A facile synthesis of the angucyclinone antibiotic (+)-rubiginone B 2 involving the BF3-mediated Diels-Alder reaction of juglone

Article abstract of DOI:10.1055/s-2004-829196

A short synthesis of (+)-rubiginone B₂ is reported. The BF ₃-mediated Diels-Alder reaction of juglone and (R)-3-methyl-1- vinylcyclohexene followed by aromatization gave the anthraquinone as the desired regioisomer, which was converted into the target antibiotic after a two-step operation.

Full text of DOI:10.1055/s-2004-829196

PAPER
2099
A Facile Synthesis of the Angucyclinone Antibiotic (+)-Rubiginone B2
Involving the BF3-Mediated Diels–Alder Reaction of Juglone
Synthesis
i
of the
A
r
ngucyc
o
linone
A
ntibiotic
(
M
B
2 otoyoshiya,* Yusuke Masue, Gento Iwayama, Sachiko Yoshioka, Yoshinori Nishii, Hiromu Aoyama
Department of Chemistry, Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, 386-8567 Japan
Fax +81(268)215391; E-mail: jmotoyo@giptc.shinshu-u.ac.jp
Received 13 February 2004; revised 18 May 2004
mycinone. We report here the short synthesis of (+)-rubig-
inone B2 involving the BF3-mediated Diels–Alder
reaction of juglone and 1-vinylcyclohexenes.
Abstract: A short synthesis of (+)-rubiginone B2 is reported. The
BF3-mediated Diels–Alder reaction of juglone and (R)-3-methyl-1-
vinylcyclohexene followed by aromatization gave the anthraqui-
none as the desired regioisomer, which was converted into the target
antibiotic after a two-step operation.
To provide a benz[a]anthraquinone skeleton, the Diels–
Alder reaction of benzoquinones and 1-vinylcyclo-
hexenes seems to be the most convenient and straightfor-
ward way. However, many efforts have already been
made to achieve a high regio- and stereoselectivity in the
reaction of the unsymmetrical benzoquinones and the un-
symmetrically substituted dienes. We have shown in pre-
ceding studies that a high regioselectivity could be
obtained in the Lewis acid mediated Diels–Alder reaction
of juglone and unsymmetrical aliphatic dienes, which was
well explained by control of the secondary orbital interac-
tion.8 In fact, the reaction of juglone and 1-vinylcyclo-
hexene in the presence of BF3·OEt2 followed by
aromatization, as expected, afforded 8-hydroxy-1,2,3,4-
tetrahydrobenz[a]anthracene-7,12-dione in 55% isolated
yield as the sole product, whose structure was unambigu-
ously confirmed by the NOE observation of H-12 between
both H-1 and H-11 after selective reduction of the 12-car-
bonyl group as shown in Scheme 1. On the contrary, the
reaction without the Lewis acid gave a mixture of both re-
gioisomers in 75% yield after the same workup procedure
in which the 11-hydroxy isomer predominated in the ratio
of 80:20. These results provide a convenient synthetic
way to (+)-rubiginone B2 involving the BF3-mediated Di-
els–Alder reaction of juglone and (R)-5-methyl-1-vinyl-
cyclohexene.
Key words: angucyclinone antibiotics, asymmetric synthesis, qui-
nines, Diels–Alder reactions, photooxidations
Because of their important biological activities, much at-
tention has been paid to a series of the angucyclinone-type
antibiotics,1 whose structures characteristically feature a
benz[a]anthracene skeleton. The rubiginones, a class of
the angucyclinone antibiotics, were isolated by Oka and
co-workers2from the cultured broth of Streptomyces
griseorubiginosus and have been shown to potentiate the
cyctotoxicity of vincristine against vincristine-resistant
P388 leukemia and Moser cells. (+)-Ochromycinone3 is
also an angucyclinone antibiotic having a structure similar
to (+)-rubiginone B2 but lacking the phenolic methyl
group.
