A new route to 3-(2-vinylphenyl)-2-methyl-2H-isoquinolin-1-ones and benzo[c]phenanthridines: Total synthesis of fagaronine

Article abstract of DOI:10.1016/S0040-4039(02)01013-4

Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-(2-vinylphenyl)-2-phenylethylenes, which can be transformed into 3-(2-vinylphenyl)-2-methyl-2H-isoquinolin-1-ones by Bischler-Napieralski reactions, and thence

Full text of DOI:10.1016/S0040-4039(02)01013-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5323–5325
A new route to 3-(2-vinylphenyl)-2-methyl-2H-isoquinolin-1-ones
and benzo[c]phenanthridines: total synthesis of fagaronine
Mo´nica Treus, Juan C. Este´vez, Luis Castedo and Ramo´n J. Este´vez*
Departamento de Qu´ımica Orga´nica and Unidade Asociada (CSIC), Universidade de Santiago, 15782 Santiago de Compostela,
Spain
Received 3 March 2002; accepted 27 May 2002
Abstract—Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-(2-vinylphenyl)-
2-phenylethylenes, which can be transformed into 3-(2-vinylphenyl)-2-methyl-2H-isoquinolin-1-ones by Bischler–Napieralski
reactions, and thence into benzo[c]phenanthridin-6-ones. The use of this route for a new total synthesis of fagaronine is described.
© 2002 Published by Elsevier Science Ltd.
Benzo[c]phenanthridines are attractive synthetic targets
because of their widespread occurrence in nature and
broad range of biological activities.1,2 In the cases of
nitidine (6a) and other 8,9-disubstituted planar ben-
zophenanthridinium salts such as fagaronine (6b), anti-
tumour activity in animal models has been traced to
inhibition of DNA topoisomerase, an action that has
been attributed to their conformationally rigid embed-
ded 2-phenylnaphthalene subunit.3,4 The toxicity of the
most active members of these groups, and the conse-
quent desire to study structure–activity relationships,
has led to a search for new synthetic methods that
would make it easy to prepare appropriate series of
compounds.5 Among the many methods developed for
this aim, those in which the key step is the annelation
of a 3-(2-vinylphenyl)isoquinolin-1-one6 are specially
interesting because compound 3c has a strong antitu-
mour activity7 and can be considered as a bioisostere of
the benzo[c]phenanthridine chelerythrine (6c). How-
ever, most of the few reported preparations of 3-
an easy, efficient access to vinylphenylisoquinolinones
3, and hence a new method for the total synthesis of
benzophenanthridinones 5 and we report the applica-
tion of the new method to the synthesis of fagaronine
(6b) (Scheme 1).
When the previously obtained9 N-methyl derivative 2b
was reacted with Tf2O and DMAP in CH2Cl2, the
expected Bischler–Napieralski cyclization afforded
vinylphenylisoquinolinone 3a,10 which was directly con-
verted into benzo[c]phenanthridinone 5a by oxidation11
with thallium trinitrate and subsequent reaction of the
resulting acetal 4a with aqueous HCl.
The utility of this new approach to benzo[c]-
phenanthridines was corroborated by the analogous
synthesis of fagaronine (6b) starting from the readily
available
N-ethoxycarbonylbenzylideneisoquinoline
1b,12 in which the OH group of fagaronine is protected
as an isopropoxy group. Proceeding as for 5a, treat-
ment of 1b with LDA at 0°C cleaved the CꢀN bond as
expected, and the resulting styrylurethane 2c was con-
verted into its N-methyl derivative 2d by treatment with
MeI. Compound 2d was next transformed into ben-
zophenanthridinone 5b via 3-vinylphenylisoquinolinone
3b and acetal 4b. After reduction of 5b with lithium
aluminium hydride and oxidation of the resulting dihy-
droderivative with DDQ had given the quaternary salt
6d, this latter was O-dealkylated with sulfuric acid,
furnishing fagaronine (6b).13
vinylphenylisoquinolinones
3
are onerous and/or
low-yielding.8
We recently described the first direct transformation of
1-benzylisoquinolines into benzo[c]phenanthridines by
a route in which CꢀN cleavage of 1-benzylidine deriva-
tives 1 gave the novel stilbene-like compounds 2, in
which rings C and B of the benzo[c]phenanthridine
skeleton were then sequentially constructed.9 Here we
describe a modification of this approach that provides
To sum up, this paper presents the first fruits of a new
strategy toward the synthesis of potentially antitumoral
* Corresponding author. Tel.: +34-981-563100, ext. 14242; fax: +34-
981-591014; e-mail: qorjec@usc.es
3-(2-vinylphenyl)-2-methyl-2H-isoquinolin-1-ones
3
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01013-4

