Synthesis of anthracyclinone precursor: 5,12-dihydroxy-1,3,4- trihydronaphthacene-2,6,11-quinone

Article abstract of DOI:10.1081/SCC-200028508

Two practical and efficient approaches for preparing large quantities of 5,12-dihydroxy-1,3,4-trihydronaphthacene-2,6,11-quinone 9 are described. Both synthetic approaches involve a simple route with a fewer number of steps and utilize readily available and inexpensive starting materials. Large-scale production of this precursor may prove to be useful for further research involving the synthesis of antineoplastic anthracyclines and development of their analogs with increased activity and decreased toxicity.

Full text of DOI:10.1081/SCC-200028508

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Synthesis of
Anthracyclinone Precursor:
5,12‐Dihydroxy‐1,3,4‐trihydronap
Gasirat Tririya a & Murray Zanger a
a Department of Chemistry and Biochemistry,
University of the Sciences in Philadelphia, 600
South 43rd, Philadelphia, PA, 19104, USA
Available online: 10 Jan 2011
To cite this article: Gasirat Tririya & Murray Zanger
(2004): Synthesis of Anthracyclinone Precursor:
5,12‐Dihydroxy‐1,3,4‐trihydronaphthacene‐2,6,11‐quinone, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:17, 3047-3059
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3047–3059, 2004
Synthesis of Anthracyclinone Precursor:
5,12-Dihydroxy-1,3,4-trihydronaphthacene-
2,6,11-quinone
*
Gasirat Tririya and Murray Zanger
Department of Chemistry and Biochemistry, University of the Sciences in
Philadelphia, Philadelphia, USA
ABSTRACT
Two practical and efficient approaches for preparing large quantities of
5,12-dihydroxy-1,3,4-trihydronaphthacene-2,6,11-quinone 9 are described.
Both synthetic approaches involve a simple route with a fewer number of
steps and utilize readily available and inexpensive starting materials.
Large-scale production of this precursor may prove to be useful for
further research involving the synthesis of antineoplastic anthracyclines
and development of their analogs with increased activity and decreased
toxicity.
Key Words: Anthracyclines; Anthracyclinones; Daunorubicin; 4-
Demethoxyaglycones; Doxorubicin; Idarubicin.
*
Correspondence: Gasirat Tririya, Department of Chemistry and Biochemistry,
University of the Sciences in Philadelphia, 600 South 43rd, Philadelphia, PA 19104,
USA; E-mail: gtririya@hotmail.com.
3047
DOI: 10.1081/SCC-200028508
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3048
Tririya and Zanger
INTRODUCTION
Daunorubicin 1 and doxorubicin 2 are structurally related to the group of
glycoside antibiotics called anthracyclines. These agents have shown a very
high activity against a wide variety of human cancers. However, chemotherapy
employing these anthracyclines is hampered by various undesired side effects,
the most notable and serious one of which is dose-related cardiotoxicity.[1]
This important class of antineoplastic agents has been obtained only by
fermentation of different fungi belonging to the genus Streptomyces.[1] They
cannot be produced economically by known synthetic methods; thus, the
cost of the drugs is extremely high. These factors have prompted a great inter-
est in development of synthetic routes to these compounds and their analogs
with improved therapeutic indices.
In a search for superior analogs, it was established by Arcamone and
coworkers that the two unnatural anthracyclines, 4-demethoxydaunorubicin
3 and 4-demethoxydoxorubicin 4, possess increased activity and decreased
toxicity.[1] Currently, 4-demethoxydaunorubicin, called idarubicin, is clini-
cally available in the United States. Clinical studies indicate that the drug
possesses higher affinity for lipids than both parent drugs, which suggests
possible oral administration of the drug, and thus provides a distinct advantage
over the parent drugs.[2,3]
The majority of anthracycline syntheses has been concentrated on the
total syntheses of the aglycones such as daunorubicinone 5, adriamycinone

