Syntheses of prekinamycin and a tetracyclic quinone from common synthetic intermediates

Article abstract of DOI:10.1002/hlca.201000296

Towards total synthesis of a series of kinamycin and related antibiotics via common synthetic intermediates, total synthesis of prekinamycin was achieved via Suzuki coupling of naphthaleneboronic acid and bromobenzene derivative, intramolecular Friedel-Crafts reaction of 2-(naphthalen-2-yl)benzoic acid, and diazotization in ten steps from 3,5-dimethylphenol. Synthetic studies towards kinamycin antibiotics was also examined, and the tetracyclic quinone core for kinamycins was synthesized. Palladium-catalyzed site-selective hydroxylation of a benzoic acid derivative with the AB-D ring part was successfully applied to the selective D-ring functionalizations. Copyright

Full text of DOI:10.1002/hlca.201000296

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Helvetica Chimica Acta – Vol. 94 (2011)
Syntheses of Prekinamycin and a Tetracyclic Quinone from Common
Synthetic Intermediates
by Shingo Kimura, Satoshi Kobayashi, Takuya Kumamoto*1), Aki Akagi, Naomi Sato,
and Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan
Towards total synthesis of a series of kinamycin and related antibiotics via common synthetic
intermediates, total synthesis of prekinamycin was achieved via Suzuki coupling of naphthaleneboronic
acid and bromobenzene derivative, intramolecular FriedelꢀCrafts reaction of 2-(naphthalen-2-yl)ben-
zoic acid, and diazotization in ten steps from 3,5-dimethylphenol. Synthetic studies towards kinamycin
antibiotics was also examined, and the tetracyclic quinone core for kinamycins was synthesized.
Palladium-catalyzed site-selective hydroxylation of a benzoic acid derivative with the AB-D ring part was
successfully applied to the selective D-ring functionalizations.
Introduction. – Kinamycin antibiotics [1] were isolated from culture broth of
¯
Streptomyces murayamaensis by Omura and co-workers [2], and they possess antiviral
activity towards Gram-positive bacteria as well as antitumor activity [2b]2). The structure
was at first determined as N-cyanobenzo[b]carbazoloquinone 1 (cf. Fig. 1) [4]. Later, the so
called ꢀprekinamycinꢁ was isolated from the same bacterium by Seaton and Gould [5],
which was identified as 2, with an aromatized D ring of 1. Reinvestigation of spectroscopic
data [6], the isolation of other metabolites [7], and synthetic studies of kinamycins [8 –10]
including our work [11] resulted in the revision of the structures: i) Kinamycins are not
cyanamides 1 but diazo alkanes 3. ii) The structure of so-called ꢀprekinamycinꢁ isolated by
Seaton and Gould (vide infra) was revised as, temporarily, diazobenzo[b]fluorene 4
[6a][6b] and, finally, diazobenzo[a]fluorene 5, renamed as isoprekinamycin [6c]. iii) The
compound with the structure 4 was isolated as a metabolite produced by S. murayamensis
mutant MC2 [7] and finally named as prekinamycin [6c]. Recent progress on the isolation
[12] and synthetic studies [13] of the antitumor antibiotic lomaiviticin A (6), a dimerized
diazobenzo[b]fluorene, confirms the importance of this class of natural products.
We have continued efforts for synthetic studies towards polyketide antibiotics such
as kinamycins (3) [11][14] and jadomycin A (7) [15] (Fig. 1). Next, we planned the
total synthesis of these antibiotics including prekinamycin (4) via common synthetic
intermediates. We herein report the total synthesis of prekinamycin (4) and a
tetracyclic quinone towards kinamycins, 3.
1
)
Present address: Faculty of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi,
Nishitokyo, Tokyo 202-8585, Japan (phone/fax: þ 81-42-468-9278; e-mail: t_kum632@musashino-
u.ac.jp).
2
)
For examples of recent studies on cytotoxicity of kinamycins and related compounds, see [3].
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 94 (2011)
579
Fig. 1. Structures of kinamycin and the related antibiotics
Results and Discussion. – We considered benzofluorenone 8 or 2-(naphthalen-2-
yl)benzoic acid 93) as the common synthetic intermediates, accessible by Suzuki
coupling of oxygenated naphthalene-2-boronic acid 10 and bromobenzene 11 with a
more labile protecting group (P) than the Me group on the phenolic OH group on ring
D for selective functionalization (Scheme 1). We started the synthesis of these
intermediates according to a modified procedure reported by Koyama and Kamikawa
[16b].
At first, the (tert-butyl)(dimethyl)silyl (TBS) group was chosen as the protecting
group of phenol OH on ring D. One of the benzylic Me groups of the TBS ether 12b
derived from 3,5-dimethylphenol (12a) was brominated by N-bromosuccinimide (NBS)
in the presence of catalytic amount of azobis[isobutyronitrile] (AIBN) in refluxing
cyclohexane (Scheme 2). Benzyl bromide 13b was treated with 2-nitropropane and
NaH under HassꢀBender condition [17] to afford aldehyde 14b [18]. Site-selective
lithiationꢀbromination via aminal 15b from aldehyde 14b and lithium amide, prepared
from N,N,N’-trimethylethylenediamine and BuLi, gave the desired bromo derivative
16b only in 9% yield. Expecting a more rigid chelation toward lithium cation like 15c’,
the protecting group was changed from TBS to the methoxymethyl (MOM) group.
3
)
For similar intermediates employed for the syntheses of gilvocarcin aglycon and stealthin
derivatives, respectively, see [16].

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 1. Retrosynthetic Analysis of Kinamycins (3) and Prekinamycin (4)
Thus, the MOM-protected aldehyde 14c, prepared in a similar manner as 14b, via
MOM ether 12c was subjected to the same bromination condition, and the desired 16c
was obtained in improved yield (58%). Methyl ester 17c was prepared as an alternative
substrate for Suzuki coupling by oxidation of aldehyde 16c with I2 in the presence of
KOH in MeOH [19]. Suzuki coupling reaction with naphthalene-2-boronic acid 10 [16]
and bromo-benzaldehyde 16c in 1,2-dimethoxyethane (DME) for the conjunction of
AB and D ring parts gave the desired 2-(naphthalen-2-yl)benzaldehyde 18 in 97%
yield. However, application of ester 17c for this reaction failed: only a trace amount of
the desired ester 19 was obtained. The yield of 19 could not be improved even by using
another solvent system such as benzene/EtOH [16a] instead of DME (Scheme 2).
Next, oxidation of aldehyde 18c to ester 19 and carboxylic acid 20 was attempted.
No reaction occurred with I2/KOH in MeOH [19]. Quinone ketal 214) and the
corresponding epoxide 22 (Fig. 2) were generated instead of the desired 20 with
NaClO2 [20]. Only the system NaOH/H2O2 [16b] gave the desired carboxylic acid 20.
Attempts of intramolecular FriedelꢀCrafts reaction (IFCR) of 20 in a one-pot
procedure with (CF3CO)2O [8a] or POCl3/K2CO3 [21] led to complex mixtures.