O
O
OR
O
ochromcinone R=H
rubiginone B2 R=Me
O
Figure 1
O
a
+
Many studies have been concerned with these antibiotics
from biological and synthetic viewpoints,4 and several re-
ports have described their asymmetric syntheses.5 How-
ever, there still remains room for further improvement on
behalf of a short and economical access to these com-
pounds. Previously, we reported that the Lewis acid-me-
diated regioselective Diels–Alder reaction of the
azaquinones6 or juglone (5-hydroxy-1,4-naphthoqui-
none)7 with unsymmetrical aliphatic dienes preferentially
gave one of the regioisomers, which represents a short
synthetic path for (+)-rubiginone B2 as well as (+)-ochro-
OH
O
OH
O
b
NOE
H
H
O
O
H
H
H
1
c
12
11
OH
O
OH
Scheme 1 Reaction conditions: (a) BF3·OEt2, toluene, 0 °C, 11 h;
(b) i. O2, KOH, EtOH, ii. aq. HCl (55% over all); (c) SnCl2, HCl,
AcOH, reflux, 17 h (62%).
SYNTHESIS 2004, No. 13, pp 2099–2102
Advanced online publication: 13.08.2004
x
x.
x
x
.
2
0
0
4
DOI: 10.1055/s-2004-829196; Art ID: F02304SS
© Georg Thieme Verlag Stuttgart · New York

2100
J. Motoyoshiya et al.
PAPER
O
O
c
b
a
OH
O
OH
O
O
O
O
O
e
d
f
OMe
O
OMe
OH
O
2
1
Scheme 2 Reaction conditions: (a) CH2=CHMgBr, THF, r.t. to 40 °C, 1 h; (b) cat. H2SO4, THF, 40 °C, 16 h; (c) juglone, BF3·Et2O, toluene,
0 °C, 12 h; (d) O2, KOH, EtOH, r.t., 15 h (61%, 2 steps); (e) Me2SO4, KOH, THF, H2O, 40 °C, 16 h (60%); (f) O2, hn, benzene, 5 h (80%).
The synthetic sequence for (+)-rubiginone B2 is outlined In conclusion, (+)-rubiginone B2 is synthesized in 6 steps,
in Scheme 2. The Grignard reaction of commercially starting from commercially available chemicals, which is,
available (R)-3-methylcyclohexanone and vinylmagne- to our knowledge, the most concise synthesis of this anti-
sium bromide followed by acid-catalyzed dehydration biotic reported so far.
gave an inseparable mixture of (R)-5- and 3-methyl-1-vi-
nylcyclohexene. The BF3-mediated Diels–Alder reaction
of juglone and the diene mixture in toluene at 0 °C and se-
quential aromatization under an oxygen atmosphere in al-
kaline ethanol gave the anthraquinone 1 in 61% yield
from juglone. Fortunately, this product was that desired
for the precursor having the suitable stereochemistry for
(+)-rubiginone B2 as revealed by the following conver-
sions to the target molecule. Thus, this convenient proce-
dure involving the two-step operation proved to be much
beneficial, considering the efforts to achieve both regio-
and stereoselectivities made in the previously reported
syntheses.5
The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were re-
corded with a Bruker Avance 400 in CDCl3 as the solvent, and
chemical shifts (d) were given in ppm relative to TMS as the inter-
nal standard. The IR spectra were obtained with a Shimadzu FTIR-
8400. Mass spectra were determined using a Hitachi M-80B mass
spectrometer, and Hitachi U-3210 spectrophotometer at an ionizing
voltage of 70 eV. Elemental analyses were performed on a Perkin-
Elmer 2400 CHN Elemental Analyzer. Melting points were deter-
mined with a Mitamura Riken micro melting apparatus and are un-
corrected. All commercially available compounds were used as
received.
Diels–Alder Reaction of Juglone with 1-Vinylcyclohexene
A solution of juglone (0.25 g, 1.44 mmol) and 1-vinylcyclohexene
(0.62 g, 5.74 mmol) in benzene (25 mL) was refluxed for 48 h. After
removal of the solvent in vacuo, the residue was dissolved in
CHCl3, washed with brine, dried (Na2SO4), and concentrated under
reduced pressure. The residue was dissolved in nitrobenzene (12
mL) and pyridine (9 mL) and refluxed for 6 h. After the organic sol-
vents were removed by steam distillation, the residue was extracted
with CHCl3 dried (Na2SO4), and chromatographed on silica gel
(benzene–CHCl3) to give a mixture of 11-hydroxy-1,2,3,4-tetrahy-
drobenz[a]anthracene and 8-hydroxy-1,2,3,4-tetrahydrobenz[a]an-
thracene in a ratio of 80:20 (0.30 g, 75%).