Synthesis of Anthracyclinone Precursor
3049
6, and 4-demethoxy aglycones 7 and 8. Methodologies employed in these
syntheses include (a) Friedel-Crafts acylation and alkylation; (b) Marschalk
reaction; (c) Diels-Alder reaction; (d) Claisen rearrangement; and (e) 1,4-
dipole-metalated quinone strategy.[4] Although different approaches have
been reported, they involve a considerable number of steps and the yields
are too low for economical preparation. Herein we report two alternative
routes that provide a practical and efficient approach for larger scale prep-
aration of 4-demethoxyaglycones. Our objectives are to develop an approach
that involves fewer steps with simpler reactions and uses inexpensive and
readily available starting materials. In order to avoid stereochemical problems
of the hydroaromatic ring A in the early stage of synthesis, we were particu-
larly intrigued in the preparation of a well-known aglycone precursor, 5,12-
dihydroxy-1,3,4-trihydronaphthacene-2,6,11-quinone 9. Different functional-
ities at C-2 and C-4 of the aglycone precursor, followed by isomeric resol-
ution, can be subsequently introduced by several well-known reactions to
produce desirable 4-demethoxyaglycones 7 and 8.[5]
RESULTS AND DISCUSSION
According to our methodology, the Diels-Alder reaction was used to
construct the AB ring synthon. As illustrated in Sch. 1, we started with the
reaction between 1,4-benzoquinone and 1,3-butadiene to give an excellent
yield of the tetrahydro-1,4-naphthoquinone 10, which was aromatized with
glacial AcOH in the presence of concentrated HBr as a catalyst to afford
5,8-dihydro-1,4-dihydroxynaphthalene 11 (91%). Diacetylation by Ac2O
and dimethylation by Me2SO4 in NaOH solution of compound 11 yielded
the diacetoxy compound 12a (98%) and the dimethoxy compound 12b
(68%), respectively. Epoxidation of 12a, b with m-CPBA in CH2Cl2 gave
the epoxides 13a, b with 97% and 91% yields, respectively. It is notable
that the quinone 10 could also be diacetylated and dimethylated in a similar
manner to that described for the dihydroxy compound 11 to afford excellent
yields of compounds 12a and 12b, respectively.
Several attempts to rearrange the epoxides 13a and 13b in the presence of a
Lewis acid such as BF3 etherate or AlCl3 under different conditions[6] failed to
produce the corresponding disubstituted 2-tetralones 15a and 15b. It appeared
that BF3 etherate and AlCl3 were too reactive and the resulting sticky materials
could not be purified and identified. A very low yield of one product obtained
from the reaction of 13b with AlCl3 in dry toluene was characterized as 5,8-
dimethoxy-3-chloro-2-hydroxy-1,2,3,4-tetrahydronaphthalene 14b. Other acid
catalysts such as p-TsOH, dry HCl gas, and methane sulfonic acid were also
employed.[7] The results indicated that the epoxides underwent nucleophilic

3050
Tririya and Zanger
Scheme 1. (i) Toluene, rt, 5 days; (ii) glacial AcOH, conc. HBr, 808 and then rt,
15 min; (iii) Ac2O, conc. H2SO4, rt, 15 min; (iv) Me2SO4, NaOH/H2O, 108 and then
rt, 12 hr; (v) m-CPBA, CH2Cl2, rt, 12 hr; (vi) dry HCl gas, anhydrous ethylene glycol
dimethyl ether, (220) 2 (210)8, overnight; (vii) refluxed, AlCl3, dry toluene, 2 hr;
(viii) refluxed, MgBr2 etherate, dry toluene, 6 hr.
addition instead of the rearrangement. For example, the reaction of the epoxide
13a with dry HCl gas, in CH2Cl2 or in anhydrous ethylene glycol dimethyl ether
gave the chlorohydrin 14a in a very good yield. It is possible that the conditions
were not dry enough for a hydride shift to occur. The acid-catalyzed rearrange-
ment of the epoxide 13b was eventually achieved when the epoxide was
refluxed with excess MgBr2 etherate in dry toluene for 6 hours, resulting in
the 5,8-dimethoxy-2-tetralone 15b in a 60% yield. The rearrangement of the
epoxide 13a in the presence of MgBr2 etherate in dry toluene also yielded the
corresponding 2-tetralone 15a. Attempts to isolate and purify compound 15a
1
failed but a H nmr spectrum of its 2,4-dinitrophenyl hydrazone indicated
that the tetralone 15a was actually formed.
A similar approach (Sch. 2) was conducted by utilizing 2-chloro-1,3-buta-
diene (chloroprene) as a diene. This procedure was modified from the pro-
cedure developed by Grob and Jundt in 1952.[8]