Conversion of acid 20 to acid chloride 23 with (COCl)2 in CH2Cl2 at room temperature,
followed by IFCR with SnCl4 [16b], gave the key MOM-deprotected benzo[b]fluor-
enone 8 only in 4% yield (Scheme 3). Preparation of acid chloride 23 in MeCN instead
of CH2Cl2 as a solvent at higher temperature (808) and application of AlCl3 as a Lewis
acid for IFCR improved the yield of 8 up to 81%5). Demethylation of 8 with BBr3 gave
4
)
)
For similar oxidation reaction with ceric ammonium nitrate (CAN), see [16a].
Yields of IFCR with other Lewis acids: TiCl4, 33%; SnCl4, 67%.
5

Helvetica Chimica Acta – Vol. 94 (2011)
581
Scheme 2. Synthesis of 2-(Naphthalen-2-yl)benzaldehyde 18
a) TBSCl, 1H-imidazole, DMF, r.t., 1.5 h; 98%. b) NBS, AIBN, cyclohexane, reflux, 1 h; 88%. c) NaH, 2-
nitropropane, DMF, 08, 2 h; 85% for 14b from 13b, and 58% for 14c from 12c. d) 1. N,N,N’-
Trimethylethylenediamine, BuLi, THF, ꢀ 658, 30 min, then 14, ꢀ 658, 45 min; 2. BuLi, ꢀ 208, 10 – 30 h.
e) BrCF2CF2Br, r.t., 1.5 h; 9% for 16b, 58% for 16c. f) MOMCl, NaH, DMF, r.t., 4 h; 84%. g) NBS,
benzoyl peroxide, CCl4, reflux, 1 h. h) I2, KOH, MeOH, r.t., 4 h; 92%. i) Pd(PPh3)4, 2m aq. Na2CO3,
DME, 908, 48 h; 97% for 18, trace for 19. j) Pd(PPh3)4, 2m aq. Na2CO3, benzene/EtOH 1:1, reflux, 48 h;
10% for 19 from 17c.
tetraol 24, to which TsNHNH2 was added to afford hydrazone 25. Oxidation of the
hydrazone and hydroquinone part of 25 by Fetizonꢁs reagent (Ag2CO3 on Celiteꢄ) [22]
gave prekinamycin (4) in 47% yield in three steps from 8 (Scheme 3). In this study, we
have achieved the total synthesis of prekinamycin (4) in 7% yield in ten steps from 3,5-
dimethylphenol (12a).
Fig. 2. Structures of products of NaClO2 oxidation of aldehyde 18
Neither the 13C-NMR chemical shift of the diazo alkane C-atom, nor the molecular-
ion peak in the mass spectrum of prekinamycin (4) were reported in the precedent
examples of isolation [7] and total syntheses [9]. Our attempt to detect the 13C-NMR

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 3. Synthesis of Prekinamycin (4)
a) 15% NaOH, 30% H2O2, MeOH, 1208, 1 h; 80%. b) (COCl)2, MeCN, 808, 10 min. c) AlCl3, CH2Cl2,
r.t., 2.5 h; 81%. d) BBr3, CH2Cl2, ꢀ 408, 24 h. e) TsNHNH2, 1m HCl, EtOH, 908, 2 h. f) Fetizonꢁs reagent,
Et3N, MeCN, r.t., 30 min; 47% in 3 steps.
signal failed probably because of the low solubility of 4 in CDCl3, C6D6, and
(D6)acetone, and the low sensitivity of quaternary diazo alkane C-atom. Application of
HMBC technique resulted in the detection of a cross-peak from 6.85 ppm in 1H-NMR
13
(HꢀC(4)) to ca. 70.5 ppm in C-NMR6), which implies that the signal derived from
diazo alkane C-atom of prekinamycin (4) could be observed at ca. 70.5 ppm7). On the
other hand, the molecular-ion peak was not detected in EI- or FAB-MS of 4, but the
application of negative-ion-mode ESI-MS led to the observation of the molecular-ion
peak of 4 (m/z 317.0576; calc. for C18H9N2O4: 317.0562).
Next, we proceeded to synthetic studies towards kinamycins including phenol
oxidation of D ring of 8 to quinone 28, followed by stereoselective introduction of the
O-functionality (Scheme 4)8). Iodosobenzene bis(trifluoroacetate) (PIFA) [26] oxi-
dation of 8 in MeCN/H2O led to B-ring oxidation to give the undesired quinone 29 in
11% yield, whereas the reaction in MeOH gave quinone ketal 30 in 72% yield. The
position of ketal C-atom in 30 was identified as C(11) by HMBC correlation with
HꢀC(10). On the other hand, ceric ammonium nitrate (CAN) oxidation of 8 led to the
desired 28 and undesired quinone 29, each in low yield (13 – 22%). Trials for oxidation
of 8 to 28 and the corresponding alcohol 31 to 32, expecting the increase of electron
6
)
A similar correlation on a long-range heteronuclear COSY experiment of kinamycin D was
reported: see [23]; see also [6b].
)
13C-NMR Chemical shifts of diazo alkane C-atom of 1,7-O-diacetylprekinamycin and 1,7-O-
dimethylprekinamycin-11-13C were reported as 70.53 (in CD2Cl2) [9a] and 69.99 ppm (in CDCl3)
[24], respectively.
7
8
)
When we started this research, stereoselective introduction of the O-functionality towards
naphthoquinone derivatives to model D ring core of kinamycin F was reported; see [25].

Helvetica Chimica Acta – Vol. 94 (2011)
583
Scheme 4. Trials for Oxidation of D Rings of 8 and 31
a) NaBH4, CeCl3 · 7 H2O, EtOH, r.t., 5 h; 99%.
density on D ring, with Fremyꢁs salt (potassium nitrosodisulfonate; K2NO(SO3)2) [27]
or salcomine/O2 system [28] were unsuccessful.
Consequently, transformation of carboxylic acid 20 was investigated (Scheme 5).
Palladium-catalyzed ortho-selective hydroxylation of benzoic acid derivatives reported
by Zhang and Yu [29] was applied for the site-selective introduction of the O-
functionality of D ring in 20 (Table). In the first trial based on the reported procedure
(catalytic amount of Pd(OAc)2, stoichiometric amount of AcOK, and p-benzoquinone
Scheme 5. Synthesis of Quinone 36
a) (COCl)2, MeCN, 808, 10 min. b) FeCl3, CH2Cl2, THF, r.t., 90 min; 73% from 33. c) Ag2O, MgSO4,
THF, O2, r.t., 7 h; 91%.

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Helvetica Chimica Acta – Vol. 94 (2011)
Table. Pd-Catalyzed Hydroxylation of Carboxylic Acid 20a)
Entry
PdX2
Base
BQ [equiv.]