The remaining operation to accomplish the synthesis of
(+)-rubiginone B2 is the methylation of the phenolic hy-
droxyl group followed by the introduction of the carbonyl
oxygen at C-1 via the Norrish type II photoreaction.5f,9
The methylation of 1 was done using dimethyl sulfate in
the presence of KOH to give the methyl ether 2 in 60%
yield, which was then photooxygenated by irradiation for
five hours in benzene under an oxygen atmosphere. Con-
sequently, (+)-rubiginone B2 was obtained in 80% yield
from 2, and its spectral data well agreed with those al-
1H NMR: d = 1.67–1.90 (m, 4 H, H-2 and 3), 2.87 (t, 3J = 5.6 Hz, 2
25
ready reported5f and its optical rotation value was [a]D
2
H, H-4), 3.30 (t, J = 6.0 Hz, 2 H, H-1), 7.00–8.00 (m, 5 Harom),
+67 (c = 0.5, CHCl3) (86% ee). This short synthesis of (+)-
rubiginone B2 also provides a concise synthesis of (+)-
ochromycinone, because it is known that demethylation of
(+)-rubiginone B2 readily affords (+)-ochromycinone.5c
However, an attempt to convert 1 into (+)-ochromycinone
by photooxygenation was also made, but this reaction not
only needed a much longer irradiation time but resulted in
a lower yield accompanied by a formation of a by-prod-
uct. Such a lower efficiency in the photooxygenation of 1
than that of the methylated 2 would be due to a low con-
centration of the triplet excited state as found in the pho-
toreaction of 2-hydroxybenzophenone.10
12.20 (s, 0.2 H, 11-OH), 12.50 (s, 0.8 H, 8-OH).
MS (EI): m/z = 278 [M+].
Anal. Calcd for C18H14O3: C, 77.68; H, 5.07. Found: C, 77.62; H,
4.68.
BF3-Mediated Diels–Alder Reaction of Juglone with 1-Vinylcy-
clohexene and Reduction
A solution of 1-vinylcyclohexene (0.62 g, 5.74 mmol) in toluene (5
mL) was added to a solution of juglone (0.30 g, 1.72 mmol) and
BF3·OEt2 (0.22 mL, 1.72 mmol) in toluene (15 mL) at 0 °C. After
stirring for 24 h at 0 °C, the solution was neutralized with aq sat.
NaHCO3 solution, and the products were extracted with CHCl3 and
dried (Na2SO4). The residue obtained after removal of the solvent
Synthesis 2004, No. 13, 2099–2102 © Thieme Stuttgart · New York

PAPER
Synthesis of the Angucyclinone Antibiotic (+)-Rubiginone B2
2101
was treated similarly using the above described procedure for aro-
matization. The purification by column chromatography on silica
gel (benzene–CHCl3) gave 8-hydroxy-1,2,3,4-tetrahydrobenz[a]an-
thracene-7,12-dione (0.26 g, 55%); mp 169–174 °C (benzene–
CHCl3).
benzene and the organic layer was washed with aq sat. NaHCO3 so-
lution. After drying (Na2SO4), the solvent was removed to give the
crude product, which was purified by column chromatography on
silica gel (benzene) to give 2 (0.338 g, 60%); mp 171–173 °C (ben-
zene–hexane).
1H NMR: d = 1.09 (d, J = 6.6 Hz, 3 H, CH3), 1.37 (ddd, J = 11.4,
1
8-Hydroxy-1,2,3,4-tetrahydrobenz[a]anthracene-7,12-dione
1H NMR: d = 1.79–1.89 (m, 4 H, H-2 and 3), 2.94 (t, 3J = 5.6 Hz, 2
H, H-4), 3.38 (t, 2J = 6.0 Hz, 2 H, H-1), 7.23 (d, 6J = 8.4 Hz, 1 H, H-
5), 7.48 (d, 10J = 8.0 Hz, 1 H, H-9), 7.63 (t, 9,11J = 8.0 Hz, 1 H, H-
10), 7.75 (d, 10J = 8.0 Hz, 1 H, H-11), 8.14 (d, 5J = 8.4 Hz, 1 H, H-
6), 12.53 (s, 1 H, OH).