Synthesis of Anthracyclinone Precursor
3051
As illustrated in Sch. 2, diacetylation and dimethylation of either com-
pound 16 or 17 yielded the vinyl chlorides 18a and 18b in good yields. The
5,8-dimethoxy-2-tetralone 15b was then obtained in 40% yield from the
hydrolysis of the corresponding vinyl chloride 18b with concentrated
H2SO4. This modified method was able to produce large quantities of the 2-
tetralone 15b in just three steps with less-expensive reagents. Acid hydrolysis
of the vinyl chlorides 17 and 18a, however, failed to give the corresponding
2-tetralones. The ethylene ketal 19 was prepared in order to protect the keto
functional group of compound 15b before condensation with phthalic anhy-
dride; however, this step was unnecessary. Finally, the aglycone precursor,
5,12-dihydroxy-1,3,4-trihydronaphthacene-2,6,11-quinione 9, was obtained
Scheme 2. (i) refluxed, benzene/xylene, 6 h; (ii) glacial AcOH, conc. HBr, 808 and
then rt, 15 min; (iii) Ac2O, conc. H2SO4, rt, 15 min; (iv) Me2SO4, NaOH/H2O, 108
and then rt, 12 h; (v) conc. H2SO4, 08, 2.5 h; (vi) refluxed, ethylene glycol, benzene,
p-TsOH; (vii) AlCl3/NaCl, 1808, 2 min.

3052
Tririya and Zanger
in 80% yield by the Friedel-Crafts acylation of 15b with phthalic anhydride in
a single pot procedure.
CONCLUSION
These syntheses may prove to be a practical and efficient approach for
preparing large quantities of 5,12-dihydroxy-1,3,4-trihydronaphthacene-
2,6,11-quinone 9, which will be a useful precursor for further research invol-
ving the synthesis of anthracycline antibiotics and development of their ana-
logues with increased activity and decreased toxicity.
EXPERIMENTAL
All melting points are uncorrected. All infrared spectra (FT-IR) were
recorded with thin film on NaCl plate, except when mentioned in the experi-
mental, and only noteworthy absorptions (cm21) are listed. 1H and 13C NMR
spectra were recorded at 90 MHz and at 400 MHz with TMS as an internal
reference. All mass spectra were determined with a gas chromatograph with
a mass detector utilizing electron impact ionization. The results of elemental
analyses are within +0.3% of the theoretical values.
4a,5,8,8a-Tetrahydronaphthoquinone-1,4-dione (10)
A gas delivery system consisted of a reaction cylinder, a gas dispersion
tube, and a 1, 3-butadiene tank; all were interconnected by a 2-inch tygon
tube. The reaction cylinder was charged with 50g (0.46 mol) of 1,4-benzoqui-
none and 120 mL of toluene. To the magnetically stirred suspension the 1,3-
butadiene gas was added at a slow rate through the gas dispersion tube until
the weight of the cylinder increased by the required amount of the diene
(24.9g, 0.48mol). After the addition was complete, the cylinder was stoppered
and the dark green reaction mixture was stirred at room temperature for 5 days.
Then the reaction mixture was filtered and the solvent was evaporated to give
65.4g (88%) of 10 as a pale yellow solid. A part of the crude product was
recrystallized from petroleum ether to afford the pure adduct of 10 as pale
1
green needles, mp 56–578 (ref. 55–608).9 IR: 1676 (C55O) cm21; H nmr
(400 MHz, CDCl3): d 2.15–2.21 (2H, m), 2.44–2.50 (2H, m), 3.21–3.26
(2H, m), 5.66–5.72 (2H, t, J ¼ 1.5 Hz), 6.66 (2H, s); 13C nmr (90 MHz,
.
CDCl3): d 24.38, 46.57, 125.12, 140.10, 201.04; GC-MS: m/z 162 (Mþ ),