Temp. [8]
Time
33 [%]
1
2
3
4
5b)
6b)
7b)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(O2CCF3)2
AcOK
AcOK
AcOCs
AcOCs
AcOCs
AcOCs
AcOCs
1.2
1.2
1.2
2.3
2.3
2.3
2.3
115
150
150
150
150
140
140
2 d
2 d
0
4
1.5 d
15 h
15 h
20 h
20 h
33
38
49
57
62
a) PdX2 (11 mmol-%), base (2.4 equiv.), BQ (p-Benzoquinone) in DMA under O2 atmosphere was
applied unless otherwise noted. b) O2 was introduced via bubbling.
(BQ) in N,N-dimethylacetamide (DMA) at 1158 under O2 atmosphere) [29], phenol
33 could not be obtained (Entry 1). An experiment at elevated temperature, 1508, gave
the desired 33 in 4% yield (Entry 2). Use of AcOCs as a base instead of AcOK (Entry
3), increase of equivalent of BQ (Entry 4), and introduction of O2 gas via bubbling
(Entry 5) led to improved yields. No reaction was observed, when air was bubbled
through the mixture instead of O2. Observing the generation of trace amount of by-
products such as decarboxylated product at 1508, the same reaction was examined at
1408 to afford 33 in 57% yield (Entry 6). Finally, application of palladium
bis(trifluoroacetate) (Pd(O2CCF3)2) instead of Pd(OAc)2 gave the best yield (62%)
among our trials (Entry 7).
Following IFCR of carboxylic acid 33 via acid chloride 34 with SnCl4 gave the
desired fluorenone 35 in 51% yield from 33. The yield was improved with FeCl3 to 73%.
Successful oxidation of the hydroquinone part of 35 with Ag2O under O2 [30] afforded
tetracyclic quinone 36 in 91% yield.
Conclusions. – Towards the total synthesis of a series of kinamycins and related
antibiotics, we have completed the total synthesis of prekinamycin (4) from 3,5-
dimethylphenol (12a) via fluorenone 8 in ten steps, including Suzuki coupling of
naphthalene-2-boronic acid and bromobenzene derivative, intramolecular Friedelꢀ
Crafts reaction of 2-(naphthalen-2-yl)benzoic acid, and diazotization. In synthetic
studies towards kinamycins from the common synthetic intermediate 8, selective
phenol oxidation on D ring failed. Pd-Catalyzed ortho-selective hydroxylation of
benzoic acid 20, followed by IFCR-oxidation sequence, gave the desired quinone 36.
Trials for stereoselective introduction of the O-functionalities of quinone 36 and
completion of the total synthesis of kinamycins are now in progress.
Ms. Sayaka Yoshida and Dr. Hiroko Seki, Chemical Analytical Center, and Dr. Natsuko Kagawa,
Graduate School of Pharmaceutical Sciences, Chiba University, were acknowledged for recording ESI-
MS. This work was partially supported by a Grant-in-Aid for Scientific Research (C) (20590002) from the
Japan Society for the Promotion of Science (JSPS).
Experimental Part
General. Anh. CH2Cl2 and DMF were used as purchased from Kanto Chemical, and anh. THF was
used as purchased from Wako Chemical. TLC: Merck Art 5715 DC-Fertigplatten Kieselgel 60 F254
.

Helvetica Chimica Acta – Vol. 94 (2011)
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Column chromatography (CC): Kanto Chemical silica gel 60 spherical. M.p.: Yanagimoto MPSI melting
point apparatus; uncorrected. IR Spectra: Attenuated Total Reflectance (ATR) system on a JASCO FT/
1
IR-300E spectrophotometer; ˜n in cmꢀ1. H- and 13C-NMR spectra: JEOL JNM-ECP-400, JNM-ECA-
600, and JNM-ECP-600 instruments; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS:
JEOL JNM MS-GCMATE for EI-MS, JEOL JNM HX-110 for HR-FAB-MS, and JEOL AccuTOF and
Thermo Scientific Exactive system for HR-ESI-MS, resp.; in m/z (rel. %).
(1,4,5-Trimethoxynaphthalen-2-yl)boronic Acid (10). BuLi (1.59m; 0.95 ml, 1.51 mmol) was added to
a soln. of 2-bromo-1,4,5-trimethoxynaphthalene (300 mg, 1.01 mmol) in THF (3 ml) at ꢀ 788, and the
mixture was stirred at ꢀ 788 for 1 h. (i-PrO)3B (0.46 ml, 2.99 mmol) was added, and the mixture was
stirred at ꢀ 788 for 15 min and at r.t. for 1 h. H2O (10 ml) and 5% HCl (10 ml) were added, and the
mixture was extracted with CH2Cl2 (3 ꢁ 10 ml). The combined org. layers were washed with H2O (2 ꢁ
10 ml) and brine (1 ꢁ 10 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by
1
CC (hexane/AcOEt 10 :1) to give 10 (215 mg, 81%). Colorless needles. H-NMR (400 MHz): 3.95 (s,
3 H); 3.99 (s, 3 H); 4.00 (s, 3 H); 6.51 (br. s, 2 H); 6.95 (d, J ¼ 7.8, 1 H); 7.17 (s, 1 H); 7.45 (dd, J ¼ 8.3, 7.8,
1 H); 7.67 (dd, J ¼ 8.3, 1.0, 1 H).
1-{[(tert-Butyl)(dimethyl)sily]oxy}-3,5-dimethylbenzene (12b).
A mixture of 12a (4.63 g,
37.9 mmol), 1H-imidazole (8.01 g, 118 mmol), and TBSCl (6.80 g, 45.1 mmol) in DMF (4.5 ml) was
stirred at r.t. for 1.5 h. AcOEt (75 ml) was added, and the mixture was washed with H2O (10 ꢁ 10 ml) and
brine (1 ꢁ 10 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (hexane) to
give 12b (8.75 g, 98%). Colorless oil. IR: no characteristic absorption. 1H-NMR (400 MHz): 0.20 (s, 6 H);
1.00 (s, 9 H); 2.27 (s, 6 H); 6.48 (s, 2 H); 6.61 (s, 1 H). 13C-NMR (100 MHz): ꢀ 4.4; 18.2; 21.3; 25.7; 117.8;
123.0; 139.0; 155.5. HR-EI-MS: 236.1608 (Mþ, C14H24OSiþ; calc. 236.1596).
