Biomimetic synthesis of the dinaphthofuranquinone violet-quinone, utilizing oxidative dimerization with the ZrO2/O2 system

Article abstract of DOI:10.1016/j.tet.2004.03.038

The first total and biomimetic synthesis of violet-quinone (1), which has a dinaphthofuranquinone (DNFQ) framework, is described. This synthesis features the oxidative dimerization of 1-naphthol 4 and the construction of the DNFQ framework by photochemica

Full text of DOI:10.1016/j.tet.2004.03.038

Tetrahedron 60 (2004) 3941–3948
Biomimetic synthesis of the dinaphthofuranquinone
violet-quinone, utilizing oxidative dimerization with the
ZrO2/O2 system
*
Tokutaro Ogata, Iwao Okamoto, Eiichi Kotani and Tetsuya Takeya
Pharmaceutical Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
Received 10 February 2004; revised 11 March 2004; accepted 11 March 2004
Abstract—The first total and biomimetic synthesis of violet-quinone (1), which has a dinaphthofuranquinone (DNFQ) framework, is
described. This synthesis features the oxidative dimerization of 1-naphthol 4 and the construction of the DNFQ framework by photochemical
ring closure of 2,20-binaphthoquinone 7 as a key intermediate. Compound 7 was prepared by the n0ovel oxidative dimerization of 4 with a
semiconductor (such as ZrO2) in the presence of dioxygen, followed by oxidation of the resulting 2,2 -binaphthyl-1,10-quinone 6 with HNO3.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
subsequent intramolecular ring closure of biarylquinones C
or D to form the corresponding furan rings, as shown in
Figure 2.3 There is some support for such a biogenetic
pathway. Thus, violet-quinone (1), along with diosindigo B
(6c) and biramentaceone (7c), which are related to the
intermediates C and D, have been isolated from the
heartwood of Diospyros melanoxyloin,1 and its congener
Diospyros celebica4 also contains dihydrodiosindigo B (5c),
corresponding to B, together with 6c and 7c (refer to Fig. 2,
Schemes 2 and 3).
Among natural biarylquinones, dinaphthofuranquinones
(DNFQ) such as violet-quinone (1)1 and balsaminone A
(2),2 and dibenzofuranquinones (DBFQ) such as popolo-
huanone E (3),3 having the dibenzofuran-1,4-dione moiety
as a key structural element, have been isolated from several
plants and marine products. Compounds 2 and 3 show
antipruritic activity2 and selective cytotoxicity against A549
non-small cell lung cancer cells, respectively (Fig. 1).3
Figure 2.
Figure 1.
Although the synthesis of 3 has been explored5 owing to the
biological activity of 3, as described above, a total synthesis
has not yet been achieved. Violet-quinone (1) has an
analogous framework (the diarylfuran-1,4-dione moiety) to
popolohuanone E (3). From the viewpoint of the structure–
cytotoxic activity relationship of 3, compound 1 is of great
interest as a synthetic target. As yet, its synthesis has not yet
been accomplished.
A possible biogenetic pathway to biarylfuranquinones E
(DNFQs and DBFQs) would involve (i) the oxidative biaryl
coupling of the corresponding two aryls A (1-naphthols or
phenols), (ii) selective oxidation of biaryls B, and (iii)
Keywords: Violet-quinone; Dinaphthofuranquinone; First synthesis;
Oxidation; Zirconium dioxide.
*
Corresponding author. Tel./fax: þ81-427211579;
Several methods have been developed for the preparation of
e-mail address: takeya@ac.shoyaku.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.038

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T. Ogata et al. / Tetrahedron 60 (2004) 3941–3948
2,20-binaphthyl derivatives such as B, C and D by the
oxidative dimerization of 1-naphthols. These involve
chemical,6 electrolytic,7 thermal disproportionation8 and
air oxidation9 reactions. However, the reactions are difficult
to control, mostly showing poor selectivity and low yield of
the desired products, accompanied with side reactions.
Recently, much attention has been focused on the use of
various semiconductor catalysts,10 particularly TiO2, to
achieve a variety of organic reactions and syntheses on the
basis of the concept of green chemistry.11 More recently, we
developed a new and efficient method for the direct
synthesis of 2,20-binaphthyls, utilizing an oxidative dimer-
ization of 1-naphthols (NPOH), with semiconductors such
as ZrO2 and activated charcoal (Act-C) in the presence of
dioxygen (O2).12
This method has stimulated further studies with the aim of
applying it to biomimetic synthesis of natural products.
Here, we present the first total synthesis of violet-quinone
(1), utilizing the oxidative dimerization of NPOH 4b with
the ZrO2/O2 reagent system.
Scheme 1.
BNPQs. These include photochemical,13a,d thermal,13e and
chemical (with acid13d or base13f – h) reactions. We
examined the photolysis of 6a and 7a under various
conditions.
2. Results and discussion
2.1. Synthetic plan
The photolysis of 6a using a 60 W Hg lamp in CHCl3 with a
Pyrex vessel for a long time (80 h) gave 8a13a in 88% yield.