Synthesis of Anthracyclinone Precursor
3053
147, 134, 115, 105, 79, 77, 54; Anal. Calcd. for C10H10O2 (162.18): C, 74.06; H,
6.21; O, 19.73. Found: C, 74.05; H, 6.19.
5,8-Dihydronaphthalene-1,4-diol (11)
A mixture of 24g (0.15 mol) of the quinone 10 in 60mL glacial AcOH was
heated until the temperature reached 808. The heating was stopped and a few
drops of concentrated HBr were added to the hot solution. A vigorous exother-
mic reaction occurred, the temperature rapidly increasing to 110–1158. The sol-
ution was stirred at room temperature for 15min and then it was allowed to
stand and cool down to room temperature. Upon cooling, a mass of white crys-
tals separated. The precipitate was filtered and dried to give 21.8g (91%) of 11.
A part of the crude product was recrystallized from benzene/acetone solvent
pair to afford pure 11 as white crystals, mp 209–2118 (ref. 208–2098).9 IR:
1
3258 (OH), 1482, 1424, 1405, 1380cm21; H nmr (90 MHz, acetone-d6):
d 3.24 (4H, d, J ¼ 1.4 Hz), 5.87–5.91 (2H, t, J ¼ 1.4 Hz), 6.54 (2H, s), 7.52
(2H, s); 13C nmr (90 MHz, DMSO-d6): d 24.71, 112.59, 122.47, 124.70,
.
147.98; GC-MS: m/z 162 (Mþ ), 147, 115, 105, 77; Anal. Calcd. for
C10H10O2 (162.18): C, 74.06; H, 6.21; O, 19.73. Found: C, 74.01; H, 6.27.
4-Acetyloxy-5,8-dihydronaphthalen-1-yl acetate (12a)
A mixture of 21.2 g (0.13 mol) of compound 11 in 80 mL Ac2O was
stirred at room temperature until a clear solution was obtained. To the solution
was added a few drops of concentrated H2SO4. The resulting deep red solution
was stirred for 15 min and then it was poured onto crushed ice. The reaction
mixture was stirred until all the sticky material turned to a solid. The solid
was filtered and dried, resulting in 31.3 g (98%) of 12a as white powder.
Recrystallization from 95% EtOH yielded pure 12a as white needles, mp
1
130–1328 (ref. 133–133.58).9 IR: 1757 (C55O), 1471, 1369, 1201 cm21; H
nmr (90 MHz, CDCl3): d 2.28 (6H, s), 3.17–3.19 (4H, d, J ¼ 1.3 Hz), 5.81–
5.84 (2H, t, J ¼ 1.3 Hz), 6.93 (2H, s); 13C nmr (90 MHz, CDCl3): d 20.86,
24.44, 120.58, 123.52, 128.94, 146.95, 170.00; GC-MS: m/z 204 (Mþ†),
162, 144, 115, 105, 77; Anal. Calcd. for C14H14O4 (246.26): C, 68.28; H,
5.73; O, 25.99. Found: C, 68.26; H, 5.74.
5,8-Dimethoxy-1,4-dihydronaphthalene (12b)
A mixture of 36.8g (0.23 mol) of the quinone 10 and 37g (0.92 mol) of
NaOH in 400 mL water was cooled to a temperature between 5 and 108 in an

3054
Tririya and Zanger
ice-acetone bath. Dimethyl sulfate, 60mL (0.63 mol), was slowly added and the
reaction mixture was stirred at room temperature for 12h.10 The precipitate was
filtered, washed with NaOH solution and water, and dried. To the filtrate was
added an additional 10mL of Me2SO4 and stirred for additional 6 h.
The second precipitate was collected and combined with the previous one.
The resulting 34.6g (79%) of a brown solid was extracted with hexane. After
the hexane was evaporated, 29.7g (68%) of a yellow solid was obtained and sub-
sequently recrystallized from MeOH to give relatively pure 12b as off-white
needles. Pure 12b was obtained from repeated recrystallizations from MeOH,
mp 48.5–49 8. IR: 2938, 2832, 1481, 1253cm21; 1H nmr (90 MHz, CDCl3): d
3.25–3.26 (4H, d, J ¼ 1.3 Hz), 3.76 (6H, s), 5.85–5.88 (2H, t, J ¼ 1.3 Hz),
6.62 (2H, s); 13C nmr (90 MHz, CDCl3): d 24.76, 55.99, 107.20, 124.0,
.
124.84, 151.46; GC-MS: m/z 190 (Mþ ), 175, 159, 144, 115; Anal. Calcd. for
C12H14O2 (190.24): C, 75.76; H, 7.42; O, 16.82. Found: C, 75.46; H, 7.40.
6-Acetyloxy-1a,2,7,7a-tetrahydronaphtho[2,3-b]oxiren-3-yl
Acetate (13a)
A solution of 4.5 g (0.02 mol) of m-CPBA (77%) in 80 mL CH2Cl2 was
dried over anhydrous MgSO4 and filtered. This solution was added dropwise
to a solution of 4.4 g (0.018 mol) of the alkene 12a in 20 mL CH2Cl2.[11] The
reaction mixture was stirred at room temperature for 12 h. The mixture was
filtered to remove m-chlorobenzoic acid formed during the epoxidation.
The CH2Cl2 filtrate was first washed with 3 ꢀ 40 mL saturated solution of
NaHCO3 and then with 3 ꢀ 40 mL of 10% NaHSO4 solution to remove residual
acid and excess m-CPBA, respectively. The organic layer was washed with water
and dried over anhydrous MgSO4. After evaporation, the resulting 4.6 g (97%) of
a white solid was recrystallized from 95% EtOH to afford pure 13a as white
crystals, mp 165–1668. IR: 3002, 1755 (C55O), 1470, 1371, 1196,
1041 cm21; 1H nmr (90 MHz, DMSO-d6): d 2.32 (6H, s), 2.70 and 2.90 (2H, 2
2
2
br s, J ¼ 18 Hz), 3.10 and 3.30 (2H, 2 br s, J ¼ 18 Hz), 3.45 (2H, br s), 7.02
(2H, s); 13C nmr (90 MHz, PENDANT, CDCl3): d 20.65, 23.63, 50.44,
120.25, 125.49, 146.32, 168.74; GC-MS: m/z 262 (Mþ ), 220, 178, 160;
.
Anal. Calcd. for C14H14O5 (262.26): C, 64.12; H, 5.38; O, 30.50. Found: C,
64.10; H, 5.33.
3,6-Dimethoxy-1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirene (13b)
A solution of 23 g (0.10 mol) of m-CPBA (77%) in 150 mL CH2Cl2
was added dropwise to a solution of 17.5 g (0.092 mol) of the alkene 12b in