1-(Bromomethyl)-3-{[(tert-butyl)(dimethyl)sily]oxy}-5-methylbenzene (13b). A mixture of 12b
(8.75 g, 37.0 mmol), NBS (7.63 g, 42.9 mmol), and AIBN (365 mg, 2.22 mmol) in cyclohexane (135 ml)
was refluxed for 1 h. The reaction vessel was shielded from light with covering with alminium foil. After
cooling, the mixture was filtered, and and the precipitate was washed with cyclohexane. The mixture was
washed with H2O (1 ꢁ 70 ml) and brine (1 ꢁ 70 ml), dried (MgSO4), and evaporated in vacuo. The
residue was purified by CC (hexane) to give 13b (10.3 g, 88%). Colorless oil. IR: no characteristic
absorption. 1H-NMR (400 MHz): 0.20 (s, 6 H); 0.99 (s, 9 H); 2.29 (s, 3 H); 4.40 (s, 2 H); 6.59 (s, 1 H); 6.68
(s, 1 H); 6.80 (s, 1 H). 13C-NMR (100 MHz): ꢀ 4.4; 18.1; 21.3; 25.6; 33.6; 117.7; 121.0; 122.8; 138.7; 139.8;
155.7. HR-EI-MS: 316.0707 (Mþ, C14H2381BrOSiþ; calc. 316.0681).
3-{[(tert-Butyl)(dimethyl)sily]oxy}-5-methylbenzaldehyde (14b). A mixture of NaH (60%, 41 mg,
1.70 mmol), washed with hexane (3 ꢁ 4 ml), and a soln. of 2-nitropropane (0.30 ml, 3.40 mmol) in DMF
(6 ml) was stirred at 08 for 15 min. Compound 13b (536 mg, 1.70 mmol) was added, and the mixture was
stirred at 08 for 2 h. H2O (20 ml) was added, and the aq. layer was neutralized with 10% HCl. The mixture
was extracted with AcOEt (25 ml). The org. layer was washed with H2O (10 ꢁ 10 ml) and brine (1 ꢁ
10 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (hexane/AcOEt
10 :1) to give 14b (339 mg, 85%). Yellow oil. IR: 1701. 1H-NMR (400 MHz): 0.22 (s, 6 H); 1.00 (s, 9 H);
2.38 (s, 3 H); 6.93 (s, 1 H); 7.13 (s, 1 H); 7.29 (s, 1 H); 9.91 (s, 9 H). 13C-NMR (100 MHz): ꢀ 4.5; 18.2;
21.3; 25.6; 177.2; 124.2; 127.2; 137.8; 140.3; 156.2; 192.2.
2-Bromo-3-{[(tert-butyl)(dimethyl)sily]oxy}-5-methylbenzaldehyde (16b). BuLi (1.40m; 0.50 ml,
0.71 mmol) was added to a soln. of N,N,N’-trimethylethylenediamine (0.10 ml, 0.77 mmol) in THF
(0.15 ml) at ꢀ 658, and the mixture was stirred at ꢀ 658 for 30 min. Compound 14b (161 mg, 0.64 mmol)
in THF (1.0 ml) was added at ꢀ 658, and the mixture was stirred at ꢀ 658 for 45 min. BuLi (1.40m;
1.35 ml, 1.92 mmol) was added at ꢀ 658, and the mixture was stirred at ꢀ 208 for 10 h. BrCF2CF2Br
(0.40 ml, 3.33 mmol) was added, and the mixture was stirred at r.t. for 1.5 h. H2O (5 ml) was added, and
the mixture was evaporated in vacuo. The residue was diluted with 10% HCl (5 ml) and extracted with
CH2Cl2 (3 ꢁ 5 ml). The combined org. layers were washed with H2O (1 ꢁ 5 ml) and brine (1 ꢁ 5 ml),
dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (hexane/AcOEt 20 :1) to give
16b (19 mg, 9%). Colorless needles. M.p. 112 – 1168. IR: 1668. 1H-NMR (400 MHz): 0.41 (s, 6 H); 0.99 (s,
9 H); 2.32 (s, 3 H); 6.77 (s, 1 H); 7.40 (s, 1 H); 10.30 (s, 1 H). 13C-NMR (100 MHz): ꢀ 0.09; 18.4; 20.9;
27.1; 121.1; 121.2; 121.7; 141.3; 144.4; 161.5; 194.6.

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Helvetica Chimica Acta – Vol. 94 (2011)
1-(Methoxymethoxy)-3,5-dimethylbenzene (12c). MOMCl (0.93 ml, 12.3 mmol) was added to a
mixture of NaH (60%, 654 mg, 16.4 mmol), washed with hexane (3 ꢁ 10 ml), and 12a (1.00 g, 8.18 mmol)
in DMF (6 ml) at 08, and the mixture was stirred at r.t. for 4 h. Ice-H2O (20 ml) was added, and the
mixture was extracted with hexane (1 ꢁ 25 ml). The org. layer was washed with H2O (10 ꢁ 10 ml) and
brine (1 ꢁ 10 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (hexane/
AcOEt 100 :1 to 10 :1) to give 12c (1.14 g, 84%). Colorless oil. IR: no characteristic absorbtion. 1H-NMR
(400 MHz): 2.29 (s, 6 H); 3.47 (s, 3 H); 5.15 (s, 2 H); 6.66 (s, 1 H); 6.67 (s, 2 H). 13C-NMR (100 MHz):
21.4; 55.9; 94.3; 113.9; 123.6; 139.2; 157.2. HR-EI-MS: 166.0998 (Mþ, C10H14O2þ ; calc. 166.0994).
3-(Methoxymethoxy)-5-methylbenzaldehyde (14c). A mixture of 12c (100 mg, 0.60 mmol), NBS
(118 mg, 0.66 mmol), and benzoyl peroxide (15 mg, 0.06 mmol) in CCl4 (10 ml) was refluxed for 1 h.
After cooling, the mixture was filtered, and the precipitate was washed with CCl4. The filtrate and the
washing were combined and washed with H2O (1 ꢁ 5 ml) and brine (1 ꢁ 5 ml), dried (MgSO4), and
evaporated in vacuo. The residual crude 13c was used in the next step without further purification. A
mixture of NaH (60%, 36 mg, 0.90 mmol), washed with hexane (3 ꢁ 5 ml), and 2-nitropropane (0.11 ml,
1.20 mmol) in DMF (6 ml) was stirred at 08 for 15 min. A soln. of crude 13c (vide infra) in DMF (1 ml)
was added, and the mixture was stirred at r.t. for 2 h. Ice-H2O (5 ml) was added, and the aq. layer was
neutralized with 10% HCl. The mixture was extracted with hexane (25 ml). The org. layer was washed
with H2O (3 ꢁ 10 ml) and brine (1 ꢁ 10 ml), dried (MgSO4), and evaporated in vacuo. The residue was
purified by CC (hexane/AcOEt 25 :1 to 10 :1) to give 14c (63 mg, 58%; 2 steps). Yellow oil. IR: 1698.
1H-NMR (400 MHz): 2.41 (s, 3 H); 3.49 (s, 3 H); 5.22 (s, 2 H); 7.12 (br. s, 1 H); 7.35 (br. s, 2 H); 9.93 (s,
1 H). 13C-NMR (100 MHz): 21.2; 56.1; 94.3; 113.4; 123.4; 124.4; 137.7; 140.5; 157.6; 192.2. HR-EI-MS:
180.0786 (Mþ, C10H12Oþ3 ; calc. 180.0786).
2-Bromo-3-(methoxymethoxy)-5-methylbenzaldehyde (16c). BuLi (1.57m; 11.4 ml, 17.8 mmol) was
added to a soln. of N,N,N’-trimethylethylenediamine (2.50 ml, 19.5 mmol) in THF (2 ml) at ꢀ 658, and
the mixture was stirred at ꢀ 658 for 30 min. A soln. of 14c (2.92 g, 16.2 mmol) in THF (30 ml) was added
at ꢀ 658, and the mixture was stirred at ꢀ 658 for 45 min. BuLi (1.57m; 31.0 ml, 48.7 mmol) was added at
ꢀ 658, and the mixture was stirred at ꢀ 208 for 30 h. BrCF2CF2Br (10.0 ml, 84.3 mmol) was added, and
the mixture was stirred at r.t. for 1.5 h. H2O (10 ml) was added, and the mixture was evaporated in vacuo.
