Syntheses of naturally occurring terphenyls and related compounds

Article abstract of DOI:10.1271/bbb.60389

Naturally occurring terphenyls and related compounds such as terferol and its corresponding quinone and phlebiarubrone were synthesized from 2,5-diphenyl-1,4-benzoquinone. According to the proposed biosynthetic pathway, chemical conversion of phlebiarubro

Full text of DOI:10.1271/bbb.60389

Biosci. Biotechnol. Biochem., 70 (12), 2998–3003, 2006
Syntheses of Naturally Occurring Terphenyls and Related Compounds
y
Yusuke SAWAYAMA,1 Takashi TSUJIMOTO,2 Kumi SUGINO,1 Toshio NISHIKAWA,1;2;
3
Minoru ISOBE,1 and Hirokazu KAWAGISHI
1Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
2PRESTO of Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
3Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
Received July 10, 2006; Accepted August 4, 2006; Online Publication, December 7, 2006
[doi:10.1271/bbb.60389]
Naturally occurring terphenyls and related com-
pounds such as terferol and its corresponding quinone
OMe
OMe
and phlebiarubrone were synthesized from 2,5-diphen-
yl-1,4-benzoquinone. According to the proposed biosyn-
thetic pathway, chemical conversion of phlebiarubrone
to ustalic acid, a toxic compound isolated from the
poisonous mushroom, Tricholoma ustale, was examined
to find a low-yield conversion to the ustalic acid
dimethyl ester.
O
HO
O
O
OH
2
Terferol (1)
Key words: terphenyl; quinone; ustalic acid; phlebiaru-
brone; terferol
COOH
COOH
O
Terphenyl is a common structural motif found in
various natural products, largely isolated from micro-
organisms and mushrooms.1) Because of the diverse
structure as well as its wide variety of biological
activities, including antioxidative, neurotoxicity, immu-
nosuppressive, plant growth regulation, antibacterial and
insecticidal, these natural products have attracted great
attention.2) Although many highly oxygenated terphenyl
compounds with hydroxyl groups in the aromatic rings
have been isolated, relatively simple terphenyl com-
pounds also exhibit interesting biological activities.
Terferol (1) isolated from Streptomyces showdoensis
O
O
O
O
Phlebiarubrone (4)
Ustalic acid (3)
Fig. 1. Structures of Naturally Occurring Terphenyl Compounds.
**
terphenyl and related compound, and attempts at the
chemical conversion of phlebiarubrone to ustalic acid
according to the biosynthetic hypothesis.7)
SANK65080 is an inhibitor of cyclic AMP- and cyclic
;
Results and Discussion
GMP-phosphodiesterase (Fig. 1).3,4) Recently, corre-
*
sponding o-quinone 2 was isolated from a Phoma sp. as
an inhibitor of parasite cyclic GMP-dependent protein
kinase.6) Ustalic acid (3) was isolated as a toxic principle
of mushroom poisoning by Tricholoma ustale (Kaki-
shimeji in Japanese), and inhibited Naþ, Kþ-ATPase.7)
The unique structure of 3 is assumed to be biosynthe-
sized by oxidative cleavage of phlebiarubrone (4), a
well-known red pigment, originally isolated from cul-
tured mycelia of the toadstool, Phlebia strigosozonata.8)
We have been interested in the chemical relationship
among these structurally unique natural products with
significant biological activities. We describe herein an
efficient and expeditious synthetic route for the simple
Key compounds 7 and 10 for the synthetic studies
were synthesized from commercially available 2,5-
diphenyl-1,4-benzoquinone (5) according to modified
procedures of Nozaki and co-workers.10) Thiele-Winter
acetoxylation of 2,5-diphenyl-1,4-benzoquinone (5)
with perchloric acid in acetic anhydride gave triacetate
6 (Scheme 1).11) Upon treatment of product 6 with
K2CO3 in methanol, the acetyl group at the 50 position
was selectively removed to give 7 in a 90% yield.