When we used a 450 W Hg lamp under similar conditions
but for a short time (1 h), DNFQ 9 (59%) and 8a (25%) were
obtained. In the photolysis of 7a, the best result was
obtained with a 450 W Hg lamp in CHCl3 for 2 h, affording
DNFQ 10 in 90% yield, and methylation of 10 with CH3I
gave 9 in 91% yield. This mechanism for the photochemical
conversion of 7a into 10 was proposed to proceed via ring
closure with rearrangement.13d,i The synthetic compounds
913a and 1013d,e were identical with the corresponding
compounds reported previously. In addition, the structures 9
and 10 were confirmed by analyses of the IR, 1H-, 13C NMR
spectra with the aid of 2D NMR analyses.
For our feasibility study, we envisioned the biomimetic
synthesis of DNFQ 1 through pathway (I) or (II), based on
our biogenetic hypotheses mentioned above (Fig. 2).
Pat0hway (I) consists of the formation of 2,20-binaphthyl-
1,1 -quinone (6; BNPTQ), which is related to intermediate
C, by the oxidative dimerization of NPOH 4 and the
construction of DNFQ framework by intramolecular ring
closure of 6. In contrast, pathway (II) involves the formation
of 2,20-binaphthoquinone (7; BNPQ), which is related to
intermediate D, and the construction of DNFQ framework
by ring closure of 7. These approaches are attractive because
of the simplicity of the reaction and its possible involvement
in biosynthesis of naturally occurring DNFQs and DBFQs
as described above.
2.3. First total synthesis of violet-quinone
On the basis of the results and information obtained from the
above model experiments, the synthesis of 1 utilizing 7b as
the key intermediate was investigated based on pathway
(II). First, NPOH 4b was synthesized according to the
protocol reported previously.14a,b,15a
2.2. Preliminary experiments for synthesis of violet-
quinone
As a prelude to the synthesis of violet-quinone (1),
preliminary experiments using 4-methoxy-1-naphthol 4a
as a model substrate were examined. These were based on
pathways (I) and (II) described above (Scheme 1).
In order to obtain BNPOH 5b or BNPTQ 6b as a precursor
for obtaining 7b, oxidative dimerization of 4b using several
reagents was examined (Table 1 and Scheme 2). The
reaction with Ag2O gave a mixture of 5b, 6b and the ortho-
naphthoquinone 11a (entry 1). However, 5b could not be
isolated because it proved very susceptible to air oxidation
and decomposition. The structure 5b was thus confirmed
by converting this compound into the benzylated derivative
5d.
First, BNPTQ 6a,13a the required model intermediate in
pathway (I), was prepared in 95% yield by the oxidative
dimerization of 4a with the Act-C/O2 system12 in MeCN.
The reaction with the ZrO2/O2 system under similar
conditions gave 6a (75%) along with 4-methoxy-1,2-
naphthoquinone (17%). Subsequently, 6a could be easily
converted to BNPQ 7a13d as the model intermediate in
pathway (II), in 99% yield, by oxidation with 69% HNO3.
In the case of the well-known AgO/HNO3 system,6m the
desired compound 7b was obtained in one step, but the yield
was not satisfactory (entry 2). Laatsch15a reported that the
Several methods have been reported for the construction of
the DNFQ framework by ring closure of BNPTQs or

T. Ogata et al. / Tetrahedron 60 (2004) 3941–3948
3943
Scheme 2.
oxidative dimerization of 4b with the Ag2O/NEt3 system6n
gave only 6b without any by-product. Re-examination of
the reaction by us afforded 6b (92%) together with the para-
naphthoquinone 11b (4%) (entry 3). The best result was
obtained by employing the novel oxidative dimerization
with the ZrO2/O2 reagent system, which we recently
developed, affording BNPTQ 6b15a selectively in excellent
yield (entry 5). Subsequent oxidation of 6b with 69% HNO3
produced 7b15a in 99% yield. When 6b prepared by means
of the above oxidation was used without purification, 7b
was obtained in a similar yield.
7b to produce 7c as a natural product, the so-called
biramentaceone,15a in 80% yield. The naphtholic hydroxyl
group of 7c was protected with a benzyl group using benzyl
iodide16 in the presence of K2CO3 to yield BNPQ 12.
Subsequently, the ring closure of 12 was achieved by means
of photolysis13a,b using a 450 W Hg lamp in CHCl3 with a
Pyrex vessel for 1 h to give DNFQ 13 in 87% yield. Next,
compound 14 was obtained by methylation of 13 with
methyl iodide. Finally, the reductive deprotection of the
benzyl group of 14 with 10% Pd/C–H2 gave violet-quinone
(1) in 96% yield, as a violet solid. All physical data, such as
1
the melting point, MS (Mass), IR (infrared) and H NMR
spectra of the synthetic product 1 were identical with those
of the natural product.1
Furthermore, the synthesis of 1 from the resulting 7b was
investigated, as shown in Scheme 3. Magnesium bromide
(MgBr2) effected demethylation of the methoxyl group of
Table 1. Oxidative dimerization of 4b with various reagents
Entry
Reagent
Time (h)
Product (isolated yield, %)
5d
6b
7b
11a
11b
1a,b
2b
Ag2O
0.5
0.5
0.5
24
30c
—
34
—
92
44
96
—
50
—
—
—
8
—
17
4
9
—
AgO/HNO3
Ag2O/NEt3
Act-Cd/O2
ZrO2/O2
—
—
11
—
3b
—
4a
5e
20c
—
19
a
This reaction with Ag2O in CHCl3 gave a complex mixture containing 5b.
