Novel synthesis of the 2-azaanthraquinone alkaloid, scorpinone, based on two microwave-assisted pericyclic reactions

Article abstract of DOI:10.1016/j.tetlet.2008.04.033

The total synthesis of the 2-azaanthraquinone alkaloid, scorpinone (4), isolated from the mycelium of a Bispora-like tropical fungus, has been completed in nine steps. The two key steps involve a microwave-assisted thermal electrocyclic reaction for the synthesis of an 8-oxygenated isoquinoline skeleton from a 1-aza 6π-hexatriene system, and a regioselective microwave-assisted [4+2] cycloaddition for the construction of a 2-azaanthraquinone framework.

Full text of DOI:10.1016/j.tetlet.2008.04.033

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3725–3728
Novel synthesis of the 2-azaanthraquinone alkaloid, scorpinone,
based on two microwave-assisted pericyclic reactions
Tominari Choshi , Teppei Kumemura, Junko Nobuhiro, Satoshi Hibino *
*
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
Received 7 March 2008; revised 2 April 2008; accepted 7 April 2008
Available online 9 April 2008
Abstract
The total synthesis of the 2-azaanthraquinone alkaloid, scorpinone (4), isolated from the mycelium of a Bispora-like tropical fungus,
has been completed in nine steps. The two key steps involve a microwave-assisted thermal electrocyclic reaction for the synthesis of an
8
-oxygenated isoquinoline skeleton from a 1-aza 6p-hexatriene system, and a regioselective microwave-assisted [4+2] cycloaddition for
the construction of a 2-azaanthraquinone framework.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Microwave; Electrocyclic reaction; [4+2] Cycloaddition; 2-Azaanthraquinone; Scorpinone
2
Recently, much attention has been paid to a family of
R
O
5
4
1
R3
6
R1
naturally
occurring
2-azaanthraquinones
having
3
7
benz[g]isoquinoline-5,10-dione (Fig. 1). Several biological
8
N2
activities of this class of compounds have been reported.
For example, the simple azaanthraquinone 1 exhibits anti-
9
R4
10
1
O
malarial activity and trypanocidal activity against Trypano-
soma congolense. Bostrycoidin (2) also shows antibiotic
benz[g]isoquinoline-5,10-dione
2
1
2
3
4
1
: R =H, R =R =R =H
activity against the tubercle bacillus. In 2001, Miljkovic
and co-workers isolated a new 2-azaanthraquinone, scor-
bostrycoidin
3
1
2
3
4
2: R =Me, R =OH, R =OMe, R =OH
6
-deoxybostrycoidin
pinone (4), from the mycelium of a Bispora-like tropical
fungus. The structure was elucidated by the analysis of
X-ray and 2D NMR spectral data.
1
2
3
4
3
: R =Me, R =H, R =OMe, R =OH
scorpinone
1
2
3
4
4
: R =Me, R =H, R =R =OMe
Because of the physiological importance of 2-azaanthr-
aquinones, several methods have been developed for the
Fig. 1.
4
synthesis of scorpinone (4). Cameron attempted a
synthetic study of azaanthraquinone derivatives by the
cycloaddition of isoquinoline-5,8-dione with 1,1-di-
methoxyethene to give scorpinone (4) in low yield as a
by-product. The same group also developed a syn-
thetic method for the synthesis of scorpinone using the
5
Houben–Hoesch reaction (intermolecular Friedel–Crafts
6
reaction) of 3-cyano-4-benzoylpyridines. Krapcho
*
reported the syntheses of an azaanthraquinone skeleton
in which the key step was an intermolecular Friedel–Crafts
reaction of a 4-benzylnicotinic acid derivative in the
Corresponding authors.
E-mail addresses: choshi@fupharm.fukuyama-u.ac.jp (T. Choshi),
hibino@fupharm.fukuyama-u.ac.jp (S. Hibino).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.033