Phenol 7 was methylated with CH3I in the presence of
K2CO3, and the remaining two acetates of 8 were
hydrolyzed under acidic conditions to afford terferol (1)
in a good yield. On the other hand, oxidation of 1 with
y
To whom correspondence should be addressed. Fax: +81-52-789-4111; E-mail: nisikawa@agr.nagoya-u.ac.jp

Syntheses of Terphenyls and Related Compounds
2999
O
OAc
OR
HClO4
Ac2O
K2CO3
O
AcO
AcO
MeOH
OAc
OAc
(73%)
(90%)
5
6
7 R = H
8 R = Me
MeI, K2CO3
DMF (88%)
OMe
OMe
Fetizon's
reagent
p-TsOH
MeOH
(87%)
HO
O
CH2Cl2
(93%)
OH
Terferol (1)
O
2
Scheme 1. Synthesis of Terferol (1) and Its o-Quinone Compound 2.
OBn
OBn
BnBr, K2CO3
DMF
CH2I2
3M HCl
dioxane
7
AcO
HO
K2CO3
DMF
OAc
OH
(84%)
9
10
(74% in 2 steps)
O
O
OH
OBn
H2, Pd-C
Fremy's salt
O
O
O
EtOAc-EtOH
acetone-H2O
O
O
O
(93% in 2 steps)
Phlebiarubrone (4)
11
12
Scheme 2. Synthesis of Phlebiarubrone (4).
Fetizon’s reagent12) gave corresponding o-quinone 2 in
a high yield. However, the NMR spectra of synthetic 2
oxygen-free conditions (see the experimental section),
ketal 11 could be obtained reproducibly in a good
overall yield from 9. Deprotection of the benzyl group
under hydrogenolytic conditions was followed by
oxidation with Fremy’s salt13) to afford phlebiarubrone
(4) in a high yield. NMR data for the synthetic material
were good agreement with those of the literature.14)
Since the scalable synthesis of phlebiarubrone had
been established, chemical conversion of phlebiarubrone
(4) to ustalic acid (3) was next examined. Many
reactions for the oxidative cleavage of o-quinones or
their o-dihydroquinones (catechols) to dicarboxylic
acids have been reported: Baeyer-Villiger type of
oxidation with peracids,15,16) oxidation with potassium
superoxide,17) oxygen with copper-pyridine complex,18)
potassium permanganate19) and lead tetraacetate,20) and
a photo-induced reaction.21) However, the dihydroqui-
none obtained by reduction of 4 could not be isolated
because of its extreme instability. Instead, hydroquinone
monoacetate 13 was prepared by a brief treatment of 4
;
were not identical to those of the literature.6)
***
Phlebiarubrone (4) was synthesized from 7 as shown
in Scheme 2. Protection of phenol 7 with a benzyl group
under conventional conditions gave 9, in which two
acetates were hydrolyzed with hydrochloric acid in
dioxane to give catechol 10. In the transformation of
10 to methylene ketal 11 with diiodomethane in the
presence of K2CO3, we found that dissolved oxygen
caused the decomposition of substrate 10 and product 11
during the reaction, resulting in low yields (up to ca.
30%). Thus, when the reaction was conducted under
*
Terferol (1) was synthesized before its isolation from a natural
source.5)
Phlebiarubrone (4) was synthesized from polyporic acid.9)
Direct comparison between synthetic 2 and the natural com-
**
***
pound indicated clear differences. Reexamination of the
structure of natural 2 is currently underway by Dr. S. B. Singh
(personal communication).