Synthesis of Anthracyclinone Precursor
3055
150 mL CH2Cl2. The reaction mixture was stirred at room temperature for
12 h, followed by the work-up in a manner similar to that described for the
epoxide 13a. The resulting 17.2 g (91%) of a white solid was recrystallized
from 95% EtOH to afford pure 13b as white crystals, mp 129–130 8. IR:
1
2994, 2938, 2834, 1479, 1252, 1093 cm21; H nmr (400 MHz, CDCl3): d
2.82–2.88 (2H, dd, 2J ¼ 18.2 Hz, J ¼ 1.3 Hz), 3.49 and 3.54 (2H, t,
2J ¼ 18.2 Hz, J ¼ 1.3 Hz), 3.50–3.51 (2H, t, J ¼ 1.3 Hz), 3.79 (6H, s), 6.66
(2H, s); 13C nmr (400 MHz, CDCl3): d 23.71, 51.74, 56.04, 107.86, 121.77,
.
151.81; GC-MS: m/z 206 (Mþ ), 191, 173; Anal. Calcd. for C12H14O3
(206.24): C, 69.89; H, 6.84; O, 23.27. Found: C, 69.67; H, 6.81.
4-Acetyloxy-6-chloro-7-hydroxy-5,6,7,8-
tetrahydronaphthalen-1-yl Acetate (14a)
A solution of 2.5 g (0.0095 mol) of the epoxide 13a in 15 mL anhydrous
ethylene glycol dimethyl ether was cooled in a dry ice-acetone bath to a temp-
erature between 220 and 2108. Dry HCl gas was then delivered into the
cooled solution for 1 hour to ensure saturation of the acid. The reaction
[7]
mixture was kept refrigerated overnight
and then the solvent was evapor-
ated to yield 2.5 g (88%) of 14a as a white solid. Recrystallization from
95% EtOH afforded pure 14a as white needles, mp 156–1588. IR: 3521
1
(OH), 1755 (C55O), 1471, 1370, 1201 cm21; H nmr (400 MHz, CDCl3):
d 2.33 (3H, s), 2.34 (3H, s), 2.57–2.64 (1H, td, J ¼ 9.35 Hz), 2.83 (1H, br
s), 2.87–2.94 (1H, td, J ¼ 10.36 Hz), 3.20–3.26 (1H, dd, 2J ¼ 17.2 Hz,
2
J ¼ 5.8 Hz), 3.32–3.37 (1H, dd, J ¼ 17.2 Hz, J ¼ 5.8 Hz), 3.96–4.02 (1H,
m), 4.10–4.16 (1H, m), 6.98 (2H, s); 13C nmr (400 MHz, CDCl3): d 20.74,
20.78, 30.86, 32.66, 61.54, 70.40, 120.71, 120.98, 127.43, 127.85, 145.78,
.
146.33, 169.02, 169.03; GC-MS: m/z 298 (Mþ ), 256, 214, 161; Anal.
Calcd. for C14H15ClO5 (298.72): C, 56.29; H, 5.06; Cl, 11.87; O, 26.78.
Found: C, 56.10; H, 5.04; Cl, 11.71.
6-Chloro-4a,5,8,8a-tetrahydronaphthalene-1,4-dione (16)
To a stirred suspension of 95.6 g (0.88 mol) 1,4-benzoquinone in 600 mL
of benzene/xylene mixture (5:1) was added 156 mL (0.90 mol) of freshly dis-
tilled 2-chloro-1,3-butadiene (50% w/v in xylene obtained from Monomer-
Polymer & Dajac Labs, Inc.). The reaction mixture was refluxed for 6 h and
then it was cooled in an ice-water bath. The residual undissolved solid was fil-
tered and the filtrate was evaporated, resulting in 144.7 g of a yellow solid,
which turned gray upon air exposure.[8] A GC-MS on this crude product