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M. Treus et al. / Tetrahedron Letters 43 (2002) 5323–5325
Scheme 1. Reagents and conditions: (i) LDA, THF, 0°C, 30–60 min (100% yield); (ii) (a) NaH, THF, rt, 30 min, (b) MeI, rt, 45–60
min (74–100% yield); (iii) Tf2O, DMAP, CH2Cl2, 0°C“rt, 1.5 h (40–50% yield); (iv) Tl(NO3)3·3H2O, MeOH, rt, 5 min; (v) 10%
aq. HCl, rt, 40–60 min (80–95% yield); (vi) (a) LiAlH4, THF, 35°C, 3 h (95% yield), (b) DDQ, benzene, 25°C, 2 h (80% yield),
(c) H2SO4, AcOH, rt, 2.5 h (80% yield).
which is original and more efficient than the few previ-
ous syntheses of these compounds and may be suitable
for large-scale work. Optimization of this new route,
and its application to the synthesis of pharmacologi-
cally active benzo[c]phenanthridines other than faga-
ronine (6b), is now under investigation. Additionally,
we are completing a systematic study of the chemical
4. Cheng, C. C. In Progress in Medicinal Chemistry; Ellis,
G. P.; West, G. B., Eds. Structural aspects of antineo-
plastic agents—a new approach; Elsevier Science BV
(Biomedical Division): Amsterdam, 1988; Vol. 25, pp.
35–83.
5. For a recent review of benzo[c]phenanthridine synthesis,
see: Ishikawa, T; Ishii, H. Heterocycles 1999, 50, 627.
6. Onda, M.; Yamaguchi, I. Chem. Pharm. Bull. 1979, 27,
2076.
properties
of
N-ethoxycarbonyl-1-amino-1-(2-
vinylphenyl)-2-phenylethylenes 2 with a view to the
synthesis of other interesting anticancer compounds
such as benzofuronaphthoquinones, indolonaphtho-
quinones and ellipticines.14
7. Cho, W.-J.; Yoo, S.-J.; Chung, B.-H.; Whang, S.-H.;
Kim, S.-K.; Kang, B.-H.; Lee, C.-O. Arch. Pharm. Res.
1996, 19, 231.
8. Cho, W.-J.; Park, M.-J.; Chung, B.-H.; Lee, C.-O.
Bioorg. Med. Chem. Lett. 1998, 8, 41.
9. Treus, M.; Este´vez, J. C.; Castedo, L.; Este´vez, R. J.
Tetrahedron Lett. 2000, 41, 6351.
Acknowledgements
10. All new compounds gave satisfactory analytical and spec-
troscopic data. Selected physical and spectroscopic data
follow.
We thank the Ministry of Education, Culture and
Sports (DGEU) and the Xunta de Galicia for financial
support, and the latter for a grant to Mo´nica Treus.
1
Compound 3a. Mp 205–208°C (methanol). H NMR (l,
ppm, CDCl3): 3.30 (s, 3H, -NCH3), 3.90 (s, 3H, -OCH3),
3.99 (s, 3H, -OCH3), 4.00 (s, 3H, -OCH3), 4.04 (s, 3H,
-OCH3), 5.15 (d, J=11 Hz, 1H, -CꢁCH2), 5.63 (d, J=
17.5 Hz, 1H, -CꢁCH2), 6.40 (s, 1H, Ar-H), 6.46 (dd,
J=17.5 Hz, J=11 Hz, 1H, -CHꢁCH2), 6.77 (s, 1H,
Ar-H), 6.86 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 7.84 (s,
1H, Ar-H). MS (m/z, %): 381 (M+, 100).
References
1. (a) Shamma, M. The Isoquinoline Alkaloids: Chemistry
and Pharmacology; Academic Press: New York, 1972; (b)
Shamma, M.; Moniot, J. L. Isoquinoline Alkaloids
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Guinaudeau, H.; Leboeuf, M.; Cave´, A. J. Nat. Prod.
1990, 53, 235.
2. Sima´nek, V. In The Alkaloids. Chemistry and Pharmacol-
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3. Taira, Z.; Matsumoto, M.; Ishida, S.; Icikawa, T.;
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1
Compound 2c. Mp 119–121°C (methanol). H NMR (l,
ppm, CDCl3): 0.86 (t, J=7.1 Hz, 3H, -CH3), 1.40 (d,
J=6.1 Hz, 6H, 2×-CH3), 3.03 (s, 3H, -NCH3), 3.84–3.97
(m, 11H, 3×-OCH3+-OCH2-), 4.63 (h, J=6.1 Hz, 1H,
-CHMe2), 5.13 (dd, J=10.9 Hz, J=1.1 Hz, 1H, -CꢁCH2),
5.52 (dd, J=17.4 Hz, J=1.1 Hz, 1H, -CꢁCH2), 6.12 (s,
1H, Ar-H), 6.77 (s, 1H, Ar-H), 6.83–7.05 (m, 4H, 3×Ar-
H+-CHꢁCH2), 7.07 (s, 1H, Ar-H). MS (m/z, %): 455
(M+, 32), 310 (100).