3000
Y. SAWAYAMA et al.
COOMe
COOMe
Pb(OAc)4
toluene-MeOH
(5.2%)
Phlebiarubrone (4)
O
O
14
Zn-Cu
(90%)
Ac2O
OAc
OH
O
O
13
Scheme 3. Attempted Transformation of 4 to Ustalic Acid Dimethyl Ester 14.
with Zn–Cu in acetic anhydride (Scheme 3), while the
prolonged reaction time gave the corresponding diace-
tate.8) We then examined the conversion of 4 and 13
to ustalic acid. Many experiments under the above-
mentioned conditions led us to find that phlebiarubrone
was treated with a large excess of lead tetraacetate in
methanol and toluene to give ustalic acid dimethyl ester
14 in a poor yield. Unfortunately, all attempts to
improve this yield failed. Thus, it has been the sole
condition for the transformation, while all the other
conditions have never yielded ustalic acid (3) and its
ester or anhydride. Spectroscopic data for synthetic 14
were identical to those derived from the methylation of
natural ustalic acid with TMS-diazomethane.22) Because
of the limited amount of dimethyl ester 14, hydrolysis of
the ester has not yet been examined.
In conclusion, we developed a new practical route for
the synthesis of terferol, its o-quinone, and phlebiaru-
brone from the same starting material. Chemical
conversion of phlebiarubrone (4) to ustalic acid deriv-
ative 14 was achieved for the first time by oxidative
cleavage with lead tetraacetate, although the yield was
poor.
integration, multiplicity (s = singlet, d = doublet, br =
broadened, m = multiplet), and assignment. Carbon
nuclear magnetic resonance (13C-NMR) spectra were
recorded by a Bruker ARX-400 (100 MHz), Avance-400
(100 MHz) or Varian Gemini-2000 (75 MHz) spectrom-
eter. Chemical shifts are reported in ppm from chloro-
form-d1 (ꢀ ¼ 77:0 ppm) or acetone-d6 (ꢀ ¼ 206:0 ppm).
Electron ionization mass spectra (EI-MS) were recorded
by a JEOL JMS-700 instrument and are reported in m=z.
High resolution mass spectra (HR-MS FAB) in fast atom
bombardment ionization (FAB) mode were recorded by
a JEOL LCMATE mass spectrometer. Elemental analy-
ses were performed by the analytical laboratory at
Graduate School of Bioagricultural Sciences of Nagoya
University.
20,30,50-Triacetoxy-p-terphenyl (6). To a stirred sus-
pension of 2,5-diphenyl-1,4-benzoquinone 5 (5.20 g,
20.0 mmol) in Ac2O (52 ml) was added 70% HClO4
(1.2 ml, 20.0 mmol) under an argon atmosphere. After
being stirred at 70 ꢁC for 2 h, the mixture was cooled to
room temperature, and then poured into ice-cold water
(100 ml). The mixture was extracted with EtOAc (50
ml ꢂ 4). The combined organic layers were dried over
anhydrous Na2SO4 and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product
which was crystallized from MeOH to give triacetate
6 (5.81 g, 73%) as colorless crystals. Mp 193–194 ꢁC,
(lit.11) 189.7 ꢁC); IR (KBr) ꢁmax (cmꢀ1): 3062, 1772,
1469, 1415, 1370, 1189, 1096, 1042, 916; 1H-NMR (300
MHz, CDCl3) ꢀ (ppm): 1.97 (6H, s, Ac ꢂ 2), 2.08 (3H,
s, Ac), 7.13 (1H, s, Ar), 7.31 (2H, dd, J ¼ 7:5, 2 Hz, Ar),
7.35–7.49 (8H, m, Ar); 13C-NMR (75 MHz, CDCl3) ꢀ
(ppm): 20.0, 20.3, 20.4, 122.0, 128.1, 128.5, 128.8,
129.6, 131.9, 136.0, 136.2, 138.4, 141.6, 146.2, 167.9,
168.1, 169.0, Anal. Calcd. for C24H20O6: C, 71.28; H,
4.98%. Found: C, 71.28; H, 4.98%.
Experimental
Melting point (Mp) data were recorded by a Yanaco
MP-S3 melting point apparatus and are not corrected.