3726
T. Choshi et al. / Tetrahedron Letters 49 (2008) 3725–3728
presence of fuming sulfuric acid. De Kimpe published an
effective synthesis of 2-azaanthraquinones via the
Tf O
2
OH
OTf
pyridine
ammonia-induced cyclization of 2-acetonyl-3-bromo-
CHO
CH Cl
0 C, 2 h
77%
CHO
7
2
2
methyl-1,4-naphthoquinones
acetonyl-1,4-naphthoquinone, where the leaving group is
a bromo atom or a phenoxide moiety, respectively.
or 3-phenoxymethyl-2-
o
OMe
OMe
8
9
10
9,10
Me
In the course of our studies, we have developed the syn-
theses of biologically active condensed heterocyclic com-
pounds, including natural products, based on a thermal
Bu Sn
3
RONH2 HCl
AcONa
Et NCl
4
Me
PdCl (PPh )
2
3 2
1
1–13
14–16
electrocyclic reaction
hexatriene
of either hexatriene
or aza-
DMF
CHO
EtOH
1
4,15,17
systems incorporating a principal aro-
o
o
8
0 C, 1.5 h
OMe
80 C, 2 h
matic or heteroaromatic moiety. In this Letter, we
present a new approach to the synthesis of scorpinone (4)
using two pericyclic reactions as a key step. In a retro-syn-
thetic analysis (Scheme 1), we envisaged that scorpinone (4)
could be derived from the known 6-deoxybostrycoidin (3),
which can be obtained by a regioselective Diels–Alder reac-
99%
88%
1
1
Me
Me
see Table 1
NOR
N
OMe
OMe
1
8
tion of an oxygenated diene 5 with a 7-bromoisoquino-
line-5,8-dione 6. An 8-oxygenated isoquinoline 7 as a
precursor of the isoquinoline-5,8-dione 6 might be
obtained by a thermal electrocyclic reaction of o-alkenyl-
benzaldoxime 8 derived from the cleavage of the 2,3-bond
of isoquinoline frameworks by using an 1-azahexatriene
system.
8
a: R=H
b: R=Me
7
8
Scheme 2.
2
1
trans = 2:1) was examined in 1,2-dichlorobenzene at
180 °C to afford the desired isoquinoline 7 in low yield
together with oxazepine 12 as a major product (Table 1,
entry 1). The same compounds were also obtained from a
thermal electrocyclic reaction using an isomeric mixture
of the propenyl group of 8a (cis:trans =1:5.7) by employ-
ing identical reaction conditions (entry 2). Thus, the gener-
ation of oxazepine 12 is not based on the geometry of the
propenyl group. We attempted to perform the same cycli-
zation using the benzaldoxime methyl ether 8b, prepared
from aldehyde 11 with hydroxylamine. As depicted in
entries 3 and 4, these reactions provided isoquinoline 7
in moderate yield without the formation of 12. Recently,
we have achieved the total synthesis of furoisoquinoline
As shown in Scheme 2, the 2-propenylbenzaldoxime 8a
was prepared from 2-hydroxy-6-methoxybenzaldehyde
1
9
(
9) in three steps as follows. The treatment of 2-hydroxy-
2
1
benzaldehyde 9 with trifluoromethanesulfonic anhydride
2
0
(
Tf O) in the presence of pyridine afforded triflate 10,
2
which was subjected to Stille reaction with propenyl tribu-
2
1
tylstannane in the presence of PdCl (PPh ) to give the 3-
2
3 2
propenylbenzaldehyde 11. Aldoxime 8a was obtained by
treating 11 with hydroxylamine.
Next, a thermal electrocyclic reaction of an isomeric
mixture of the propenyl group of benzaldoxime 8a (cis:
2
2
alkaloid, TMC-120B using a microwave-assisted thermal
electrocyclic reaction as a key step. In a similar way, the
microwave-assisted electrocyclic reaction of benzaldoxime
methyl ether 8b was performed to study the effects of
microwave irradiation using the same substrate. Initially,
we examined the effect of reaction temperature (entries
O
MeO
Me
N
OR
O
3
4
: R=H
: R=Me
5
–8). The best result was obtained when the reaction was
performed at 180 °C for 10 min in 1,2-dichlorobenzene
entry 7). Next, we examined the effect of replacing 1,2-
O
O
(
MeO
Me
dichlorobenzene with a different solvent, that is, toluene,
bromobenzene or DMF (entries 9–17). Furthermore, the
reaction was performed using a conventional procedure
under optimal conditions determined from the microwave
irradiation reaction for each solvent (entries 7, 11, 14 and
+
OTMS
N
Br
OMe
5
6
17). These reactions did not go to completion and the start-
Me
Me
NOR
ing material 11 was recovered with isoquinoline 7. Based
on these results, 1,2-dichlorobenzene was the best solvent
for the reaction. Furthermore, microwave-assisted condi-
tions were more effective than conventional conditions in
terms of increasing the yield (54?71%) and decreasing
the reaction time (30?10 min).
N
OMe
OMe
7
8
Scheme 1.