3056
Tririya and Zanger
showed two major peaks, which were characterized as compound 16 and 17.
Several recrystallizations from petroleum ether did not yield a pure
compound.
6-Chloro-5,8-dihydronaphthalene-1,4-diol (17)
Compound 17 was prepared by heating a mixture of 129.2 g (0.66 mol) of
the impure quinone 16 in 300 mL glacial AcOH in a manner similar to that
described for compound 11. After the reaction mixture cooled down to
room temperature, it was poured onto crushed ice. The precipitate was filtered
and dried to give 112 g (87%) of gray powder, which acquired purplish tinge
upon air exposure. A part of the crude product was recrystallized from
benzene/acetone solvent pair to afford pure 17 as white crystals, which
would later turn a pale bluish color, mp 191–1928 (ref. 197–1998).[8] IR:
3217 (OH), 1487, 1425 cm21 1H nmr (90 MHz, DMSO-d6): d 3.28–
;
3.41(4H, m), 6.02–6.04 (1H, m), 6.54 (2H, s), 8.73 (1H, s), 8.78 (1H, s);
13C nmr (90 MHz, DMSO-d6): d 26.58, 31.86, 112.79, 119.95, 120.85,
.
122.40, 128.84, 147.10, 147.55; GC-MS: m/z 196 (Mþ ), 161, 115; Anal.
Calcd. for C10H9ClO2 (196.63): C, 61.08; H, 4.61; Cl, 18.03; O, 16.27.
Found: C, 61.06; H, 4.53; Cl, 18.04.
4-Acetyloxy-6-chloro-5,8-dihydronaphthalen-1-yl
Acetate (18a)
Compound 18a was obtained by diacetylation of 3.1 g (0.016mol) of the
dihydroxy compound 16 with 20mL Ac2O in the presence of concentrated
H2SO4. The resulting 2.98g (66%) of white powder was recrystallized from
95% EtOH to give 2 g (45%) of 18a as white needles, mp 127–1288. IR:
1780 (C55O), 1473, 1370, 1180cm21; 1H nmr (90 MHz, CDCl3): d 2.32 (3H,
s), 2.35 (3H, s), 3.32–3.46 (4H, m), 5.94–5.98 (1H, t, J ¼ 1.8 Hz), 6.99 (2H,
s); 13C nmr (400MHz, CDCl3): d 20.80, 20.85, 26.54, 31.54, 120.29, 120.67,
120.68, 126.32, 127.25, 128.07, 145.72, 146.14, 169.02, 169.05; GC-MS:
m/z 280 (Mþ†), 196, 161; Anal. Calcd. for C14H13ClO4 (280.70): C, 59.90;
H, 4.67; Cl, 12.63; O, 22.80. Found: C, 60.01; H, 4.59; Cl, 12.34.
2-Chloro-5,8-dimethoxy-1,4-dihydronaphthalene (18b)
To a cooled solution of 100 g (0.51 mol) of compound 16 and 82 g
(2.05 mol) of NaOH in 500 mL water was slowly added 145 mL (1.53 mol)