Infrared spectra (IR) were recorded by a JASCO FT/IR-
8300 spectrophotometer and are reported in wave
number (cmꢀ1). Proton nuclear magnetic resonance
(1H-NMR) spectra were recorded by a Bruker ARX-400
(400 MHz), Avance-400 (400 MHz) or Varian Gemini-
2000 (300 MHz) spectrometer. Chemical shifts of all
compounds are reported in ppm from tetramethylsilane
(ꢀ ¼ 0:00 ppm) or acetone (ꢀ ¼ 2:04 ppm) as internal
standards. Data are reported as follows: chemical shift,

Syntheses of Terphenyls and Related Compounds
3001
20,30-Diacetoxy-50-hydroxy-p-terphenyl (7). A suspen-
sion of 6 (14.0 g, 34.5 mmol) and K2CO3 (5.67 g, 41.4
mmol) in MeOH (475 ml) was stirred at 0 ꢁC for 3 h. The
reaction mixture was quenched with a sat. aqueous
NH4Cl solution and extracted with EtOAc (ꢂ3). The
combined organic layers were successively washed
with water (ꢂ2) and brine (ꢂ1), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chroma-
tography (300 g of silica gel, EtOAc/hexane = 1:3 to
1:1) to afford 7 (11.3 g, 90%) as a pale yellow
amorphous solid. IR (film) ꢁmax (cmꢀ1): 3428, 3023,
1771, 1419, 1371, 1212, 1094, 1045; 1H-NMR (300
MHz, CDCl3) ꢀ (ppm): 1.96 (3H, s, Ac), 2.05 (3H, s,
Ac), 5.15 (1H, s, –OH), 6.97 (1H, s, Ar), 7.31–7.53
(10H, m, Ar); 13C-NMR (75 MHz, CDCl3) ꢀ (ppm):
20.0, 20.2, 114.7, 122.2, 127.9, 128.4, 128.8, 128.9,
129.4, 130.2, 131.0, 133.8, 136.4, 136.7, 141.0, 151.1,
168.3, 168.8; HRMS (FAB, negative): calcd. for
C22H17O5 (M ꢀ H), 361.10760; found. 361.10757, Anal.
Calcd. for C22H18O5: C, 72.92; H, 5.01%. Found: C,
72.92; H, 5.07%.
NMR (75 MHz, acetone-d6) ꢀ (ppm): 55.9, 104.4, 118.5,
127.4, 127.5, 128.4, 128.7, 129.8, 131.7, 134.8, 137.1,
139.4, 144.6, 151.4; HR-MS (FAB, negative): calcd. for
C19H15O3 (M ꢀ H), 291.1021; found, 291.1025.
4-Methoxy-3,6-diphenylcyclohexa-3,5-diene-1,2-dione
(2). To a stirred solution of terferol (10; 8.3 mg, 0.028
mmol) in CH2Cl2 (3.0 ml) was added 65 mg of Ag2CO3
on Celite (1.75 mmol Ag2CO3/1 g). The mixture was
stirred at room temperature for 5 min, and then filtered
through a pad of Hyflo Super-CelÒ (filter aid), the
residue being rinsed with CH2Cl2. The combined filtrate
was concentrated. The crude product was purified by
preparative TLC (CHCl3/CH3CN = 20:1) to give 2 as
a deep-purple solid (7.7 mg, 93%). Mp 179–182 ꢁC; IR
(KBr) ꢁmax (cmꢀ1): 3057, 1687, 1637, 1617, 1557, 1493,
1
1377, 1232, 1058, 955; H-NMR (300 MHz, CDCl3) ꢀ
(ppm): 3.84 (3H, s, OMe), 7.27 (1H, s, Ar), 7.30–7.48
(8H, m, Ar), 7.50–7.56 (2H, m, Ar); 13C-NMR (100
MHz, CDCl3) ꢀ (ppm): 58.6, 120.7, 128.0, 128.1, 128.6,
128.7, 129.7, 130.7, 130.8, 131.5, 133.2, 140.3, 163.4,
178.1, 179.1; HR-MS (FAB, positive): calcd. for
C19H16O3 (M þ 2H),23) 291.1100; found, 291.1004.
