A new synthesis of the benzo[c]phenanthridines nornitidine, noravicine, and isodecarine, based on a microwave-assisted electrocyclic reaction of the aza 6π-electron system

Article abstract of DOI:10.1016/j.tetlet.2008.11.076

A new and versatile synthetic route to a benzophenanthridine alkaloid was developed by a bond formation between C4b and N5 on the benzo[c]phenanthridine nucleus, using a microwave-assisted electrocyclic reaction of the aza 6π-electron system. This strateg

Full text of DOI:10.1016/j.tetlet.2008.11.076

Tetrahedron Letters 50 (2009) 590–592
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Tetrahedron Letters
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A new synthesis of the benzo[c]phenanthridines nornitidine, noravicine,
and isodecarine, based on a microwave-assisted electrocyclic reaction
of the aza 6p-electron system
*
Kakujiro Kohno, Shuhei Azuma, Tominari Choshi, Junko Nobuhiro, Satoshi Hibino
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and versatile synthetic route to a benzophenanthridine alkaloid was developed by a bond forma-
Received 22 October 2008
Revised 18 November 2008
Accepted 20 November 2008
Available online 24 November 2008
tion between C4b and N5 on the benzo[c]phenanthridine nucleus, using a microwave-assisted electrocy-
clic reaction of the aza 6
p-electron system. This strategy was successfully used to synthesize nornitidine
(1b), noravicine (1d), and isodecaline (1f).
Ó 2008 Elsevier Ltd. All rights reserved.
1
4
11
New and more versatile synthetic routes to benzo[c]phenanthri-
dines are in high demand,1–7 because of their potent anti-tumor
activity.8–17 Among benzo[c]phenanthridines, nitidine (1a) and
7-hydroxy-8-methoxy-5-methyl-2,3-methylenedioxybenzo[c]phe-
nanthridinium hydrogen sulfate (NK109) (1e) are the most promis-
ing compounds, exhibiting significant anti-tumor activity against
drug-resistant human tumor cell lines.18–21 Nitidine (1e) is a potent
inhibitor of topoisomerase II.21
In our laboratory, we have focused on the construction of
fused pyridine ring systems, such as furoisoquinoline,22 phenan-
thridine,23 b-carboline,24 and azaanthraquinone alkaloids,25
using a microwave-assisted electrocyclic reaction of the aza
2
3
O
O
10
R3
9
8
R2
X
5
7
6
R1
1a : R1 = H, R2 = R3 = OMe, X = +N-Me (nitidine)
1b : R1 = H, R2 = R3 = OMe, X = N (nornitidine)
1c : R1 = H, R2 + R3 = OCH2O, X = +N-Me (avicine)
1d : R1 = H, R2 + R3 = OCH2O, X = N (noravicine)
1e : R1 = OH, R2 = OMe, R3 = H, X = +N-Me (NK109, fagaridine)
1f : R1 = OH, R2 = OMe, R3 = H, X = N (isodecaline)
Figure 1.
6p
-electron system. Here, we describe a new and versatile syn-
thesis of benzo[c]phenanthridine alkaloids, using the micro-
wave-assisted electrocyclic reaction of the aza -electron
system to induce bond formation between the C4b and N5-
positions13 in the tetracyclic benzo[c]phenanthridine nucleus
(Fig. 1).
We planned the syntheses of nornitidine (1b), noravicine
(1d), and isodecarine (1f), derived from 11,12-dihydro-
benzo[c]phenanthridines 2 as shown in retro-synthetic Scheme
1. Dihydro-compound 2 would be obtained from a 2-cyclo-
alkenylbenzaldoxime methyl ether 3 through a microwave-as-
(8)26 with trifluoromethanesulfonyl anhydride (Tf2O) and pyri-
dine afforded the O-triflate 9,27 which was subjected to the
Stille reaction with allyltributyltin in the presence of
PdCl2(PPh3)2 and LiCl to give the diallylbenzene 10. Olefin
metathesis of diallylbenzene 10 with the Grubbs’s I catalyst
yielded 1,4-dihydronaphthalene 11, which was subjected to
hydroboration followed by oxidation to afford 2-hydroxytetra-
hydronaphthalene 12. The alcohol 12 was subsequently oxidized
by pyridinium chlorochromate (PCC) in CH2Cl2 to give the
known b-tetralone 7.28 The unstable tetralone 7 was immedi-
ately treated with N-phenylbis(trifluoromethanesulfonamide
(Tf2NPh) and LDA to obtain the triflate 13, via a reaction with
bis(pinacolate)diborane and PdCl2(dppf)29 to afford the expected
pinacol borate 6.
6p
sisted electrocyclic reaction. An oxime ether
3 could be
prepared from 2-cycloalkenylbenzaldehyde 4, which would be
provided by the Suzuki–Miyaura reaction between 2-bromo-
benzaldehyde
5 and 2-(6,7-methylenedioxy-3,4-dihydronaph-
thyl)boronic acid pinacol ester 6.
Initially, to obtain a required pinacol borate 6, we attempted
an alternative synthesis of 6,7-methylenedioxy-b-tetralone (7)
(Scheme 2). Treatment of 2-allyl-4,5-methylenedioxyphenol
Next, the Suzuki–Miyaura reaction of readily available
2-bromobenzaldehydes (5b, 5d, and 5f) with the prepared
pinacol borate
6 smoothly proceeded in the presence of
PdCl2(PPh3)2 to give the 2-cycloalkenylbenzaldehydes 4b and
4d, or in the presence of PdCl2(dppf)30 to give 4f. The reaction
of 5f with 6, however, yielded the deacetylated product 4f.
* Corresponding author. Tel.: +81 84 936 2111; fax: +81 84 936 2024.
E-mail address: hibino@fupharm.fukuyama-u.ac.jp (S. Hibino).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.076