In order to isolate 5b, we performed column chromatography of the
reaction mixture under various conditions. However, all the attempts
were unsuccessful, producing mainly solid mixtures of 5b and 6b.
Furthermore, the mixture of 5b and 6b was treated with benzyl iodide/
K2CO3 to give 5d together with non-reacted 6b.
Under air at 23 8C.
Yield from 4b.
Activated charcoal.
Using a dioxygen (O2)-saturated solvent (MeCN) at 70 8C.
b
c
d
e
Scheme 3.

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T. Ogata et al. / Tetrahedron 60 (2004) 3941–3948
2.4. Structure of violet-quinone
There is, to our knowledge, only one article relating to
violet-quinone (1). This was published by Shidhu et al. in
1981.1 In this article, a structural analysis of naturally
occurring 1 based on the analysis of 1H NMR spectrum was
described. However, 2D NMR methods and 13C NMR
spectroscopy were not employed. We therefore confirmed
the structure of the synthetic compound 1 by means of
detailed analyses of the 1H- and 13C NMR spectra with the
aid of various 2D NMR experiments.17
Figure 3. Long-range correlation in the HMBC spectrum of violet-quinone
(1).
quaternary, and five bearing oxygen (Table 2). Accordingly,
the above data proved that violet-quinone has the structure 1.
All 1H- and 13C NMR signal assignments, except for those
of the carbons C6a and C6b, were confirmed by means of
H–H COSY, C–H COSY and HMBC spectral analyses and
by comparison of the spectra with those of the reference
compounds 9, 10 (which were synthesized by us), and
balsaminone A (2) described in a previous report 2 (refer to
Table 2 and Fig. 3).
3. Conclusion
The first and biomimetic synthesis of the natural product
violet-quinone (1) using BNTQ 7b as a key intermediate
was accomplished, based on pathway (II), in 11 steps from
methyl 3-methyl-2-butenoate14a as a starting material with
an overall yield of ca. 13%. In this first synthesis, a key
intermediate 7b was selectively synthesized in excellent
yield by utilizing a novel oxidative dimerization of 4b with
the ZrO2/O2 system. Furthermore, the construction of the
DNFQ framework from BNPQ 12 was achieved by
photolysis using a 450 W Hg lamp. The structure of
violet-quinone has been established as 1 by this synthesis.
Investigations of the biological activity of the synthetic
compounds 1, 9 and 10 are in progress.
1
The H NMR spectrum of 1 showed the following signals:
(i) two singlets (d 2.52 and d 2.47) due to the C2- and C9-
methyl protons, a singlet (d 4.18) due to the C5-methoxyl
protons, and a singlet (d 7.35) assignable to the C6-proton;
(ii) a singlet (d 12.12) due to the hydrogen-bonded hydroxyl
at C-11 was observed at lower field than a singlet (d 9.41)
due to the C4-hydroxyl group. The 13C NMR spectrum of 1
displayed signals for all 23 carbons in the molecule: one
methoxyl, two carbonyls, two aromatic methyls and 18
aromatic carbons, five of which were protonated, eight
Table 2. 13C and 1H NMR spectral data (d, ppm) for compounds 1,a 2,a 9a and 10b
Carbon no.
Violet-quinone (1)
1Hd
Balsaminone A (2)2
9c
10c
13C
13C
1H
13C
1Hd
13C
1Hd
1
2
3
4
4a
5
6
6a
6b
7
7a
8
9
10
11
11a
12
12a
13a
13b
2-Me
4-OH
5-OMe
5-OH
6-OMe
9-Me
11-OH
112.2
140.8
115.9
155.3
113.1
156.1
95.0
123.2e
125.4e
181.3
133.3
121.3
148.3
124.7
162.9
113.2
178.8
152.2
149.8
118.9
21.7
7.75 br s
121.2
127.8
127.1
123.1
125.6
142.8
134.7
114.6
118.9
174.6
133.7
127.4
134.2
133.8
126.7
132.3
180.2
153.1
148.8
125.0
8.48 m
7.67 m
7.67 m
8.34 m
121.0
128.0
127.4
123.7
127.1
154.3
96.5
125.3
119.4
174.3
133.4f
126.9f
133.9f
133.8f
126.7f
132.9f
182.1
152.5
149.0
121.5
8.43 d (8.2)
120.0
127.9
126.8
123.4
125.7
146.9
98.6
124.1
119.0
173.4
132.7
125.9f
133.78f
133.82f
126.0f
132.3
181.2
152.2
152.4
120.7
8.35 m
7.70 dt (8.2, 1.2)
7.63 dt (8.2, 1.2)
8.38 d (8.2)
7.79 br t (7.9)
7.71 br t (7.9)
8.35 m
6.92 d (0.9)
7.35 s
7.46 s
7.55 s
7.57 d (0.9)
7.09 br s
8.30 m
7.80 m
7.80 m
8.30 m
8.25 m
7.78 m
7.78 m
8.25 m
8.18 m
7.91 m
7.91 m
8.18 m
2.52 s
9.41 s
4.18 s
55.8
22.2
56.2
4.12 s
6.33 s
4.09 s
10.54 s
63.4
2.47 sf
12.12 s
a
Data recorded in CDCl3 at 300 MHz (1H NMR) and 125 MHz (13C NMR).
Data recorded in CD3SOCD3 at 300 MHz (1H NMR) and 125 MHz (13C NMR).