20,30-Diacetoxy-50-methoxy-p-terphenyl (8). To a stir-
red solution of diacetate 7 (1.30 g, 3.59 mmol) in DMF
(40 ml) were added CH3I (1.0 ml, 16 mmol) and K2CO3
(700 mg, 5.07 mmol) at 0 ꢁC. The resulting purple
mixture was stirred at room temperature for 2 h, cooled
back to 0 ꢁC, and then diluted with Et2O (40 ml). The
mixture was successively washed with a sat. aqueous
NH4Cl solution, sat. aqueous NaHCO3 solution (50 ml),
and brine (50 ml). The organic layer was dried over
anhydrous Na2SO4, filtered through a cotton pad, and
concentrated in vacuo. The residue was purified by
crystallization from Et2O to afford methyl ether 8
(1.18 g, 88%) as colorless crystals. Mp 164–167 ꢁC; IR
(KBr) ꢁmax (cmꢀ1): 3062, 1772, 1618, 1476, 1370, 1205,
1103, 1082, 1011, 929, 886; 1H-NMR (300 MHz,
CDCl3) ꢀ (ppm): 1.96 (3H, s, Ac), 2.06 (3H, s, Ac),
3.78 (3H, s, –OMe), 6.90 (1H, s, Ar), 7.30–7.52 (10H,
m, Ar); 13C-NMR (75 MHz, CDCl3): ꢀ (ppm) 20.1, 20.3,
56.1, 110.3, 124.8, 127.7, 128.0, 128.5, 128.8, 130.2,
132.6, 135.5, 137.2, 155.0, 168.3, 168.8; Anal. Calcd.
for C23H20O5: C, 73.39; H, 5.36%. Found: C, 73.39; H,
5.44%.
20,30-Diacetoxy-50-benzyloxy-p-terphenyl (9). To a
stirred solution of 7 (11.2 g, 31.0 mmol) in DMF
(343 ml) were added BnBr (7.3 ml, 62 mmol) and
K2CO3 (6.00 g, 43.4 mmol). The reaction mixture was
successively stirred at room temperature for 5 h, and
then diluted with EtOAc. The mixture was washed with
water (ꢂ2), a sat. aqueous NaHCO3 solution (ꢂ1) and
brine (ꢂ1), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resulting
residue was washed with hexane to afford 9 as a white
solid (11.8 g, 84%). Mp 143–145 ꢁC; IR (KBr) ꢁmax
(cmꢀ1): 3063, 1775, 1475, 1415, 1370, 1207, 1100,
1066; 1H-NMR (300 MHz, CDCl3): ꢀ (ppm) 1.97 (3H, s,
COCH3), 2.06 (3H, s, COCH3), 5.05 (2H, s, OCH2Ph),
6.97 (1H, s, Ar), 7.18–7.47 (15H, m, Ar); 13C-NMR
(75 MHz, CDCl3) ꢀ (ppm): 20.1, 20.2, 70.9, 112.4,
125.7, 126.8, 127.6, 127.7, 127.9, 128.5, 128.8, 130.3,
132.6, 134.4, 135.5, 136.7, 137.1, 141.6, 154.1, 168.3,
168.7. Anal. Calcd for C29H24O5: C, 76.98; H, 5.35%.
Found: C, 76.96; H, 5.15%.