The residue was diluted with H2O (10 ml) and extracted with CH2Cl2 (3 ꢁ 20 ml). The combined org.
layers were washed with H2O (1 ꢁ 10 ml) and brine (1 ꢁ 10 ml), dried (MgSO4), and evaporated in
vacuo. The residue was purified by CC (hexane/AcOEt 20 :1) to give 16c (2.45 g, 58%). Colorless
needles. M.p. 50 – 518 (hexane). IR: 1682. 1H-NMR (400 MHz): 2.35 (s, 3 H); 3.54 (s, 3 H); 5.28 (s, 2 H);
7.21 (s, 1 H); 7.37 (s, 1 H); 10.37 (s, 1 H). 13C-NMR (100 MHz): 21.0; 56.4; 95.1; 114.7; 122.0; 123.1; 134.1;
138.6; 153.8; 192.0. FAB-MS: 261 ([M(81Br) þ H]þ), 259 ([M(79Br) þ H]þ). Anal. calc. for C10H11BrO3
(259.10): C 46.36, H 4.28; found: C 46.39, H 4.02.
Methyl 2-Bromo-3-(methoxymethoxy)-5-methylbenzoate (17c). To a soln. of 16c (100 mg,
0.39 mmol) in MeOH (3 ml), a soln. of KOH (85%, 56 mg, 0.85 mmol) in MeOH (3 ml) was added at
08. A soln. of I2 (127 mg, 0.50 mmol) in MeOH (3 ml) was added, and the mixture was stirred at 08 for 1 h
and at r.t. for 4 h. H2O (5 ml) and sat. aq. Na2S2O3 (5 ml) were added, and the mixture was evaporated in
vacuo. The residue was extracted with CHCl3 (1 ꢁ 10 ml). The org. layer was washed with H2O (1 ꢁ 5 ml)
and brine (1 ꢁ 5 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (hexane/
1
AcOEt 25 :1 to 10 :1) to give 17c (102 mg, 92%). Colorless oil. IR: 1730. H-NMR (400 MHz): 2.33 (s,
3 H); 3.52 (s, 3 H); 3.92 (s, 3 H); 5.25 (s, 2 H); 7.08 (br. s, 1 H); 7.16 (br. s, 1 H). 13C-NMR (100 MHz):
21.1; 52.5; 56.4; 95.1; 108.8; 119.2; 124.3; 134.2; 138.4; 154.1; 167.2. HR-EI-MS: 288.0025 (Mþ,
C11H1379BrOþ4 ; calc. 287.9997).
3-(Methoxymethoxy)-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde (18). A mixture of
10 (50 mg, 0.19 mmol), 16c (50 mg, 0.19 mmol), Pd(PPh3)4 (6 mg, 5.5 mmol) in DME (3 ml), and 2m aq.
Na2CO3 (0.12 ml, 0.24 mmol) was heated at 908 for 2 d. After cooling, the mixture was diluted with H2O
(3 ml), and the org. layer was separated. The aq. layer was extracted with CH2Cl2 (3 ꢁ 10 ml). The
combined org. layers were washed with H2O (2 ꢁ 5 ml) and brine (1 ꢁ 5 ml), dried (MgSO4), and
evaporated in vacuo. The residue was purified by CC (hexane/AcOEt 10 :1 to 3 :1) to give 18 (73 mg,
97%). Colorless prisms. M.p. 163 – 1648 (AcOEt). IR: 1684. 1H-NMR (400 MHz): 2.48 (s, 3 H); 3.33 (s,
3 H); 3.46 (s, 3 H); 3.92 (s, 3 H); 4.01 (s, 3 H); 5.10 (d, J ¼ 8.4, 1 H); 5.13 (d, J ¼ 8.4, 1 H); 6.72 (s, 1 H);

Helvetica Chimica Acta – Vol. 94 (2011)
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6.94 (d, J ¼ 7.1, 1 H ) ; 7.31 ( br. s, 1 H); 7.46 (t, J ¼ 8.2, 1 H); 7.57 (br. s, 1 H); 7.76 (d, J ¼ 8.4, 1 H); 9.72 (s,
1 H). 13C-NMR (100 MHz): 21.6; 56.1; 56.5; 56.8; 60.8; 94.8; 107.1; 109.5; 115.1; 118.3; 120.8; 121.2; 122.2;
126.9; 129.0; 131.2; 134.7; 139.4; 147.7; 152.7; 154.7; 157.3; 192.6. FAB-MS: 419 ([M þ Na]þ), 396 (Mþ).
Anal. calc. for C23H24O6 (396.43): C 69.68, H 6.10; found: C 69.56, H 6.06.
Methyl 3-(Methoxymethoxy)-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzoate (19). A mixture
of 10 (265 mg, 1.01 mmol), 17c (292 mg, 1.01 mmol), Pd(PPh3)4 (10 mg, 8.3 mmol) in benzene/EtOH
(10 :1, 5.0 ml), and 2m Na2CO3 (0.6 ml, 1.20 mmol) was heated at 908 for 2 d. After cooling, the mixture
was diluted with H2O (10 ml), and the org. layer was separated. The aq. layer was extracted with CH2Cl2
(3 ꢁ 20 ml). The combined org. layers were washed with H2O (3 ꢁ 10 ml) and brine (1 ꢁ 10 ml), dried
(MgSO4), and evaporated in vacuo. The residue was purified by CC (CHCl3) and prep. TLC (CHCl3) to
give 19 (43 mg, 10%). Yellow oil. IR: 1726. 1H-NMR (400 MHz): 2.45 (s, 3 H); 3.27 (s, 3 H); 3.50 (s, 3 H);
3.52 (d, 3 H); 3.90 (s, 3 H); 4.00 (s, 3 H); 5.00 (d, J ¼ 7.0, 1 H); 5.09 (d, J ¼ 7.0, 1 H); 6.66 (s, 1 H); 6.89 (d,
J ¼ 7.0, 1 H); 7.20 (br. s, 1 H); 7.41 (diffused t, J ¼ 8.1, 1 H); 7.41 (br. s, 1 H); 7.75 (dd, J ¼ 8.4, 0.9, 1 H).
13C-NMR (100 MHz): 21.4; 51.9; 56.0; 56.4; 56.9; 60.8; 94.9; 106.3; 109.3; 115.2; 117.8; 119.5; 123.9; 125.7;
126.0; 126.3; 131.2; 132.8; 138.9; 147.0; 152.4; 154.8; 157.2; 168.5. HR-EI-MS: 426.1680 (Mþ, C24H26O7þ ;
calc. 426.1679).