Assignment based on 1H–1H COSY, 1H–13C COSY and HMBC spectra.
Coupling constants (J in Hz) are in parentheses.
b
c
d
e
f
Only the chemical schift of a methyl proton signal (d 2.47) at the C9 position was different from that (d 2.74) in the previous report.1
Interchangeable.

T. Ogata et al. / Tetrahedron 60 (2004) 3941–3948
3945
4. Experimental
4.1.2. Oxidation of 6a with 69% HNO3. A mixture of 69%
HNO3 (2 ml) and 6a (46 mg, 0.27 mmol) was stirred at 0 8C
for 15 min. The reaction mixture was poured into a large
volume of ice–water. The precipitated product was
recrystallized from CHCl3 to yield 42 mg (99%) of 2,20-
binaphthalenyl-1,4,10,40-tetraone (7a), as yellow needles,
4.1. General
All melting points are uncorrected Infrared (IR) spectra
were recorded with a JASCO IR-700 spectrometer, and 1H-
and 13C NMR spectra with JEOL JNM-AL300 and
JNM-alpha 500 spectrometers, with tetramethylsilane as
an internal standard (CDCl3, CD3COCD3 or CD3SOCD3
solution). Mass spectra were recorded on a JEOL
JMS-D300 or Shimadzu QP-5000 spectrometer. Elemental
analyses were done using a Yanaco CHN-MT-3 apparatus.
Merck Kieselgel 60 (230–400 mesh), Wako silica gel
C-200 (200 mesh) and Merck Kieselgel 60 F254 were used
for flash column chromatography, column chromatography
and thin-layer chromatography (TLC), respectively. Each
organic extract was dried over MgSO4 or Na2SO4.
Photolyses were conducted with a Eikohsha 60 W low-
pressure or 450 W high-pressure mercury lamp and
irradiation was performed through a Pyrex vessel. The
semiconductors, such as ZrO2 and activated charcoal
powders, are commercially available (Wako Pure Chemical
Industries, Ltd, Japan).
mp 288 8C (decomp.) (lit.13b 270–280 8C). IR (KBr) cm21
:
1
1664, 1613, 1587. H NMR (CDCl3) d: 7.07 (2H, s, 3 and
30-H), 7.75–7.80 (4H, m, Ar–H), 8.12–8.16 (4H, m,
Ar–H). LR-MS m/z: 314 (Mþ). HR-MS calcd for
C20H10O4: 314.0576. Found: 314.0561.
4.1.3. Photolysis of 6a. Method A (with a 450 W mercury
lamp). A solution of 6a (25 mg, 0.15 mmol) in an argon-
saturated CHCl3 (10 ml) in a Pyrex vessel was irradiated
using a 450 W high-pressure Hg lamp for 1 h, and then
evaporated. The residue was subjected to flash column
chromatography on silica gel. The eluate with CH2Cl2/
hexane (2:1,0 v/v) gave 6 mg (25%) of 10-hydroxy-40-
methoxy-[2,2 ]binaphthalenyl-1,4-dione (8a) and 14 mg
(59%) of 5-methoxy-dinaphtho[1,2-b;20,30-d]furan-7,12-
dione (9).
Compound 8a. Deep violet needles (benzene), mp 189 8C
(lit.13c 185–186 8C). IR (KBr) cm21: 3328, 1655, 1590. 1H
NMR (CDCl3) d: 3.99 (3H, s, 40-OMe), 6.56 (1H, s, 30-H),
7.15 (1H, s, 3-H), 7.57–7.60 (2H, m, Ar–H), 7.81–7.85
(2H, m, Ar–H), 8.14–8.28 (3H, m, Ar–H), 8.39–8.42 (1H,
m, Ar–H), 8.51 (1H, s, 10-OH). 13C NMR (CDCl3) d: 55.81
(C40-OMe),0 104.65 (C30), 114.43 (C20), 121.73 (C800),
123.77 (C5 ), 126.30 (C5 or C8), 126.72 (C60 or C7 ),
127.32 (C8a0), 127.55 (C60 or C70), 127.76 (C5 or C8),
127.99 (C4a0), 131.75 (C4a or C8a), 132.57 (C4a or C8a),
134.05 (C6 or C70), 134.82 (C6 or C7), 138.89 (C3), 145.48
(C10), 149.71 (C4 ), 150.00 (C2), 184.49 (C1 or C4), 188.49
(C1 or C4). LR-MS m/z: 330 (Mþ). HR-MS calcd for
C21H14O4: 330.0888. Found: 330.0922.
4.1.1. Oxidative dimerization of 4a. Method A (with the
Act-C/O2 system). A slurry of activated charcoal powder
(1 g) and 4a (100 mg, 0.58 mmol) in a dioxygen-saturated
MeCN (15 ml) was vigorously stirred at 70 8C for 16 h
under normal laboratory light. A similar result was
obtained in the dark. The insoluble reagent was filtered off
and washed with MeCN, and then the filtrate was
evaporated. The residue was subjected to flash column
chromatography on silica gel. The eluate with CH2Cl2/
hexane (1:1, v/v) gave 95 mg (95%) of 4,40-dimethoxy-
[2,20]binaphthalenylidene-1,10-dione (6a), as deep blue
needles, mp 257–258 8C (lit.13a 256–258 8C). IR
1
(KBr) cm21: 1606, 1584, 1561. H NMR (CDCl3) d: 4.08
(6H, s, 4 and 40-OMe), 7.48 (2H, broad t, J¼7.7 Hz, 7 and
70-H), 7.61 (2H, broad t, J¼7.70Hz, 6 and 60-H), 7.79 (2H,
broad d, J¼7.7 H0z, 8 and 8 -H), 8.17 (2H, broad d,
J¼7.7 Hz, 5 and 5 -H), 8.42 (2H, s, 3 and 30-H). LR-MS
m/z: 344 (Mþ). HR-MS calcd for C22H16O4: 344.1044.