20,30-Dihydroxy-50-benzyloxy-p-terphenyl (10). To a
stirred suspension of 9 (3.02 g, 6.68 mmol) in 1,4-
dioxane (55 ml) was added 3N HCl (55 ml) at rt. After
being stirred at 80 ꢁC for 24 h, the reaction mixture
was extracted with Et2O (ꢂ3). The combined organic
layers were washed with brine (ꢂ2), dried over
anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The resulting residue was washed
with hexane to afford 10 (2.40 g), which was used in the
next reaction without further purification. An analytical
sample was prepared by recrystallization from EtOAc–
hexane. Mp 132.5–135 ꢁC; IR (KBr) ꢁmax (cmꢀ1): 3531,
3501, 3061, 1481, 1455, 1428, 1375, 1273, 1235, 1101,
Terferol (1). A suspension of methyl ether 8 (625 mg,
.
1.66 mmol) and p-TsOH H2O (48 mg, 0.25 mmol) in
MeOH (20 ml) was stirred at 60 ꢁC for 24 h. The mixture
was allowed to cool to room temperature and then
concentrated under reduced pressure. The residue was
purified by column chromatography (40 g of silica gel,
CH2Cl2) to give terferol 1 (420 mg, 87%) as red crystals.
Mp 188–191 ꢁC (lit.4) 184 ꢁC); IR (KBr) ꢁmax (cmꢀ1):
3544, 3495, 3058, 3017, 2960, 1773, 1594, 1481, 1378,
1319, 1227, 1104, 1071, 823; 1H-NMR (300 MHz,
acetone-d6) ꢀ (ppm): 3.64 (3H, s, OMe), 6.50 (1H, s,
Ar), 7.22–7.42 (8H, m, Ar), 7.58–7.64 (2H, m, Ar); 13C-

3002
Y. SAWAYAMA et al.
1065; 1H-NMR (300 MHz, CDCl3) ꢀ (ppm): 4.94 (2H, s,
OCH2Ph), 5.26 (1H, s, OH), 5.39 (1H, s, OH), 6.61 (1H,
s, Ar), 7.15–7.31 (4H, m, Ar), 7.34–7.61 (11H, m, Ar);
13C-NMR (75 MHz, CDCl3) ꢀ (ppm): 71.4, 107.2, 127.0,
127.56, 127.64, 128.0, 128.4, 128.8, 128.9, 129.0, 130.7,
132.7, 135.8, 137.4, 137.5, 141.5, 150.0. Anal. Calcd.
for C25H20O3: C, 81.50; H, 5.47%. Found: C, 81.49; H,
5.57%.
(4.90 g, 18.1 mmol) was dissolved in H2O (100 ml). To
the resulting purple solution was added a solution of 12
(1.05 g, 3.62 mmol) in acetone (50 ml). The reaction
mixture was stirred at room temperature for 3 h, and then
extracted with CH2Cl2 (ꢂ4). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column
chromatography (silica gel 50 g, CH2Cl2/MeOH = 1:0
to 10:1) to afford 4 (1.11 g, 93% in 2 steps) as red
crystals. Mp 248–250 ꢁC (lit.8) 248–250 ꢁC) (CHCl3); IR
(KBr) ꢁmax (cmꢀ1): 2926, 1646, 1496, 1357, 1060, 963,
4,7-Diphenyl-5-benzyloxybenzo[d]-1,3-dioxole (11).
Into a flask were placed catechol 10 (2.00 g, 5.43 mmol),
K2CO3 (3.20 g, 23.1 mmol), DMF (60 ml) and CH2I2
(1.2 ml, 15 mmol), the whole mixture being degassed
through freeze-thaw cycles. The mixture was stirred for
1 h at 60 ꢁC, cooled to room temperature, and then
diluted with Et2O. The mixture was washed with a sat.