1,4b-Dimethoxy-10-(methoxymethoxy)-8-methyl-4bH-dibenzo[c,h]chromene-6,12-dione (¼1,4b-
Dimethoxy-10-(methoxymethoxy)-8-methyl-6H-benzo[d]naphtho[1,2-b]pyran-6,12(4bH)-dione; 21)
and
7,10b-Dimethoxy-4-(methoxymethoxy)-2-methyl-5aH,12H-dibenzo[c,h]oxireno[e]chromene-
6,12(10bH)-dione (¼ 7,10b-Dimethoxy-4-(methoxymethoxy)-2-methyl-5aH,12H-oxireno[2,3]naph-
tho[1,2-c][2]benzopyran-6,12(10bH)-dione; 22). To a suspension of 18 (50 mg, 0.13 mmol) in MeCN
(1.5 ml), a soln. of NaH2PO4 · 2 H2O (5 mg, 0.30 mmol) in H2O (1 ml) and 30% H2O2 (0.015 ml,
0.13 mmol) were added successively. After cooling to 08, a soln. of NaClO2 (16 mg, 0.14 mmol) in H2O
(1 ml) was added, and the mixture was stirred at r.t. for 12 h. After cooling to 08, 10% HCl (3 ml) was
added, and MeCN was evaporated in vacuo. The residue was extracted with AcOEt (3 ꢁ 10 ml). The
combined org. layers were washed with H2O (1 ꢁ 5 ml) and brine (1 ꢁ 5 ml), dried (MgSO4), and
evaporated in vacuo. The residue was purified by CC (hexane/AcOEt 5 :1 to 3 :1) to give 21 as yellow
needles (30 mg, 59%) and 22 as red needles (3 mg, 6%).
1
Data of 21. IR: 1741, 1657. H-NMR (400 MHz): 2.46 (s, 3 H); 2.90 (s, 3 H); 3.53 (s, 3 H); 4.01 (s,
3 H); 5.34 (d, J ¼ 7.0, 1 H); 5.40 (d, J ¼ 7.0, 1 H); 7.13 (dd, J ¼ 8.2, 1.3, 1 H); 7.36 (br. s, 1 H); 7.42 (s, 1 H);
7.64 (dd, J ¼ 7.9, 1.3, 1 H); 7.69 (t, J ¼ 8.0, 1 H); 7.76 (br. s, 1 H). 13C-NMR (100 MHz): 21.9; 51.7; 56.3;
56.6; 94.6; 96.5; 113.3; 118.2; 119.5; 121.0; 124.3; 125.5; 132.1; 134.8; 137.7; 139.9; 142.6; 155.5; 159.6;
162.8; 183.6. LR-EI-MS: 396 (11, Mþ), 351 (10, [M ꢀ MOM]þ), 320 (24), 135 (36), 91 (69), 59 (100).
1
Data of 22. IR: 1740, 1680. H-NMR (400 MHz): 2.44 (s, 3 H); 3.04 (s, 3 H); 3.52 (s, 3 H); 3.95 (s,
3 H); 5.24 (d, J ¼ 7.0, 1 H); 5.29 (d, J ¼ 7.0, 1 H); 5.39 (s, 1 H); 7.15 (dd, J ¼ 7.5, 1.8, 1 H); 7.30 (s, 1 H); 7.65
(t, J ¼ 7.5, 1 H); 7.67 (dd, J ¼ 7.5, 1.8, 1 H); 7.82 (br. s, 1 H). 13C-NMR (100 MHz): 21.6; 51.5; 56.3; 56.7;
57.1; 59.7; 94.8; 101.2; 113.7; 116.6; 117.7; 118.8; 121.8; 125.0; 128.3; 133.8; 136.1; 142.0; 155.8; 158.6; 162.1;
192.7. HR-EI-MS: 412.1149 (Mþ, C22H20O8þ ; calc. 412.1158).
3-(Methoxymethoxy)-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzoic Acid (20). To a soln. of
18 (302 mg, 0.76 mmol) in MeOH (10 ml), a mixture of 15% NaOH (10 ml, 37.5 mmol) and 30% H2O2
(6.4 ml, 56.4 mmol) was added at 608, and the mixture was stirred at 1208 for 30 min. A mixture of 15%
NaOH (10 ml, 37.5 mmol) and 30% H2O2 (6.4 ml, 56.4 mmol) was added, and the mixture was refluxed
for 1 h. After cooling, MeOH was removed by evaporation. The residue was washed with CHCl3 (4 ꢁ
10 ml) to recover 18. The aq. layer was acidified with 10% HCl to pH 4 and extracted with CHCl3
(4 ꢁ 10 ml). The combined org. layers were washed with H2O (1 ꢁ 5 ml) and brine (1 ꢁ 5 ml), dried
(MgSO4), and evaporated in vacuo to give crude 20 (182 mg, 58%). For the recovery of 18, the CHCl3
washings were combined, washed with H2O (1 ꢁ 5 ml) and brine (1 ꢁ 5 ml), dried (MgSO4) and
evaporated in vacuo. The recovered crude 18 was directly subjected to similar reaction conditions (15%
NaOH (10 ml), 30% H2O2 (6.4 ml) at 1208 for 1 h) to give crude 20 (122 mg, 39%). The combined crude
20 was recrystallized from toluene to give 20 (251 mg, 80%). Pale yellow needles. M.p. 164 – 1678. IR:
3200, 1716. 1H-NMR (400 MHz): 2.44 (s, 3 H); 3.27 (s, 3 H); 3.54 (s, 3 H); 3.87 (s, 3 H); 3.99 (s, 3 H); 5.00
(d, J ¼ 7.2, 1 H); 5.08 (d, J ¼ 7.2, 1 H); 6.63 (s, 1 H); 6.90 (d, J ¼ 7.2, 1 H); 7.22 (br. s, 1 H); 7.42 (t, J ¼ 8.2,
1 H); 7.46 (br. s, 1 H); 7.72 (d, J ¼ 8.4, 1 H). 13C-NMR (100 MHz): 21.4; 56.0; 56.4; 56.8; 60.9; 94.8; 106.5;

588
Helvetica Chimica Acta – Vol. 94 (2011)
109.5; 115.2; 118.0; 120.1; 124.6; 125.6; 126.3; 126.4; 131.2; 131.5; 139.0; 146.8; 152.5; 154.9; 157.2; 171.8.
HR-ESI-MS: 413.1586 ([M þ H]þ, C23H25O7þ ; calc. 413.1600); 435.1401 ([M þ Na]þ, C23H24NaOþ7 ; calc.
435.1420). Anal. calc. for C23H24O7 (412.43): C 66.98, H 5.87; found: C 66.72, H 5.75.
4-Hydroxy-5,9,10-trimethoxy-2-methyl-11H-benzo[b]fluoren-11-one (8). (COCl)2 (0.02 ml,
0.23 mmol) was added to a soln. of 20 (15 mg, 0.037 mmol) in MeCN (1 ml), and the mixture was
stirred at 808 for 10 min. The solvent was evaporated in vacuo, and the residue was dissolved in CH2Cl2
(1 ml). AlCl3 (49 mg, 0.36 mmol) was added, and the mixture was stirred at r.t. for 2.5 h. Sat. aq. NaHCO3
(2.0 ml) was added, and the mixture was stirred for 5 min. MgSO4 was added and then filtered. The
precipitate was washed with AcOEt (3 ꢁ 10 ml). The org. layers were combined and evaporated in vacuo.