2J = 12.6, 3J = 5.3 Hz, 1 H, H-2), 1.88 (m, 1 H, H-3), 2.01 (m, 1 H,
H-2), 2.50 (dd, 3J = 10.6, 4J = 17.2 Hz, 1 H, H-4), 2.93 (dd, 3J = 4.3,
4J = 16.9 Hz, 1 H, H-4), 3.23 (ddd, 1J = 18.2, 2J = 11.1, 6.3 Hz, 1
H, H-1), 3.52 (m, 1 H, H-1), 4.03 (s, 3 H, OCH3), 7.26 (d, 10J = 8.3
Hz, 1 H, H-9), 7.42 (d, 6J = 7.8 Hz, 1 H, H-5), 7.67 (t, 11J = 7.8 Hz,
1 H, H-10), 7.84 (d, 10J = 7.8 Hz, 1 H, H-11), 8.07 (d, 5J = 8.34 Hz,
1 H, H-6).
This product (0.14 g, 0.50 mmol) was dissolved in a warm solution
of Sn2Cl2·2H2O (1.22 g, 5.40 mmol) and conc. HCl (1.5 mL) in
AcOH (4.5 mL) and refluxed for 17 h. The solution was neutralized
with aq sat. NaHCO3 solution and the precipitate was collected by
filtration. The product was washed with H2O and dried (0.08 g,
62%); mp 168–170 °C (CHCl3–MeOH–hexane).
13C NMR: d = 22.0 (3-CH3), 28.3 (C-2), 29.3 (C-3), 31.8 (C-4), 39.9
(C-1), 56.9 (OCH3), 117.2, 120.0, 121.4, 125.4, 128.7, 130.7, 135.1,
135.3, 138.0, 140.4, 144.7, 160.0 (Ar-C), 183.5 (12-C=O), 186.2 (7-
C=O).
MS (EI): m/z = 306 [M+].
8-Hydroxy-1,2,3,4-tetrahydrobenz[a]anthracene-7-one
1H NMR: d = 1.67, 1.83 (m, 4 H, H-2 and 3), 2.69 (m, 2 H, H-1),
2.85 (m, 2 H, H-4), 4.02 (s, 2 H, H-12), 6.87 (d, 10J = 7.4 Hz, 1 H,
H-9), 6.90 (d, 10J = 7.4 Hz, 1 H, H-11), 7.14 (d, 6J = 8.8 Hz, 1 H, H-
5), 7.43 (t, 9,11J = 7.4 Hz, 1 H, H-10), 8.05 (d, 5J = 8.8 Hz, 1 H, H-
6), 13.10 (s, 1 H, OH).
Anal. Calcd for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.27; H,
6.07.
(+)-Rubiginone B2
A solution of 2 (138 mg, 0.45 mmol) in benzene (50 mL) was bub-
bled with O2 and irradiated with a high-pressure mercury lamp for
5 h under an O2 atmosphere. The solvent was removed in vacuo and
the product was purified by column chromatography on silica gel
(EtOAc–benzene) to give (+)-rubiginone B2 (116 mg, 80%); mp
232–237 °C (dec.) (Lit.2 mp >237 °C, dec.).
MS (EI): m/z = 264 [M+].
Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.57; H,
5.89.
IR (Nujol): 1701, 1674 cm–1.
(R)-8-Hydroxy-3-methyl-1,2,3,4-tetrahydrobenz[a]anthracene-
7,12-dione (1)
1H NMR: d = 1.20 (d, J = 6.6 Hz, 3 H, CH3), 2.46 (m, 1 H, H-3),
2.56 (dd, 2J = 16.5, 3J = 11.2 Hz, 1 H, H-2), 2.68 (dd, 2J = 16.5 Hz,
3J = 10.3 Hz, 1 H, H-2), 2.99 (m, 2 H, H-4), 4.04 (s, 3 H, OCH3),
7.30 (d, 10J = 8.0 Hz, 1 H, H-9), 7.50 (d, 6J = 8.1 Hz, 1 H, H-5), 7.70
(t, 9, 11J = 8.0 Hz, 1 H, H-10), 7.77 (d, 10J = 8.0 Hz, 1 H, H-11),
8.26 (d, 5J = 8.1 Hz, 1 H, H-6).