Found: 344.1029.
Compound 9. Orange needles (CHCl3–hexane), mp 291.5–
292.5 8C (lit.13a 293–295 8C). IR (KBr) cm21: 1665, 1590.
LR-MS m/z: 328 (Mþ).
Method B (with a 60 W mercury lamp). Photolysis of 6a
(25 mg, 0.15 mmol) was carried out under a 60 W low-
pressure Hg lamp at 23 8C for 80 h by the same procedure
under the conditions described above (method A) for the
photolysis of 6a. The crude product was purified by flash
column chromatography on silica gel. The eluate with
CH2Cl2/hexane (2:1, v/v) gave 21 mg (88%) of 8a.
Method B (with the ZrO2/O2 system). A slurry of ZrO2
powder (5 g) and 4a (100 mg, 0.58 mmol) in dioxygen-
saturated MeCN (15 ml) was vigorously stirred at 70 8C for
1.5 h under normal laboratory light. The insoluble reagent
was filtered off and washed with MeCN, and then the filtrate
was evaporated. The residue was purified by the same
method described above to give 6a (75%) and 19 mg (17%)
of 4-methoxy-1,2-naphthoquinone, as yellow needles
(hexane–AcOEt), mp 192–193 8C (lit.13j 188–189 8C). IR
(KBr) cm21: 1700, 1627, 1607, 1588. 1H NMR (CDCl3) d:
4.03 (3H, s, 4-OMe), 5.99 (1H, s, 3-H), 7.59 (1H, dt, J¼7.9,
1.3 Hz, 6 or 7-H), 7.70 (1H, dt, J¼7.9, 1.3 Hz, 6 or 7-H),
7.87 (1H, dd, J¼7.9, 1.3 Hz, 5-H), 8.13 (1H, dd, J¼7.7,
1.5 Hz, 8-H). 13C NMR (CDCl3) d: 56.81 (C4–OMe),
103.04 (C3), 124.73 (Ar–C), 129.05 (Ar–C), 130.33 (C4a
or C8a), 131.52 (Ar–C), 131.96 (C4a or C8a), 134.96
(Ar–C), 168.68 (C4), 179.39 (C1 or C2), 179.49 (C1 or C2).
LR-MS m/z: 188 (Mþ). HR-MS calcd for C11H8O3:
188.0479. Found: 188.0475.
4.1.4. Photolysis of 7a. Photolysis of 7a (20 mg,
0.06 mmol) was carried out at 23 8C for 2 h by the same
procedure under the conditions described above (method A)
for the photolysis of 6a. The crude product was purified by
recrystallization from CHCl3–MeOH to yield 18 mg (90%)
of 5-hydroxy-dinaphtho[1,2-b;20,30-d]furan-7,12-dione (10)
as red needles, mp 305–308 8C (lit.13e 360 8C). IR
(KBr) cm21: 3310, 1654, 1592. LR-MS m/z: 314 (Mþ).
HR-MS calcd for C20H10O4: 314.0576. Found: 314.0560.
4.1.5. Methylation of 10. CH3I (24 ml, 0.4 mmol) was
added to a solution of 10 (30 mg, 0.10 mmol) and anhydrous
K2CO3 (132 mg) in dry DMF (12 ml), and the solution was

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T. Ogata et al. / Tetrahedron 60 (2004) 3941–3948
stirred vigorously at 23 8C for 4 h. The reaction mixture was
poured into ice–water, neutralized with 10% HCl, and
extracted with CHCl3. The organic layer was washed with
H2O, dried and concentrated. The residue was purified by
recrystallization from CHCl3–MeOH to yield 28 mg (91%)
of 9.
21.6 (7-Me), 56.75, 56.81 (4 and 5-OMe), 102.1 (C3), 116.2
(C4a), 120.8, 123.8 (C6 and C8), 132.2 (C8a), 143.8 (C7),
158.2 (C5), 172.7 (C4), 179.1, 180.6 (C1 and C2). LR-MS
m/z: 232 (Mþ). Anal. Calcd for C13H12O4: C, 67.23; H, 5.21.
Found: C, 67.20; H, 5.19.
Method B (entry 2) (with AgO/40% HNO3). To a mixture of
4b (50 mg, 0.229 mmol) and AgO (284 mg, 2.29 mmol) in
acetone (5 ml) was added 40% HNO3 (1.5 ml) over 5 min.
The reaction mixture was stirred at room temperature for
30 min, diluted with water and extracted with CHCl3. The
extracts were washed with brine, dried over MgSO4 and
evaporated. The residue was purified by flash column
chromatography on silica gel. The eluate with CHCl3/
AcOEt (20:1, v/v) gave 23 mg (50%) of 5,50-dimethoxy-
7,70-dimethyl-[2,20]binaphthalenyl-1,4,10,40-tetraone (7b)
and 8 mg (17%) of 5-methoxy-8-methyl-1,4-naphtho-
quinone (11b).