T. Choshi et al. / Tetrahedron Letters 49 (2008) 3725–3728
3727
Table 1
Effect of the microwave on the thermal electrocyclic reaction
Me
Me
Me
O
N
NOR
+
N
OMe
OMe
OMe
8a, b
7
12
a
Entry
R
Solvent
Temp (°C)
Time (min)
Microwave irradiation
Conventional method
Yield (%) of
isoquinoline
Yield (%)
of SM
Yield (%) of
isoquinoline
Yield (%) of
SM or 12
c
d
d
1
2
3
4
H
H
Me
Me
180
180
180
180
30
30
30
30
23
23
54
41
0(61 )
b
d
0(61 )
1,2-Dichlorobenzene
1,2-Dichlorobenzene
—
—
b
5
6
7
8
Me
Me
Me
Me
150
150
180
210
10
15
10
10
46
48
71
59
5
—
—
41
—
—
—
7
—
—
—
—
9
0
1
Me
Me
Me
150
150
180
10
75
10
25
56
59
61
—
—
—
—
0
—
—
100
1
1
Toluene
1
1
1
2
3
4
Me
Me
Me
150
150
180
10
20
10
44
51
64
9
—
—
—
—
21
—
—
31
Bromobenzene
1
1
1
5
6
7
a
Me
Me
Me
150
150
180
10
20
10
32
51
67
15
—
—
—
—
34
—
—
21
DMF
Cis:trans ratio of propenyl group = 2:1.
Cis:trans ratio of propenyl group = 1:5.7.
SM: starting material.
b
c
d
Yield (%) of oxazepine 12.
Br
Me
Me
N
Me
4
8% HBr
Br2
N
N
o
AcOH
rt, 10 min
1
40 C, 12 h
4%
Br
8
OH
13
OH
14
OMe
7
MeO
OMe
O
O
O
Me
MeO
Me
CAN
TMSO
5
N
N
MeCN-H O
toluene
2
Br
o
o
0
C, 20 min
110
C
O
OH
2
3% (from 13)
15
86% for 10 min with MW
3
7
3% for 30 min without MW
O
MeI, K CO
MeO
Me
2
3
rt, 1 h
N
6
8%
OMe O
4
Scheme 3.