13C NMR: d = 20.4 (3-CH3), 29.8 (C-3), 37.3 (C-4), 46.5 (C-2), 55.5
(OCH3), 116.2 (C-9), 118.6 (C-11), 128.5 (C-6), 132.0 (C-5), 134.3
(C-10), 119.6, 134.0, 134.02, 134.04, 136.6, 148.1, 158.8
(Cquart-arom), 180.5, 183.4, 197.4 (C=O).
A solution of the diene mixture of 3- and 5-methyl-1-vinylcyclo-
hexenes (0.18 g) in toluene (3 mL), prepared by the reaction of vi-
nylmagnesium bromide and (R)-3-methylcyclohexanone (99% ee)
followed by acid-catalyzed dehydration, was added to a solution of
juglone (64 mg, 0.37 mmol) and BF3·OEt2 (63 mg, 0.44 mmol) in
toluene (5 mL) at 0 °C. After stirring for 12 h at that temperature,
the solution was neutralized with aq NaOH solution, and the prod-
uct was extracted with benzene. The organic layer was dried
(Na2SO4) and the solvent was removed in vacuo. The residue was
dissolved in a solution of aq 0.89 M KOH (15 mL) and stirred at r.t.
for 15 h under an O2 atmosphere. Neutralization with aq HCl, ex-
traction with benzene, drying (Na2SO4), and removal of the solvent
gave the crude product, which was chromatographed on silica gel
(benzene) to give the anthraquinone 1 (66 mg, 61%); mp 163–
164 °C (benzene–hexane).
MS (EI): m/z = 320.
HRMS (EI): m/z calcd for C20H16O4: 320.1049; found: 320.1050.
Acknowledgment
1
1H NMR: d = 1.08 (d, J = 6.6 Hz, 3 H, CH3), 1.37 (ddd, J = 11.2
This work was partially supported by a Grant-in-Aid for 21st Cen-
tury COE program by the Ministry of Education, Culture, Sports,
Science, and Technology. The authors thank Mrs. Teruko Tsuchida
(Faculty of Engineering, Shinshu University) for recording mass
spectra.
Hz, 2J = 13.0 Hz, 3J = 5.4 Hz, 1 H, H-2), 1.88 (m, 1 H, H-3), 2.02
(m, 1 H, H-2), 2.53 (dd, 3J = 10.7 Hz, 4J = 17.2 Hz, 1 H, H-4), 2.96
(dd, 3J = 3.3 Hz, 4J = 17.2 Hz, 1 H, H-4), 3.24 (ddd, 1J = 18.6 Hz,
2J = 11.2, 6.2 Hz, 1 H, H-1), 3.56 (m, 1 H, H-1), 7.22 (d, 10J = 8.0
Hz, 1 H, H-9), 7.43 (d, 6J = 7.8 Hz, 1 H, H-5), 7.62 (t, 11J = 8.0 Hz,
1 H, H-10), 7.70 (d, 10J = 8.0 Hz, 1 H, H-11), 8.11 (d, 5J = 7.8 Hz,
1 H, H-6), 12.50 (s, 1 H, OH).
References
13C NMR: d = 22.0 (3-CH3), 28.2 (C-2), 29.6 (C-3), 31.7 (C-4), 40.2
(C-1), 119.6, 123.3, 125.0, 128.7, 131.6, 133.1, 135.0, 135.5, 136.8,
141.8, 146.8, 162.1 (Ar-C), 185.1 (12-C=O), 189.1 (7-C=O).
(1) Thomson, R. H. In Naturally Occurring Quinones III;
Chapman and Hall: London, 1987, Chap. 6.
(2) Oka, M.; Kamei, H.; Hamagishi, Y.; Tomita, K.; Miyaki, T.;
Konishi, M.; Oki, T. J. Antibiotics 1990, 43, 967.
HRMS (EI): m/z calcd for C19H16O3: 292.1099; found: 292.1112.
(3) Bowie, J. H.; Johnson, A. W. Tetrahedron Lett. 1967, 1449.