Synthesis of Anthracyclinone Precursor
3057
of Me2SO4. The reaction mixture was stirred at room temperature for 12 h.
The precipitate was collected and dried. To the filtrate was added an additional
45 mL of Me2SO4 and the solution stirred for an additional 6 h. The second
precipitate was combined with the previous one. The resulting 98.9 g (86%)
of a dark brown solid was extracted with hexane. After the hexane was evap-
orated, 78.5 g (69%) of a green solid was obtained and subsequently recrystal-
lized from MeOH. The resulting 53.1 g (46%) of a relatively pure compound
18b was ready to use in the next step. An analytical sample was obtained from
repeated recrystallizations from MeOH and yielded pure 18b as yellow
needles, mp 77–788 (ref. 77–788).[8] IR: 2938, 2833, 1481, 1255,
1
1098 cm21; H nmr (90 MHz, DMSO-d6): d 3.28–3.41 (4H, m), 3.75 (6H,
s), 5.99–6.06 (1H, m), 6.78 (2H, s); 13C nmr (90 MHz, DMSO-d3): d 26.21,
31.34, 39.53, 55.44, 108.21, 121.96, 128.40, 150.38, 150.87; GC-MS: m/z
224 (Mþ†), 189, 174, 158; Anal. Calcd. for C12H13ClO2 (224.68): C, 64.15;
H, 5.83; Cl, 15.78; O, 14.24. Found: C, 64.24; H, 5.80; Cl, 15.62.
5,8-Dimethoxy-3,4-dihydronaphthalen-2(1H)-one or
5,8-Dimethoxy-2-tetralone (15b)
Method A
Following the procedure described by Grob and Jundt,[8] 80 g (0.36 mol)
of the vinyl chloride 18b was cooled in an ice-acetone bath to 25 to 08 under
N2 atmosphere. Then 320 mL of cooled concentrated H2SO4 was added to the
system and the reaction mixture was stirred at 25 to 08 for 2.5 h. The resulting
dark brown solution was poured onto crushed ice and the mixture was stirred
and additional water was added until all sticky materials turned to a solid. The
precipitate was filtered, washed several times with water, and dried to give a
light brown solid, which was subsequently extracted with hexane. The hexane
was evaporated to obtain 29.4 g (40%) of 15b as yellow needles. Recrystalli-
zation from 95% EtOH afforded 17.8 g (24%) of yellow needles, mp 97–988
(ref. 97–998).[8,12]
Method B
To 100 mL of toluene dried overnight with Na metal was added 5 g of
MgBr2 etherate and the suspension was stirred at room temperature for
15 min. To the suspension was added 3.5 g (0.017 mol) of the epoxide 13b.
The reaction mixture was refluxed for 6 h and then allowed to cool to room
temperature. The precipitate was filtered and washed with benzene. The
dried solids were added to water to remove MgBr2 and the white residue

3058
Tririya and Zanger
was collected and air dried to give 2.1 g (60%) of crude 15b, which was
extracted with hot hexane. The resulting 1.5 g (42%) of light yellow crystals
was recrystallized from 95% EtOH. IR: 2952, 2835, 1716 (C55O), 1482,
1260, 1085 cm21
;
1H nmr (400 MHz, CDCl3): d 2.54–2.57 (2H, t,
J ¼ 6.8 Hz), 3.07–3.10 (2H, t, J ¼ 6.8 Hz), 3.52 (2H, s), 3.79 (3H, s), 3.82
(3H, s), 6.70–6.72 (1H, d, J ¼ 8.8 Hz), 6.73–6.75 (1H, d, J ¼ 8.8 Hz); 13C
nmr (400 MHz, CDCl3): d 22.36, 38.55, 38.61, 56.06, 56.26, 108.50,
.
108.74, 124.16, 126.52, 150.93, 151.12, 211.16; GC-MS: m/z 206 (Mþ ),
164, 149; Anal. Calcd. for C12H14O3 (206.24): C, 69.89; H, 6.84; O, 23.27.
Found: C, 69.75; H, 6.70.
50,80-Dimethoxy-30,40-dihydro-10H-spiro[1,3-dioxolane-2,20-
naphthalene] (19)
The reaction mixture containing 4.5 g (0.022 mol) of the tetralone 15b,
10 mL (0.18 mol) of ethylene glycol, 80 mL of benzene, and 0.25 g of p-
TsOH was refluxed until approximately 0.4 mL of water was collected in
the water separator. After cooling, the reaction mixture was washed first
with 3 ꢀ 20 mL of 10% NaOH solution and then with 3 ꢀ 20 mL of water.
The benzene layer was dried over anhydrous MgSO4 and evaporated to give
4.8 g (87%) of a yellow solid, which was recrystallized from 95% EtOH,
yielding pure 19 as yellow needles, mp 100–1018. IR: 2945, 2833, 1480,
1250, 1121, 1081 cm21 1H nmr (90 MHz, CDCl3): d 1.82–1.97 (2H, t,
;
J ¼ 7 Hz), 2.82–2.96 (4H, m), 3.75 (3H, s), 3.76 (3H, s), 4.02 (4H, s), 6.62
(2H, s); 13C nmr (90 MHz, CDCl3): d 22.21, 30.53, 33.31, 55.42, 64.33,
.
107.32, 108.25, 125.06, 125.80, 151.60, 151.76; GC-MS: m/z 250 (Mþ ),
164, 149; Anal. Calcd. for C14H18O4 (250.29): C, 67.18; H, 7.25; O, 25.57.
Found: C, 67.29; H, 7.29.
5,12-Dihydroxy-1,3,4-trihydronaphthacene-2,6,11-quinone (9)
A solid mixture, containing 40.6 g of AlCl3, 8 g of NaCl, 3 g (0.02mol) of
finely ground phthalic anhydride, and 4 g (0.019mol) of finely ground tetra-
lone 15b, was thoroughly mixed and heated in a silicone oil bath at 1808.
After the reaction mixture was melted, it was mechanically stirred for
2 min. After cooling, the mixture was treated with 200 mL of a saturated
aqueous solution of oxalic acid.[13] The resulting 4.8 g (80%) of a red-
orange solid was collected and subjected to column chromatography on
silica gel (60–200 mesh), with CHCl3 as the eluting solvent. Yield after
removal of CHCl3 was 3.2 g (54%). Recrystallization from glacial AcOH