K. Kohno et al. / Tetrahedron Letters 50 (2009) 590–592
591
O
O
O
O
R3
R2
R3
R2
N
N
R1
R1
1b, 1d and 1f
2
O
O
O
O
MW-assisted
electrocyclic reaction
R3
R3
R2
NOMe
R2
CHO
R1
R1
3
4
Suzuki-Miyaura
R3
R2
Br
CHO
reaction
O
O
O
+
Me
Me
O
O
B
O
O
R1
5
6
7
Me
Me
Scheme 1.
Subsequent treatment of 4 with hydroxylamine methyl ether
afforded oximes (3b, 3d, and 3f). The oxime ether 3f was con-
verted to the acetyl compound 3g, and then oximes 3b, 3d,
and 3g were subjected to a microwave-assisted electrocyclic
reaction at 180 °C to give the tetracyclic 11,12-dihydro-
benzo[c]phenanthridines (2b, 2d, and 2g) in good to excellent
yield (Scheme 3).31,32
OTf
OH
O
O
O
O
a
c
8
9
b
O
O
O
O
Finally, the dihydrobenzophenanthridines 2b, 2d, and 2g were
oxidized by refluxing with 10% Pd–C in 1,2-dichlorobenzene to give
norniitidine (1b), noravicine (1d), and O-acetylisodecaline (1g),
respectively. Hydrolysis of the acetyl group of 1g with KHCO3 affor-
ded isodecaline (1f). The physical and spectroscopic data of 1b,32–
11
10
d
O
OH
O
O
O
e
1d,32–34 and 1f34,35 were identified by comparing them with
34
those previously reported.36
O
12
7
In conclusion, an alternative synthesis of 6,7-methylenedioxy-
b-tetralone (7) was achieved in a five-step sequence, and the de-
sired reagent of the Suzuki–Miyaura reaction, pinacol borate 6,
was derived in two steps. After the C–C bond connection between
C9a and C9b by the Suzuki–Miyaura reaction, a new synthetic
strategy for anti-tumor benzo[c]phenanthridines was established
by inducing a bond formation between C4b and N5 using a micro-
f
Me
Me
O
Me
Me
B
OTf
O
O
O
O
O
g
6
13
wave-assisted electrocyclic reaction of the aza 6p-electron system.
Scheme 2. Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2, rt, 2 h, 93%; (b)
allyltributyltin, LiCl, PdCl2(PPh3)2, dppf, DMF, 180 °C, 2 h, 99%; (c) Grubbs’s
catalyst, CH2Cl2, 50 °C, 1 h, 99%; (d) (i) BH3, THF, 0 °C, 1 h, (ii) 28% H2O2, 3 M NaOH,
50 °C, 1 h, 86%; (e) PCC, CH2Cl2, rt, 1.5 h, 74%; (f) LDA, Tf2NPh, THF, À78 °C to rt, 4 h,
84%; (g) bis(pinacolate)diborane, AcOK, PdCl2(dppf), DMSO, 70 °C, 1 h, 86%.
Formal total syntheses of nitidine (1a) and avicine (1c) were
achieved. In addition, the total synthesis of isodecaline (1f) was
completed. This new synthetic strategy will be an useful procedure
for the synthesis of other benzo[c]phenanthridine alkaloids.
I
R3
R2
Br
O
O
O
O
a
+
R3
R2
Me
O
CHO
B
O
Me
R1
CHO
Me
Me
5b: R1=H, R2=R3=OMe
R1
6
5d: R1=H, R2 + R3=OCH2O
5f : R1=OH, R2=OMe, R3=H
4b : R1=H, R2=R3=OMe
4d : R1=H, R2 + R3=OCH2O
4f : R1=OH, R2=OMe, R3=H
O
O
O
O
O
R3
b
R3
R3
R2
d
e
O
NOMe
R2
N
N
R2
R1
R1
R1
3b : R1=H, R2=R3=OMe
2b : R1=H, R2=R3=OMe
1b: R1=H, R2=R3=OMe
1d: R1=H, R2 + R3=OCH2O
1g: R1=OAc, R2=OMe, R3=H
1f : R1=OH, R2=OMe, R3=H
3d : R1=H, R2 + R3=OCH2O
3f : R1=OH, R2=OMe, R3=H
2d : R1=H, R2 + R3=OCH2O
2g : R1=OAc, R2=OMe, R3=H
c
f
3g : R1=OAc, R2=OMe, R3=H
Scheme 3. Reagents and conditions: (a) PdCl2(PPh3)2, or PdCl2(dppf) in the case of 4f, K2CO3, MeOH, DMF, 80 °C, 0.5–1 h, 98% (4b), 78% (4d), 97% (4f); (b) MeONH2 Á HCl,
AcONa, EtOH, 80 °C, 1 h, 95% (3b), 98% (3d), 95% (3f); (c) Ac2O, Et3N, DMAP, CH2Cl2, 80 °C, 1 h, 94%; (d) microwave, 1,2-dichlorobenzene, 180 °C, 84%(2b), 94%(2d),77%(2g); (e)
10% Pd–C, 1,2-dichlorobenzene, 180 °C, 97% (1b), 74% (1d), 93% (1g); (f) KHCO3, MeOH, H2O, rt, 4 h, 74%.

