Foundation for Advanced Talents (36000-18821101); Guang-
dong Natural Science Foundation (2017A030313751); the
Fundamental Research Funds for the Central Universities
(16ykpy33) of Sun Yat-sen University, Guangzhou, China; the
Medical Scientific Research Foundation of Guangdong
(17) Master, H. E.; Khan, S. I.; Poojari, K. A. D. Bioorg. Med. Chem.
2005, 13, 4891−4899.
H
DOI: 10.1021/acs.jnatprod.7b00709
J. Nat. Prod. XXXX, XXX, XXX−XXX