Synthesis of Anthracyclinone Precursor
3059
yielded 2.9 g (48%) of pure 9 as red needles, mp . 3108 (ref . 3008).[5]IR
(KBr): 1723 (C55O), 1621, 1581, 1372, 1233 cm21 1H nmr (400 MHz,
;
CDCl3): d 2.67–2.7 (2H, t, J ¼ 7.0 Hz), 3.28–3.31 (2H, t, J ¼ 7.0 Hz), 3.70
(2H, s), 7.86–7.88 (2H, dd, J ¼ 5.8 Hz), 8.38–8.40 (2H, dd, J ¼ 5.8 Hz),
13.39 (1H, s), 13.50 (1H, s); Anal. Calcd. for C18H12O5 (308.29): C, 70.13;
H, 3.92; O, 25.95. Found: C, 70.08; H, 3.90.
REFERENCES
1. Arcamone, F. Doxorubicin Anticancer Antibiotics; Medicinal Chemistry,
Academic Press: New York, 1981; Vol. 17.
2. Weiss, R.B. Semin. Oncol. 1992, 19, 670.
3. Arcamone, F.; Animati, F.; Capranico, G.; Lombardi, P.; Pratesi, G.;
Manzini, S.; Supino, R.; Zunino, F. Pharmacol. Ther. 1997, 76, 117.
4. (a) Kelly, T.R. Annu. Rep. Med. Chem. 1979, 14, 288; (b) Krohn, K.
Angew. Chem. Int. Ed. Engl. 1986, 25, 790.
5. Kende, A.S.; Mills, J.E.; Tsay, Y United States Patent 4,021,457, May 3,
1977.
6. Rickborn, B. Comprehensive Organic Synthesis; Pergamon Press:
New York, 1991; Vol. 3, 733.
7. Williamson, K.L.; Coburn, J.I.; Herr, M.F. J. Org. Chem. 1967, 32, 3934.
8. Grob, C.A.; Jundt, W. Helv. Chim. Acta 1952, 35, 2111.
9. (a) Scott, R.P. United States Patent 2,379,460, July 3, 1945; (b) Fieser, L.F.
J. Am. Chem. Soc. 1948, 70, 3165.
10. Hiers, G.S.; Hager, F.D. Organic Syntheses, Collected; Vol. I; 58.
11. McDonald, R.N.; Tabor, T.E. J. Am. Chem. Soc. 1967, 89, 6573.
12. Blade, R.J.; Hodge, P.J.C.S. Chem. Commun. 1979, 1, 85.
13. Arcamone, F.; Bernadi, L.; Patelli, B.; Di Marco, A.; Casazza, A.M.;
Sorano, C.; Pratesi, G. Experientia 1978, 34, 1255.
Received in the USA March 31, 2004