4.1.6. Oxidative dimerization of 1-naphthol 4b with
various reagents. Method A (entry 1) (with Ag2O). A
mixture of 4b (50 mg, 0.23 mmol) in CHCl3 (10 ml)
containing 1.5 equiv. of Ag2O (80 mg, 0.344 mmol) was
stirred at 23 8C in an air atmosphere for 1 h. The solvent was
removed and the residue was subjected to flash column
chromatography on silica gel using CH2Cl2/hexane (1:2,
v/v) as an eluent to give a mixture of 5b and 6b, and 4,
5-dimethoxy-7-methyl-1,2-naphthoquinone (11a). Benzyl
iodide (268 ml, 2.26 mmol) was added to a solution of the
mixture of 5b and 6b, and anhydrous K2CO3 (312 mg) in
dry DMF (5 ml), and the solution was stirred vigorously at
23 8C for 40 min. The reaction mixture was poured into
ice–water, neutralized with 10% HCl, and extracted with
CH2Cl2. The organic layer was washed with H2O, dried and
concentrated. The residue was subjected to flash column
chromatography on silica gel. The eluate with0 h0exane/
AcOEt (10:1, v/v) gave 1,10-dibenzyloxy-4,5, 4 ,5 -tetra-
methoxy-[2,20]binaphthalenyl-1,10-diol (5d) and 4,5,40,50-
tetramethoxy-7,70-dimethyl-[2,20]binaphthalenyli-dene-
1,10-dione (6b). Yields are listed in Table 1.
Compound 7b. Yellow amorphous powder (CHCl3 –
MeOH), mp 279–281 8C (lit.15a 310 8C). IR (KBr) cm21
:
1
1649, 1601, 1587. H NMR (CDCl3) d: 2.50 (6H, s, 7 and
70-Me), 4.02 (6H, s, 5 and 50-OMe), 6.94 (2H, s, 3 and 30-H),
7.13 (2H, broad s, 6 and 60-H), 7.59 (2H, broad s, 8 and
80-H). HR-MS calcd for C24H18O6: 402.1098. Found:
402.1133. Anal. Calcd for C24H18O6: C, 72.64; H, 4.51.
Found: C, 72.60; H, 4.50.
Compound 11b. Yellow needles (benzene), mp 169.5–
170 8C (lit.14b 164–166 8C). IR (KBr) cm21: 1651, 1559.
1H NMR (CDCl3) d: 2.48 (3H, s, 7-Me), 4.00 (3H, s,
5-OMe), 6.84 (2H, s, 2 and 3-H), 7.11 (1H, s, 6-H), 7.55
(1H, s, 8-H). HR-MS calcd for C12H10O3: 202.0627. Found:
202.0614.
Compound 5d. Pale yellow powder (AcOEt), mp 203.5–
204.0 8C. IR (KBr) cm21: 2922, 1604. 1H NMR (CDCl3) d:
2.50 (6H, s, 7 0and 70-Me), 3.91 (6H, s, 4 and 40-OMe), 4.02
(6H, s, 5 and 5 -OMe), 4.71 (4H, s, 2£–CH2–Ar), 6.78 (2H,
d, J¼1.29 Hz, 6 and 60-H), 7.17 (2H, s, 3 and 30-H), 7.20–
7.30 (10H, m, Ar–H), 7.67 (2H, d, J¼1.29 Hz, 8 and 80 –H).
13C NMR (CDCl3) d: 22.23 (7- and 70 –Me), 56.55 (5-OMe),
56.62 (4-OMe), 75.14 (–CH2–Ar), 108.27 (C3), 109.07
(C6), 114.49 (C8), 116.21 (C2), 127.46 (C4a), 127.87
(Ar–C), 128.10 (Ar–C), 128.35 (Ar–C), 132.104 (C8a),
136.65 (C7), 137.32 (Ar–C), 145.16 (C1), 152.82 (C4),
157.13 (C5). LR-MS m/z: 614 (Mþ). HR-MS: calcd for
C40H38O6: 614.2658. Found: 614.2642. Anal. Calcd for
C40H38O6: C, 78.15; H, 6.23. Found: C, 78.13; H, 6.20.
Method C (entry 3) (with Ag2O/NEt3). A mixture of 4b
(100 mg, 0.58 mmol) in CHCl3 (20 ml) containing 0.2%
NEt3 and 20 equiv. of Ag2O (2.66 g) was stirred at 23 8C in
an air atmosphere for 1 h. The solvent was removed and the
residue was subjected to flash column chromatography on
silica gel. The eluate with CH2Cl2/hexane (1:2, v/v) gave 7b
and 11b. Yields are listed in Table 1.
Method D (entry 4) (with the Act-C/O2 system). Oxidation
of 4b (100 mg, 0.58 mmol) was carried out at 70 8C for 24 h
by the same procedure under the conditions described
above (method A) for the oxidative dimerization of 4a.
The crude product was purified by flash column chroma-
tography on silica gel. The eluate with CH2Cl2/hexane
(1:2, v/v) gave 5d, 6b, 11a and 11b. Yields are listed in
Table 1.