The residue was purified by CC (CH2Cl2/MeOH 100 :1) to give 8 (11 mg, 81%). Yellow needles. M.p.
1
232 – 2348 (hexane/CH2Cl2). IR: 3240, 1700. H-NMR (400 MHz): 2.37 (s, 3 H); 4.01 (s, 3 H); 4.02 (s,
3 H); 4.06 (s, 3 H); 6.91 (s, 1 H); 6.91 (dd, J ¼ 7.3, 1.5, 1 H); 7.16 (s, 1 H); 7.54 (dd, J ¼ 8.4, 7.3, 1 H); 7.57
(dd, J ¼ 8.4, 1.5, 1 H); 9.43 (s, 1 H). 13C-NMR (100 MHz): 21.3; 56.4; 62.8; 63.9; 108.2; 114.7; 117.1; 121.7;
122.2; 122.9; 123.4; 128.5; 130.5; 134.8; 138.0; 142.4; 142.8; 152.1; 156.2; 159.9; 189.8. HR-ESI-MS:
351.1219 ([M þ H]þ, C21H19O5þ ; calc. 351.1232), 373.1037 ([M þ Na]þ, C21H18NaOþ5 ; calc. 373.1052).
Prekinamycin (¼11-Diazonio-10,11-dihydro-4,9-dihydroxy-2-methyl-5,10-dioxo-5H-benzo[b]fluo-
ren-11-ide; 4). BBr3 (1m soln. in CH2Cl2, 0.18 ml, 0.18 mmol) was added to a soln. of 8 (11 mg,
0.032 mmol) in CH2Cl2 (1 ml) at ꢀ 408, and the mixture was stirred at ꢀ 408 for 24 h. MeOH (2 ml) was
added, and the solvent was evaporated in vacuo. The residue was dissolved in EtOH (1 ml), and a soln. of
TsNHNH2 (60 mg, 0.32 mmol) in EtOH (3 ml) and 1m HCl (one drop) were added. The mixture was
stirred at 908 for 2 h. The solvent was evaporated in vacuo. The residue was suspended in acetone (2 ml),
and Et3N (0.5 ml, 0.5 mmol), and Fetizonꢁs reagent (273 mg) were added. The mixture was vigorously
stirred at r.t. for 30 min. The solvent was evaporated in vacuo. CH2Cl2 (5 ml) was added and filtered. The
filtrate was evaporated in vacuo, and the residue was purified by CC (hexane/CH2Cl2 1:1), followed by
washing with acetone, to give 4 (5 mg, 47%). Black-purple needles. M.p. > 3008. IR: 2119, 1607. 1H-NMR
(400 MHz): 2.44 (s, 3 H); 6.72 (s, 1 H); 6.85 (s, 1 H); 7.24 – 7.26 (m, 1 H); 7.61 (t, J ¼ 7.6, 1 H); 7.79 (d, J ¼
8.4, 1 H); 11.06 (s, 1 H); 12.15 (s, 1 H). 13C-NMR (150 MHz): 22.0; 110.3; 114.0; 115.6; 117.5; 120.7; 125.2;
128.2; 131.6; 133.5; 135.7; 136.3; 141.8; 154.5; 162.2; 181.2; 184.7. HR-ESI-MS: 317.0576 ([M ꢀ H]ꢀ,
C18H9N2Oꢀ4 ; calc. 317.0562).
4-Hydroxy-9-methoxy-2-methyl-5H-benzo[b]fluorene-5,10,11-trione (29). Iodosobenzene bis(tri-
fluoroacetate) (PIFA; 14 mg, 0.031 mmol) was added to a suspension of 8 (19 mg, 0.029 mmol) in
MeCN/H2O 2 :1 (1 ml) at r.t., and the mixture was stirred at r.t. for 50 min. Sat. aq. NaHCO3 (5 ml) was
added, and the mixture was extracted with CH2Cl2 (3 ꢁ 10 ml). The combined org. layers were washed
with brine (1 ꢁ 5 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (hexane/
AcOEt 4 :1 to 1:1) and prep. TLC (CH2Cl2) gave 29 (1 mg, 11%). Purple needles. M.p. 195 – 2008 (dec.).
IR: 3096, 1716, 1645, 1590. 1H-NMR (400 MHz): 2.37 (s, 3 H); 4.02 (s, 3 H); 6.92 (s, 1 H); 7.11 (s, 1 H);
7.46 (dd, J ¼ 8.4, 1.1, 1 H); 7.74 (dd, J ¼ 8.4, 7.5, 1 H); 7.90 (dd, J ¼ 7.5, 1.1, 1 H). 13C-NMR (100 MHz):
29.7; 56.7; 116.3; 119.6; 120.3; 121.2; 125.7; 127.6; 130.9; 132.3; 134.1; 134.7; 147.2; 154.1; 154.6; 160.3;
179.6; 187.8; 191.9. HR-EI-MS: 320.0664 (Mþ, C19H12O5þ ; calc. 320.0685).
4-Hydroxy-5,5,9-trimethoxy-2-methyl-5H-benzo[b]fluorene-10,11-dione (30). PIFA (26 mg,
0.060 mmol) was added to a suspension of 8 (10 mg, 0.030 mmol) in MeOH (5 ml) at r.t., and the
mixture was stirred at r.t. for 30 min. MeOH was evaporated in vacuo, and the residue was washed with
CHCl3 (3 ꢁ 10 ml). The combined org. layers were washed with H2O (3 ꢁ 10 ml) and brine (3 ꢁ 10 ml),
dried (MgSO4), and evaporated in vacuo. The residue was purified by prep. TLC (CH2Cl2) to give 30
(8 mg, 72%). Orange needles. M.p. 216 – 2188. IR: 1721, 1654. 1H-NMR (400 MHz): 2.37 (s, 3 H); 3.11 (s,
6 H); 3.99 (s, 3 H); 6.89 (s, 1 H); 7.09 (s, 1 H); 7.14 (d, J ¼ 8.4, 1 H); 7.41 (d, J ¼ 7.7, 1 H); 7.69 (diffused t,
J ¼ 8.1, 1 H); 8.58 (s, 1 H). 13C-NMR (150 MHz): 21.7; 52.4 ꢁ 2; 56.3; 97.3; 114.4; 117.0; 118.4; 118.7;
122.9; 124.8; 128.5; 132.9; 134.8; 138.5; 146.5; 153.1; 160.8; 164.2; 178.5; 190.9. HR-EI-MS: 366.1091 (Mþ,
C21H18Oþ6 ; calc. 366.1103).
5,9,10-Trimethoxy-2-methyl-11H-benzo[b]fluorene-4,11-diol (31). CeCl3 · 7 H2O (12 mg,
0.033 mmol) and NaBH4 (1.3 mg, 0.034 mmol) were added to a suspension of 8 (11 mg, 0.030 mmol)
in EtOH (1 ml) at ꢀ 408, and the mixture was stirred at 08 for 1 h and at r.t. for 5 h. Sat. aq. NH4Cl soln.