M. Treus et al. / Tetrahedron Letters 43 (2002) 5323–5325
5325
Compound 3b. Mp 204–206°C (ethanol). 1H NMR (l,
ppm, CDCl3): 1.43 (d, J=6.1 Hz, 6H, 2×-CH3), 3.28 (s,
3H, -NCH3), 3.85 (s, 3H, -OCH3), 3.97 (s, 3H, -OCH3),
4.02 (s, 3H, -OCH3), 4.65 (h, J=6.1 Hz, 1H, -CHMe2),
5.10 (d, J=11 Hz, 1H, -CꢁCH2), 5.55 (d, J=17.4 Hz, 1H,
-CꢁCH2), 6.37 (s, 1H, Ar-H), 6.41 (dd, J=17.4 Hz, J=11
Hz, 1H, -CHꢁCH2), 6.74 (s, 1H, Ar-H), 6.83 (s, 1H,
Ar-H), 7.16 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H). MS (m/z,
%): 409 (M+, 100).
J=8.5 Hz, 1H, Ar-H), 8.28 (d, J=8.5 Hz, 1H, Ar-H),
9.25 (s, 1H, Ar-H).
11. Hanaoka, M.; Motonishi, T.; Mukai, C. J. Chem. Soc.,
Perkin Trans. 1 1986, 2253.
12. Compound 1b was obtained according to: (a) Sala, T.;
Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979, 2593;
(b) Cava, M. P.; Mitchell, M. J.; Havlicek, S. C.; Lindert,
A.; Spangler, R. J. J. Org. Chem. 1970, 35, 175. 2-(3,4-
Dimethoxyphenyl) - N - [2 - (3 - isopropoxy - 4 - methoxy-
phenyl)ethyl]acetamide was easily prepared from 2-(3-
isopropoxy-4-methoxyphenyl)ethylamine and (3,4-di-
methoxyphenyl)acetyl chloride, and was subjected to
standard Bischler–Napieralski conditions to obtain 1-(3,4-
dimethoxybenzyl)-6-isopropoxy-7-methoxy-3,4-dihydro-
isoquinoline, which upon treatment with ethyl chlorofor-
miate gave 1-(3,4-dimethoxybenzylidene)-6-isopropoxy-7-
methoxy - 3,4 - dihydro - 1H - isoquinoline - 2 - carboxylic
acid ethyl ester (1b).
1
Compound 5b. Mp 188–189°C (methanol). H NMR (l,
ppm, CDCl3): 1.47 (d, J=6.1 Hz, 6H, 2×-CH3), 3.98 (s,
3H, -CH3), 4.00 (s, 3H, -CH3), 4.01 (s, 3H, -CH3), 4.05 (s,
3H, -CH3), 4.75 (h, J=6.1 Hz, 1H, -CHMe2), 7.15 (s, 1H,
Ar-H), 7.48–7.52 (m, 2H, 2×Ar-H), 7.57 (s, 1H, Ar-H),
7.86 (s, 1H, Ar-H), 7.90 (d, J=8.7 Hz, 1H, Ar-H). MS
(m/z, %): 407 (M+, 89), 350 (100).
Compound 6b. Mp 198–200°C (methanol/ethyl acetate).
1H NMR (l, ppm, CF3COOD): 4.14 (s, 6H, 2×-OCH3),
4.22 (s, 3H, -OCH3), 4.93 (s, 3H, -NCH3), 7.40 (s, 1H,
Ar-H), 7.61 (s, 1H, Ar-H), 7.88 (s, 2H, 2×Ar-H), 7.88 (d,
13. Smidrkal, J. Coll. Czech. Chem. Commun. 1998, 53, 3184.
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Chapman and Hall: London, 1997.