Compound 6b. Deep violet needles, mp 236.5–237 8C
(lit.15a 228 8C). IR (K0 Br) cm21: 1589. 1H NMR (CDCl3) d:
2.43 (6H, s, 7 and 7 -Me), 3.92 (6H, s, 4 and 40-OMe), 4.05
(6H, s, 5 and 50-OMe), 6.98 (2H, broad t, 0J¼0.9 Hz, 6 and
60-H), 7.070 (2H, broad t, J¼0.9 Hz, 8 and 8 -H), 8.37 (2H, s,
3 and 3 -H). 13C NMR (CDCl3) d: 21.76 (7 and 70-Me),
56.08 (Ar–OMe), 56.91 (Ar–OMe), 103.21 (C3 and C30),
117.99, 118.18 (C6 and C60,or C8 and C80), 121.74 (C6 and
C60,or C8 and C80), 130.32 (Ar–C), 133.60 (Ar–C), 140.27
(Ar–C), 156.14 (Ar–C), 159.46 (Ar–C), 188.93 (C1 and
C10). HR-MS calcd for C26H24O6: 432.1566. Found:
432.1563. Anal. Calcd for C26H24O6: C, 72.21; H, 5.59.
Found: C, 72.35; H, 5.56.
Method E (entry 5) (with the ZrO2/O2 system). Oxidation of
4b (100 mg, 0.58 mmol) was carried out at 70 8C for 19 h by
the same procedure under the conditions described above
(method B) for the oxidative dimerization of 4a. The crude
product was purified by recrystallization from benzene to
yield 6b (96%).
Compound 11a. Orange powder (CHCl3–hexane), mp
175.0–175.5 8C. IR (KBr) cm21: 1642, 1603, 1580. 1H
NMR (CDCl3) d: 2.42 (3H, s, 7 and 7-Me), 3.92, 3.97 (6H,
each s, 4 and 5-OMe), 5.89 (1H, s, 3-H), 7.07 (1H, br s,
6-H), 7.63 (1H, d, J¼0.74 Hz, 8-H). 13C NMR (CDCl3) d:
4.1.7. Oxidation of 6b with 69% HNO3. A mixture of 69%
HNO3 (3 ml) and 6b (80 mg, 0.17 mmol) was stirred at 0 8C
for 15 min. The reaction mixture was poured into a large
volume of ice–water. The precipitated product was

T. Ogata et al. / Tetrahedron 60 (2004) 3941–3948
3947
recrystallized from CHCl3/MeOH to yield 73 mg (99%) of
7b.
(Ar–C), 138.40 (C2), 146.60 (C9), 147.08 (C13a), 153.56
(C5), 154.12 (C12a), 155.67 (C4), 159.89 (C11), 174.12
(C12), 181.49 (C7). HR-MS calcd for C36H26O6: 554.1722.
Found: 554.1867. Anal. Calcd for C36H26O6: C, 77.96; H,
4.73. Found: C, 77.99; H, 4.75.
4.1.8. 5,50-Dihydroxy-7,70-dimethyl-[2,20]binaphthale-
nyl-1,4,10,40-tetraone (biramentaceone) (7c). Magnesium
bromide (2.2 g, 12 mmol) was added to a solution of 7b
(200 mg, 0.5 mmol) dissolved in anhydrous toluene (30 ml)
and the whole was refluxed for 12 h. The reaction was
quenched with cooled water and saturated NH4Cl solution,
and the whole stirred for 30 min. The mixture was extracted
with CHCl3, and the CHCl3 layer was washed with H2O,
dried, concentrated, and then the residue was subjected to
flash column chromatography on silica gel. The eluate with
hexane/AcOEt (5:1, v/v) gave 150 mg (80%) of 7c as an
orange amorphous powder (CHCl3–MeOH), mp
4.1.11. 4,11-Bis-benzyloxy-5-methoxy-2,9-dimethyl-di-
naphtho[1,2-b;2030-d]furan-7,12-dione (14). Methyl iodide
(0.14 ml, 2.29 mmol) was added to a solution of 13 (100 mg,
0.19 mmol) and anhydrous K2CO3 (260 mg) in dry DMF
(10 ml), and the solution was stirred at 23 8C for 2 h with
vigorous stirring. The reaction mixture was poured into ice–
water, and extracted with CHCl3. The organic layer was
washed with H2O, dried and concentrated. The residue was
subjected to flash column chromatography on silica gel. The
eluate with AcOEt/hexane (1:1, v/v) gave 85 mg (79%) of
14 as red needles (CHCl3–MeOH), mp 322–324 8C. IR
264–265 8C (decomp.) (lit.15a 260 8C). IR (KBr) cm21
:
3426, 1665, 1641, 1574. 1H NMR (CDCl3) d: 2.45 (6H, s, 7
and 70-Me), 7.01 (2H, s, 3 and 30-H), 7.12 (2H, dd, J¼0.9,
1.7 Hz, 6 and 60-H), 7.49 (2H, 0dd, J¼0.9, 1.7 Hz, 8 and
80-H), 11.79 (2H, s, 5 and 5 -OH). HR-MS calcd for
C22H14O6: 374.0786. Found: 374.0787. Anal. Calcd for
C22H14O6: C, 70.58; H, 3.77. Found: C, 70.47; H, 3.75.