(4) (a) Brown, P. M.; Thomson, R. H. J. Chem. Soc., Perkin
Trans. 1 1976, 997. (b) Uemura, M.; Take, K.; Minami, T.;
Hayashi, Y. Tetrahedron 1985, 41, 5771. (c) Katsuura, K.;
Snieckus, V. Can. J. Chem. 1987, 65, 124. (d) Guingant,
(R)-8-Methoxy-3-methyl-1,2,3,4-tetrahydrobenz[a]anthracene-
7,12-dione (2)
A solution of 1 (0.54 g, 1.9 mmol), dimethyl sulfate (2.32 g, 18.4
mmol) and KOH (1.18 g, 21 mmol) in THF (70 mL) and H2O (10
mL) was heated for 5 h at 40 °C. The product was extracted with
Synthesis 2004, No. 13, 2099–2102 © Thieme Stuttgart · New York

2102
J. Motoyoshiya et al.
PAPER
Larsen, D. S.; Brooker, S. J. Org. Chem. 2001, 66, 7427.
(e) Carreno, M. C.; Ribagorda, M.; Somoza, A.; Urbano, A.
Angew. Chem. Int. Ed. 2002, 41, 2755. (f) Kalogerakis, A.;
Groth, U. Synlett 2003, 1886.
A.; Barreto, M. Tetrahedron Lett. 1987, 28, 3107.
(e) Kraus, G. A.; Wu, Y. Tetrahedron 1987, 28, 3107.
(f) Kraus, G. A.; Wu, Y. Tetrahedron 1987, 28, 3107.
(g) Kraus, G. A.; Wu, Y. Tetrahedron Lett. 1991, 32, 3803.
(h) Krohn, K.; Khanbabaee, K.; Jones, P. G.; Chrapowski, A.
Liebigs Ann. Chem. 1994, 1109. (i) Krohn, K.; Khanbabaee,
K. Liebigs Ann. Chem. 1994, 1109. (j) Krohn, K.; Boeker,
N.; Floerke, U.; Freund, C. J. Org. Chem. 1997, 62, 2350.
(k) Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.;
Deshpande, V. H. Tetrahedron Lett. 1999, 40, 4437.
(l) Mal, D.; Roy, H. N. J. Chem. Soc., Perkin Trans. 1 1999,
3167. (m) Krohn, K.; Mcheel, J.; Zukowski, M. Tetrahedron
2000, 56, 4753. (n) Rozek, T.; Bowie, J. H.; Pyke, S. M.;
Skelton, B. W.; White, A. H. J. Chem. Soc., Perkin Trans. 1
2001, 1826.
(6) Ohgaki, E.; Motoyoshiya, J.; Narita, S.; Kakurai, T.;
Hayashi, S.; Hirakawa, K. J. Chem. Soc., Perkin Trans. 1
1990, 3109.
(7) Motoyoshiya, J.; Kameda, T.; Asari, M.; Miyamoto, M.;
Narita, S.; Aoyama, H.; Hayashi, S. J. Chem. Soc., Perkin
Trans. 2 1997, 1845.
(8) (a) Alston, P. V.; Ottenbrite, R. M. J. Org. Chem. 1975, 40,
1111. (b) Alston, P. V.; Gordon, M. D.; Ottenbrite, R. M.;
Cohen, T. J. Org. Chem. 1983, 48, 5051. (c) Gunter, O. F.;
Ottenbrite, R. M.; Shillady, D. D.; Alston, P. V. J. Org.
Chem. 1987, 52, 391.
(5) (a) Boyd, V. A.; Sulikowski, G. A. J. Am. Chem. Soc. 1995,
117, 8472. (b) Larsen, D. S.; O’Shea, M. D.; Brooker, S.
Chem. Commun. 1996, 203. (c) Carreno, M. C.; Urbano, A.;
Vitta, C. D. Chem. Commun. 1999, 817. (d) Caygill, G. B.;
(9) Krohn, K.; Ballwanz, F.; Baltus, W. Liebigs Ann. Chem.
1993, 911.
(10) Merril, J. R.; Bennet, R. G. J. Chem. Phys. 1965, 43, 1410.
Synthesis 2004, No. 13, 2099–2102 © Thieme Stuttgart · New York