3728
T. Choshi et al. / Tetrahedron Letters 49 (2008) 3725–3728
The obtained 8-methoxyisoquinoline 7 was heated at
40 °C in 48% HBr to give the 8-hydroxyisoquinoline 13
Scheme 3). The bromination of 13, based upon the proce-
6. Krapcho, A. P.; Waterhouse, D. J. Heterocycles 1999, 51, 737–
7
50.
1
(
7
8
. Kesteleyn, B.; De Kimpe, N. J. Org. Chem. 2000, 65, 640–
6
44.
2
3
dure of Choi, was performed to give the 5,7-dibromoiso-
quinoline 14. However, compound 14 was very unstable.
Therefore, 5,7-dibromoisoquinoline 14 was immediately
. Van, T. N.; Verniest, G.; Claessens, S.; De Kimpe, N. Tetrahedron
2005, 61, 2295–2300.
9. Claessens, S.; Jacobs, J.; De Kimpe, N. Synlett 2007, 741–744.
10. Claessens, S.; Verniest, G.; Jacobs, J.; Van Hende, E.; Habonimana,
P.; Nguyen Van, T.; Van Puyvelde, L.; De Kimpe, N. Synlett 2007,
2
4
oxidized with cerium ammonium nitrate (CAN) to afford
the isoquinoline-5,8-dione 15. Subsequently, Diels–Alder
reaction of 15 with diene 5 in toluene at 110 °C gave the
8
29–850.
1
1. B Woodward, R.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinheim, 1970; Chapter 5.
2
5
known 6-deoxybostrycoidine (3) with the elimination of
a methoxy group. In addition, the microwave-assisted
cycloaddition reaction of 15 with diene 5 was attempted.
The microwave-irradiated condition was more effective
than the conventional condition for improving the yield
12. Marvel, E. N. Thermal Electrocyclic Reactions; Academic Press: New
York, 1980; Chapter 2.
1
3. Okamura, W. H.; de Lera, A. R. In Comprehensive Organic Synthesis;
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York, 1991; Vol. 5, pp 699–750.
(
73?86%) and decreasing the reaction time (30?10 min)
14. Hibino, S.; Sugino, E. In Advances in Nitrogen Heterocycles;
2
6
as reported previously in a review. Finally, the alkylation
of 3 with MeI in the presence of K CO afforded scorpi-
none (4). Physical and spectroscopic analysis of synthetic
scorpinone (4) agreed with those of natural scorpinone
Moody, C. J., Ed.; JAI Press: Greenwich, CT, 1995; Vol. 5, pp
6
99–750.
2
3
1
1
5. Choshi, T. Yakugaku Zasshi 2001, 121, 487–495.
6. Choshi, T.; Uchida, Y.; Kubota, Y.; Nobuhiro, J.; Takeshita, M.;
Hatano, T.; Hibino, S. Chem. Pharm. Bull. 2007, 55, 1060–1064 and
related references cited therein.
2
7
3
in all respects.
In conclusion, we achieved the total synthesis of scorpi-
none (4) using a novel nine-step reaction scheme via the
construction of an 8-oxygenated isoquinoline skeleton
based on the microwave-assisted thermal electrocyclic reac-
tion of a 1-azahexatriene system. Regioselective cycloaddi-
tion using microwave irradiation then afforded the
azaanthraquinone framework. Furthermore, we demon-
strated that microwave irradiation plays a useful support-
ing role for both pericyclic reactions in terms of
improving yield and reducing the reaction time.
17. Kumemura, T.; Choshi, T.; Yukawa, J.; Hirose, A.; Nobuhiro, J.;
Hibino, S. Heterocycles 2005, 66, 87–90 and related references cited
therein.
1
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Brisson, C.; Brassard, P. J. Org. Chem. 1981, 46, 1810–1814; (c)
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948.
1
2
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9
09.
0. All new compounds have been characterized by physical and
spectroscopic analyses.
21. Propenyl tributylstannanes (cis:trans = 2:1 and cis:trans = 1:5.7)
were prepared from a cis and trans mixture of 1-bromopropene
(
purchased from Aldrich) and trans-1-bromopropene (purchased
Acknowledgement
from Aldrich), respectively. Geometries of compounds 11 and 8 were
agreed with geometries of propenyl tributylstannanes on the basis of
H NMR spectra.
22. Kumemura, T.; Choshi, T.; Hirata, A.; Sera, M.; Takahashi, Y.;
This work was supported in part by Grant-in Aid for
Scientific Research (C) (No. 15590033) from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan.
1
Nobuhiro, J.; Hibino, S. Chem. Pharm. Bull. 2005, 53, 393–397.
2
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4. Hibino, S.; Okazaki, M.; Ichikawa, M.; Sato, K.; Ishizu, T.
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References and notes
2
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3
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. (a) Okunade, A. L.; Clark, A. M.; Hufford, C. D.; Oguntimein, B. O.
Planta Med. 1999, 65, 447–448; (b) Nok, A. J. Cell Biochem. Funct.
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3
. Arsenault, G. P. Tetrahedron Lett. 1965, 45, 4033–4037.
. Miljkovic, A.; Mantle, P. G.; Williams, D. J.; Rassing, B. J. Nat.
Prod. 2001, 64, 1251–1253.
27. Synthetic scorpinone, mp 193–194 °C (MeOH) (lit., 195 °C). IR
À1
1
(ATR) m: 1673, 1654, 1592 cm
3
. H NMR (CDCl ) d: 2.75 (3H, s),
4.00 (3H, s), 4.03 (3H, s), 6.84 (1H, d, J = 2.6 Hz), 7.43 (1H, d, J
1
3
4
5
. Cameron, D. W.; Deutscher, K. R.; Feutrill, G. I. Tetrahedron 1980,
= 2.6 Hz), 7.82 (1H, s), 9.41 (1H, s). C NMR (CDCl ) d: 183.4,
3
2
1, 5060–5089.
. Cameron, D. W.; Deutscher, K. R.; Feutrill, G. I. Aust. J. Chem.
982, 35, 1439–1450.
180.5, 165.0, 164.1, 162.7, 149.7, 137.5, 137.0, 117.5, 115.6, 105.4,
+
103.5, 56.6, 56.0, 25.0. MS (EI) m/z: 283 (M ). HR-MS (EI) m/z:
1
283.0840, calcd for C16H13NO : 283.0845.
4