aqueous NH4Cl solution, and the aqueous layer was
extracted with Et2O (ꢂ3). The combined organic extract
was successively washed with water, a sat. aqueous
Na2SO3 solution and brine. The organic layer was dried
over anhydrous Na2SO4, filtered through a cotton pad,
and concentrated in vacuo. The residue was purified by
column chromatography (70 g of the silica gel, hexane/
CH2Cl2 = 1:3 to 1:2) to afford methylene ketal 11
(1.86 g, 74% in 2 steps) as a colorless powder. Mp
126.5–128 ꢁC; IR (KBr): ꢁmax (cmꢀ1) 3032, 2886, 1952,
1
812; H-NMR (300 MHz, CDCl3) ꢀ (ppm): 6.13 (2H, s,
OCH2O), 7.34–7.48 (6H, m, Ar), 7.60–7.66 (4H, m, Ar);
13C-NMR (100 MHz, CDCl3) ꢀ (ppm): 102.9, 113.8,
128.4, 128.8, 128.9, 129.6, 156.4, 176.3. Anal. Calcd.
for C19H12O4: C, 74.99; H, 3.97%. Found: C, 74.82; H,
4.27%.
Dihydro-phlebiarubrone monoacetate (13). To a
suspension of 4 (102 mg, 0.34 mmol) in Ac2O (10 ml)
was added Zn–Cu (130 mg, 1.01 mmol). After stirring at
40 ꢁC for 20 min, the reaction mixture was cooled to
0 ꢁC and quenched with AcOH (a few drops). The
mixture was filtered through the pad of Hyflo Super-
CelÒ and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography
(5 g of silica gel, CH2Cl2/hexane = 2:1 to 3:1) to afford
13 (104 mg, 90%) as a white solid. Mp 168–170 ꢁC; IR
(KBr) ꢁmax (cmꢀ1): 3393, 3063, 2900, 1748, 1715, 1415,
1
1405, 1068, 952; H-NMR (300 MHz, CDCl3) ꢀ (ppm):
5.01 (2H, s, OCH2Ph), 6.01 (2H, s, OCH2O), 6.73 (1H,
s, Ar), 7.26–7.49 (11H, m, Ar), 7.62–7.73 (4H, m, Ar);
13C-NMR (75 MHz, CDCl3) ꢀ (ppm): 71.9, 101.1, 106.1,
114.4, 121.0, 127.1, 127.6, 127.7, 127.8, 128.0, 128.4,
128.7, 130.3, 132.2, 135.9, 137.2, 139.5, 146.4, 151.5.
Anal. Calcd. for C26H20O3: C, 82.08; H, 5.30%. Found:
C, 82.08; H, 5.36%.
1
1231, 1057; H-NMR (400 MHz, CDCl3) ꢀ (ppm): 2.10
(3H, s, COCH3), 4.94 (1H, s, OH), 5.94 (2H, s, OCH2O),
7.34–7.46 (4H, m, Ar), 7.47–7.53 (4H, m, Ar), 7.57–
7.61 (2H, m, Ar), 7.57–7.61 (2H, m, Ar); 13C-NMR (100
MHz, CDCl3) ꢀ (ppm): 20.5, 101.3, 112.0, 117.3, 128.1,
128.4, 128.5, 129.0, 129.5, 129.9, 130.8, 131.6, 138.7,
139.8, 142.9, 169.2.
4,7-Diphenylbenzo[d][1,3]dioxol-5-ol (12). Com-
pound 11 (1.50 g, 4.00 mmol), EtOAc (80 ml), EtOH
(40 ml), and 10% Pd/C (1.5 g, wet water content =
55 wt %, purchased from Kawaken Fine Chemicals Co.,
Ltd.) were placed in a round-shaped flask (200 ml)
connected to a three-way cock. The atmosphere in the
reaction vessel was replaced with nitrogen, and then
filled with hydrogen (1 atm). After stirring for 5 h at
room temperature, the catalyst was filtered off through a
pad of Hyflo Super-CelÒ (rinsed with EtOAc). The
combined filtrate was concentrated under reduced
pressure to afford 12 (1.10 g), which was used in
the next reaction without further purification. IR (KBr)
Ustalic acid dimethyl ester (14). Into a flask was
placed phlebiarubrone 4 (40.0 mg, 0132 mmol) and
Pb(OAc)4 (1.16 g, 2.62 mmol). The reaction vessel was
evacuated and then filled with nitrogen. Toluene (3 ml)
and MeOH (2 ml) were added, the mixture was stirred at
room temperature for 41 h, and then filtered through a
pad of Hyflo Super-CelÒ. The filtrate was diluted with
water, and ethylene glycol (a few drops) was added. The
resulting solution was extracted with Et2O. The com-
bined organic layers were successively washed with
water (ꢂ1), a sat. aqueous NaHCO3 solution (ꢂ1), and
water (ꢂ1), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was
purified by column chromatography (5 g of silica gel,
EtOAc/hexane = 1:5) followed by preparative TLC
(EtOAc/hexane = 1:2, then CH2Cl2) to afford ustalic
acid dimethyl ester 14 (2.5 mg, 5.2%) as a yellow solid.