(1 ml) was added, and EtOH was removed by evaporation in vacuo. The residue was extracted with

Helvetica Chimica Acta – Vol. 94 (2011)
589
CHCl3 (3 ꢁ 5 ml). The combined org. layers were washed with brine (3 ꢁ 5 ml), dried (MgSO4), and
evaporated in vacuo. The residue was purified by short-passed CC (hexane/AcOEt 1:1) to give 31
(10 mg, 99%). Colorless needles. M.p. 1858. IR: 3474, 3249. 1H-NMR (400 MHz): 2.38 (s, 3 H); 3.13 (br. s,
1 H); 3.98 (s, 3 H); 3.98 (s, 3 H); 4.00 (s, 3 H); 5.94 (s, 1 H); 6.77 (s, 1 H); 6.87 (d, J ¼ 7.9, 1 H); 7.03 (s,
1 H); 7.44 (t, J ¼ 8.2, 1 H); 7.63 (d, J ¼ 8.4, 1 H); 9.53 (s, 1 H). 13C-NMR (100 MHz): 21.5; 56.0; 62.5; 63.8;
73.0; 106.2; 114.6; 117.5; 117.8; 120.0; 120.3; 127.1; 128.8; 131.9; 134.1; 141.9; 142.7; 146.6; 150.8; 152.1;
156.6. HR-EI-MS: 352.1305 (Mþ, C21H20O5þ ; calc. 352.1311).
2-Hydroxy-5-(methoxymethoxy)-3-methyl-6-(1,4,5-trimethoxynaphthalen-2-yl)benzoic Acid (33) A
mixture of 20 (54 mg, 0.13 mmol), Pd(O2CCF3)2 (4.5 mg, 0.014 mmol), benzoquinone (32 mg,
0.30 mmol), and AcOCs (59 mg, 0.29 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 1408 (bath
temp.) for 20 h with bubling of O2. The solvent was evaporated in vacuo, and the residue was diluted with
AcOEt (10 ml) and sonicated. The precipitate was filtered off, and the filtrate was washed with brine
(3 ꢁ 10 ml) and extracted with sat. aq. NaHCO3 (3 ꢁ 10 ml). The aq. layers were combined, acidified
with 10% HCl to pH 7, and extracted with CHCl3 (3 ꢁ 20 ml). The combined org. layers were washed
with brine (3 ꢁ 10 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by CC
1
(hexane/AcOEt 1:1) to give 33 (35 mg, 62%). Yellow needles. M.p. 70 – 728. IR: 3170, 1659. H-NMR
(400 MHz): 2.33 (s, 3 H); 3.18 (s, 3 H); 3.55 (s, 3 H); 3.86 (s, 3 H); 3.97 (s, 3 H); 4.82 (d, J ¼ 6.7, 1 H); 4.92
(d, J ¼ 6.7, 1 H); 6.60 (s, 1 H); 6.87 (d, J ¼ 7.7, 1 H); 7.28 (s, 1 H); 7.39 (t, J ¼ 8.1, 1 H); 7.67 (d, J ¼ 8.2, 1 H).
13C-NMR (100 MHz): 16.3; 56.0; 56.3; 56.9; 60.9; 96.1; 106.6; 109.3; 110.9; 115.1; 117.9; 126.1; 126.3;
126.5; 127.3; 127.8; 131.2; 146.5; 146.8; 152.5; 156.4; 157.0; 173.3. HR-EI-MS: 428.1456 (Mþ, C23H24O8þ ;
calc. 428.1471).
1,4-Dihydroxy-5,9,10-trimethoxy-2-methyl-11H-benzo[b]fluoren-11-one (35). (COCl)2 (0.2 ml,
2.33 mmol) was added to a soln. of 33 (50 mg, 0.12 mmol) in MeCN (3 ml) at 808, and the mixture
was stirred at the same temp. for 10 min. After cooling, the solvent was evaporated in vacuo, and the
residue was diluted with CH2Cl2 (10 ml). A soln. of FeCl3 (192 mg, 1.18 mmol) in THF (10 ml) was
added, and the mixture was stirred at r.t. for 90 min. Sat. aq. NaHCO3 soln. (5 ml) was added, and the
mixture was stirred for 5 min. MgSO4 was added, and the mixture was extracted with AcOEt (3 ꢁ 20 ml).
The solvent was evaporated in vacuo, and the residue was purified by CC (hexane/AcOEt 1:1) to give 35
(31 mg, 73%). Red needles. M.p. 2338. IR: 3274, 1662. 1H-NMR (400 MHz): 2.23 (s, 3 H); 4.00 (s, 3 H);
4.01 (s, 3 H); 4.06 (s, 3 H); 6.85 (s, 1 H); 6.91 (d, J ¼ 7.3, 1 H); 7.53 (t, J ¼ 8.2, 1 H); 7.56 (d, J ¼ 6.8, 1 H);
8.82 (s, 1 H); 9.18 (s, 1 H). 13C-NMR (100 MHz): 14.8; 56.4; 62.9; 63.9; 108.1; 114.7; 119.1; 119.4; 121.4;
122.4; 127.1; 128.1; 130.58; 130.59; 134.7; 143.6; 145.1; 150.8; 156.2; 159.9; 192.8. HR-EI-MS: 366.1098
(Mþ, C21H18Oþ6 ; calc. 366.1103).
5,9,10-Trimethoxy-2-methyl-1H-benzo[b]fluorene-1,4,11-trione (36). A mixture of 35 (18 mg,
0.048 mmol), Ag2O (105 mg, 0.46 mmol), and MgSO4 (48 mg, 0.40 mmol) in THF (5 ml) was stirred
at r.t. for 20 h under O2. The solvent was evaporated in vacuo. The residue was diluted with AcOEt
(10 ml), and the precipitate was filtered through a pad of Celiteꢄ. The filtrate was evaporated in vacuo,
and the residue was purified by short-passed CC (hexane/AcOEt 1:1) to give 36 (16 mg, 91%). Purple
needles. M.p. 218 – 2208. IR: 1697. 1H-NMR (400 MHz): 2.12 (d, J ¼ 1.6, 3 H); 3.99 (s, 3 H); 4.01 (s, 3 H);
4.08 (s, 3 H); 6.74 (q, J ¼ 1.6, 1 H); 7.05 (d, J ¼ 8.2, 1 H); 7.59 (t, J ¼ 8.1, 1 H); 7.81 (dd, J ¼ 8.3, 1.0, 1 H).
13C-NMR (100 MHz): 15.2; 56.6; 62.9; 64.5; 111.1; 117.7; 118.3; 122.3; 123.6; 130.8; 131.2; 134.3; 136.5;
145.9; 151.2; 151.6; 157.2; 160.4; 183.7; 184.5; 187.4. HR-ESI-MS: 387.0842 ([M þ Na]þ, C21H16NaO6þ ;
calc. 387.0845).
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Received August 9, 2010