592
K. Kohno et al. / Tetrahedron Letters 50 (2009) 590–592
23. Kumemura, T.; Choshi, T.; Yukawa, J.; Hirose, A.; Nobuhiro, J.; Hibino, S.
Acknowledgments
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27. All new compounds have been characterized by physical and spectroscopic
analyses.
This work was supported in part by Grant-in Aid for Scientific
Research (C) from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
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NMR (DMSO-d6) d: 3.97 (3H, s), 4.07 (3H, s), 6.20(2H, s), 7.50 (1H, s), 7.69
(1H, s), 7.95 (1H, d, J = 8.7 Hz), 8.15 (1H, s), 8.54 (1H, s), 8.62 (1H, d,
J = 8.7 Hz), 9.29 (1H, s); 13C NMR (DMSO-d6) d: 55.7, 56.1, 101.0, 101.4,
102.4, 104.5, 107.7, 119.2, 119.7, 121.9, 126.3, 128.2, 128.3, 129.2, 139.5,
147.9, 148.0, 149.7, 149.9, 153.1; MS m/z: 333 (M+). HR-MS m/z: 333.1031
(Calcd for C20H15NO4: 333.1001).Noravicine (1d) mp 312 °C (EtOAc–hexane)
(Lit.,33 mp 325 °C (decomp.)); 1H NMR (DMSO-d6) d: 6.20 (2H, s), 6.27 (2H,
s), 7.50 (1H, s), 7.67 (1H, s), 7.93 (1H, d, J = 8.8 Hz), 8.31 (1H, s), 8.52 (1H, d,
J = 8.8 Hz), 8.53 (1H, s), 9.25 (1H, s); 13C NMR (DMSO-d6) d: 100.1, 101.1,
101.5, 102.1, 104.5, 104.8, 119.2, 120.2, 123.2, 126.5, 128.1, 129.3, 130.2,
139.9, 147.8, 148.0, 150.0, 151.5; MS m/z: 317 (M+). HR-MS m/z: 317.0674
(Calcd for C19H11NO4: 317.0688).Isodecarine (1f) mp 239–241 °C (CHCl3–
hexane) (Lit.,34 mp 225–227 °C, Lit.,35 mp 265–268 °C); 1H NMR (DMSO-d6)
d: 3.98 (3H, s), 6.20 (2H, s), 7.50 (1H, s), 7.74 (1H, d, J = 8.9 Hz), 7.95 (1H, d,
J = 8.9 Hz), 8.27 (1H, d, J = 8.9 Hz), 8.52 (1H, s), 8.53 (1H, d, J = 8.9 Hz), 9.65
(1H, s), 9.98 (1H, s); 13C NMR (DMSO-d6) d: 56.8, 101.0, 101.4, 104.4, 113.2,
117.3, 118.6, 118.9, 119.7, 126.8, 127.1, 128.3, 129.3, 138.9, 142.7, 144.2,
146.6, 147.9, 148.1; MS m/z: 319 (M+). HR-MS m/z: 319.0819 (Calcd for
C19H13NO4: 319.0845).
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