IR (KBr) ꢁmax (cmꢀ1): 2925, 1718, 1636, 1435, 1296,
1
ꢁmax (cmꢀ1): 3529, 3020, 2888, 1404, 1057; H-NMR
(300 MHz, CDCl3) ꢀ (ppm): 4.97 (1H, brs, OH), 5.98
(2H, s, OCH2O), 6.72 (1H, s, Ar), 7.31–7.59 (8H, m,
Ar), 7.71–7.77 (2H, m, Ar); 13C-NMR (75 MHz, CDCl3)
ꢀ (ppm): 101.2, 106.6, 111.4, 122.1, 127.7, 127.8, 128.5,
128.7, 129.3, 129.8, 131.1, 135.6, 138.6, 145.9, 148.0;
HR-MS (FAB, negative): calcd. For C19H13O3 (M ꢀ H),
289.0865; found, 289.0869.
1
1220, 1101; H-NMR (300 MHz, CDCl3) ꢀ (ppm): 3.73
(6H, s, COOCH3 ꢂ 2), 5.42 (2H, s, OCH2O), 7.31–7.41
Phlebiarubrone (4). Potassium nitrosodisulfonate
(10H, m, Ar); 13C-NMR (75 MHz, CDCl3) ꢀ (ppm):

Syntheses of Terphenyls and Related Compounds
3003
10) Yamazoe, A., Hayashi, K., Kuboki, A., Ohira, S., and
Nozaki, H., The isolation, structural determination, and
total synthesis of terfestatin A, a novel auxin signaling
inhibitor from Streptomyces sp. Tetrahedron Lett., 45,
8359–8362 (2004).
52.2, 96.1, 115.4, 128.0, 128.1, 130.0, 134.6, 148.8,
167.7; EI-MS m=z 366 (Mþ); HR-MS (FAB, positive):
calcd. for C21H19O6 (M þ H), 367.1182; found,
367.1179.
11) Cain, B. F., Potential anti-tumor agents. Part 1. Polyporic
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Acknowledgment
12) Balogh, V., Fetizon, M., and Golfier, M., Oxidation with
silver carbonate/Celite. V. Oxidations of phenols and
related compounds. J. Org. Chem., 36, 1339–1341
(1971).
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14) Jokela, R., and Lounasmaa, M., p-Terphenyl- and
phenanthraquinone derivatives: an NMR study. Planta
Med., 63, 381–383 (1997).
15) Demmin, T. R., and Rogic, M. M., Preparation of
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oxacyclohepta-3,5-diene-2,7-dione structure. J. Org.
Chem., 45, 1153–1156 (1980).
Financial support provided by PRESTO of the Japan
Science and Technology Agency (JST), Grant-in-Aid for
Specially Promoted Research and a 21st Century COE
grant from MEXT, and by the Fujisawa Foundation, is
gratefully acknowledged. We are grateful to Dr. Sheo B.
Singh (Merck Research Laboratories, NJ, USA) for his
direct comparison of synthetic and natural compound 2.
Elemental analyses were performed by Mr. S. Kitamura,
whom we thank.
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