1
(KBr) cm21: 1662, 1598, 1567. H NMR (CDCl3) d: 2.50
(3H, s, 2-Me), 2.55 (3H, s, 9-Me), 4.05 (3H, s, 5-OMe), 5.21
(2H, s, 4-OCH2), 5.31 (2H, s, 11-OCH2), 6.95 (1H, broad s,
3-H), 7.18 (1H, broad s, 10-H), 7.43 (1H, s, 6-H), 7.33–7.73
(10H, m, Ar-H), 7.73 (1H, s, 8-H), 7.93 (1H, s, 1-H).
HR-MS calcd for C37H28O6: 568.1878. Found: 568.1926.
Anal. Calcd for C37H28O6: C, 78.15; H, 4.96. Found: C,
78.13; H, 4.99.
4.1.9. 5,50-Bis-benzyloxy-7,70-dimethyl-[2,20]binaphth-
alenyl-1,4,10,40-tetraone (12). Benzyl iodide (72 ml,
0.54 mmol) was added to a solution of 7c (20 mg,
0.054 mmol) and anhydrous K2CO3 (76 mg) in dry DMF
(10 ml), and the solution was stirred vigorously at 23 8C for
1 h. The reaction mixture was poured into ice–water,
neutralized with 10% HCl, and extracted with CHCl3. The
organic layer was washed with H2O, dried and concentrated.
The residue was subjected to flash column chromatography
on silica gel. The eluate with benzene/acetone (40:1, v/v)
gave 24 mg (78%) of 12 as yellow amorphous powder
(CHCl3–MeOH), mp 192–193 8C. IR (KBr) cm21: 1654,
4.1.12. 4,11-Dihydroxy-5-methoxy-2,9-dimethyl-dinaph-
tho[1,2-b;20,30-d]furan-7,12-dione (violet-quinone) (1).
Compound 14 (46 mg, 0.08 mmol) was hydrogenated in
the presence of 10% Pd/C (20 mg) in ethyl acetate (8 ml).
The catalyst was removed, and the filtrate was concentrated.
The residue was subjected to flash column chromatography
on silica gel. The eluate with CH2Cl2 gave 30 mg (96%) of 1
as violet solid (CHCl3–MeOH), mp 332–335 8C (lit.1 335–
338 8C). IR (KBr) cm21: 3370, 1664, 1640, 1607. HR-MS
calcd for C23H16O6: 388.0942. Found: 388.0957. Anal.
Calcd for C23H16O6: C, 71.13; H, 4.15. Found: C, 71.23; H,
4.18.
0
1
1598. H NMR (CDCl3) d: 2.46 (6H, s, 7 and 7 -Me), 5.31
(4H, s, –OCH2), 6.95 (2H, s, 3 and 30-H), 7.17 (2H, broad d,
J¼0.7 Hz, 6 and 60-H), 7.33–7.600 (10H, m, Ar–H), 7.58
(2H, broad d, J¼0.7 Hz, 8 and 8 -H). HR-MS calcd for
C36H26O6: 554.1722. Found: 554.1740. Anal. Calcd for
C36H26O6: C, 77.96; H, 4.73. Found: C, 77.92; H, 4.70.
References and notes
4.1.10. 4,11-Bis-benzyloxy-5-hydroxy-2,9-dimethyl-di-
naphtho[1,2-b;20,30-d]furan-7,12-dione (13). A solution
of 17 (20 mg, 0.036 mmol) in argon-saturated CHCl3
(10 ml) in a Pyrex vessel was irradiated using a 450 W
high-pressure Hg lamp for 1 h, and then evaporated. The
residue was subjected to flash column chromatography on
silica gel. The eluate with CH2Cl2/hexane (2:1, v/v) gave
18 mg (87%) of 13 as red needles (CHCl3–MeOH), mp
258–258.5 8C. IR (KBr) cm21: 3406, 1662, 1598, 1505. 1H
NMR (CDCl3) d: 2.49 (3H, s, 9-Me), 2.54 (3H, s, 2-Me),
5.29 (2H, s, C4–OCH2), 5.30 (2H, s, C11–OCH2), 6.90
(1H, broad s, 3-H), 7.18 (1H, broad s, 10-H), 7.43 (1H, s,
6-H), 7.31–7.73 (10H, m, Ar–H), 7.73 (1H, broad d,
J¼0.9 Hz, 8-H), 7.93 (1H, broad d, J¼0.9 Hz, 1-H), 9.39
(1H, s, 5-OH). 13C NMR (CDCl3) d: 22.01 (C2–Me), 22.31
(C9–Me), 70.98 (C11–OCH2), 72.09 (C4–OCH2), 101.10
(C6), 110.08 (C3), 113.58 (C4a), 114.65 (C1), 118.37
(C11a), 120.21 (C10), 120.55 (C13b), 121.17 (C8), 122.70
(C6a or C6b), 123.27 (C6a or C6b), 126.67 (Ar–C), 127.83
(Ar–C), 128.14 (Ar–C), 128.66 (Ar–C), 129.10 (Ar–C),
129.17 (Ar–C), 134.80 (Ar–C), 135.86 (C7a), 136.25
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17. 2D NMR experiments: H–1H shift correlation spectroscopy
(H–H COSY); 13C–1H shift correlation spectroscopy (C–H
COSY), 1H-detected heteronuclear multiple bond connectivity
(HMBC); and nuclear Overhauser enhancement and exchange
spectroscopy (NOESY) experiments.