Facile synthesis of a benzindenoazepine alkaloid, bulgaramine, via samarium diiodide promoted ring expansion of an α-aminocarbonyl compound

Article abstract of DOI:10.1021/ol9004239

A novel synthetic path to a benzindenoazepine alkaloid was established by employing a samarium diiodide promoted ring expansion reaction of an α-amlnocarbonyl compound as a key reaction, In which a regloselectlve carbon-nitrogen bond cleavage followed by

Full text of DOI:10.1021/ol9004239

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1857-1859
Facile Synthesis of a
Benzindenoazepine Alkaloid,
Bulgaramine, via Samarium Diiodide
Promoted Ring Expansion of an
r-Aminocarbonyl Compound
Toshio Honda,* Eriko Aranishi, and Kyosuke Kaneda
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
honda@hoshi.ac.jp
Received March 1, 2009
ABSTRACT
A novel synthetic path to a benzindenoazepine alkaloid was established by employing a samarium diiodide promoted ring expansion reaction
of an r-aminocarbonyl compound as a key reaction, in which a regioselective carbon-nitrogen bond cleavage followed by ring-closing
reactions occurred to give the basic ring skeleton of the target compound. Bulgaramine was synthesized from the known tetrahydroisoquinoline
derivative in 5 steps in 50% overall yield.
Plants of the genus Fumaria have been used in some parts
of Asian and eastern European countries as folk medicines
for their antipyretic, analgesic, and diuretic properties.1
Because benzindenoazepines are expected to exhibit potential
biological activities of medicinal interest, interest in the
development of new synthetic methodology for this class of
alkaloids continues unabated.2
Bulgaramine 2 was isolated from Herba Fumaria offici-
nalis3 as a member of benzindenoazepines that are a distinct
group of alkaloids, probably derived biogenetically from the
rearrangement of spirobenzylisoquinolines.4 On the basis of
this consideration, a spirobenzylisoquinoline alkaloid, fu-
maricine 1, has been successfully transformed to bulgar-
amine, supporting the biogenetic hypothesis5 (Scheme 1).
Furthermore, benzindenoazepine derivatives have been em-
(1) (a) Blasko, G. In The Alkaloids; Brossi, A., Ed.; Academic Press
Inc.: New York, 1990; pp 157-224. (b) Lee, T. B. Illustrated Flora of
Korea; Hanygmoonsa: Seoul, 1989; p 385.
(2) Fidalgo, J.; Castedo, L.; Dominguez, D. Tetrahedron Lett. 1993, 34,
7317–7318.
Scheme 1. Conversion of Fumaricine to Bulgaramine
(3) (a) Blasko, G.; Hussain, S. F.; Freyer, A. J.; Shamma, M. Tetrahedron
Lett. 1981, 22, 3127–3130. (b) Murugesan, N.; Blasko, G.; Minard, R. D.;
Shamma, M. Tetrahedron Lett. 1981, 22, 3131–3134. (c) Blasko, G.;
Murugesan, N.; Hussain, S. F.; Minard, R. D.; Shamma, M.; Sener, B.;
Tanker, M. Tetrahedron Lett. 1981, 22, 3135–3138. (d) Blasko, G.;
Murugesan, N.; Freyer, A. J.; Gula, D. J.; Sener, B.; Shamma, M.
Tetrahedron Lett. 1981, 22, 3139–3142. (e) Blasko, G.; Murugesan, N.;
Freyer, A. J.; Minard, R. D.; Shamma, M. Tetrahedron Lett. 1981, 22, 3143–
3146.
(4) Yakimov, G. I.; Mollov, N. M.; Leet, J. E.; Guinaudeau, H.; Freyer,
A. J.; Shamma, M. J. Nat. Prod. 1984, 47, 1048–1049.
10.1021/ol9004239 CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

ployed as key intermediates for transformation to rhoeadine
and protopine alkaloids.6
benzazepine ring system by simple reaction sequence
(Scheme 2).
Total synthesis of bulgaramine 2 has recently been
achieved by Giese and co-workers by using an intramolecular
cyclopentannulation of the Fischer aminocarbene complex
as a key reaction to give the desired ring system,7 and this
is the only report of total synthesis for this alkaloid. The
crucial step for synthesis of this class of alkaloids obviously
lies in the facile construction of a benzindenoazepine ring
system.8 In 1999, we developed a SmI2-promoted regiose-
lective carbon-nitrogen bond cleavage reaction of R-ami-
nocarbonyl compounds.9 In relation to a project directed at
the synthesis of bioactive alkaloids by application of this
methodology,10 we are interested in establishing an entirely
new, perhaps practical and general route for the total
synthesis of a unique benzindenoazepine alkaloid, bulgar-
amine.
Scheme 2. Sml2-Promoted C-N Bond Cleavage for 5
Prior to synthesis of the natural product, we decided to
investigate efficient and mild reaction conditions for the
SmI2-promoted bond cleavage reaction of an ester 5 as
follows. The known 1-ethoxycarbonyl-2-methyl-6,7-dime-
thoxy-1,2,3,4-tetrahydroisoquinoline 411 was prepared by
treatment of 312with 37% formalin in MeOH in the presence
of a catalytic amount of 10% palladium on carbon under an
atmospheric pressure of hydrogen in 96% yield. Installation
of a benzoyl group was achieved by treatment of 4 with
benzoyl chloride in the presence of NaHMDS in THF to
give 5 in 77% yield. Attempted SmI2-promoted reductive
carbon-nitrogen cleavage reaction of 5 in THF at ambient
temperature for 1 h in the presence of MeOH as a proton
source afforded a bond-cleaved compound, which without
further purification was subjected to a recyclization in
refluxing toluene to give the desired product 6 in 43% yield
from 5.13 Thus, we were able to develop a new route for
transformation of an isoquinoline skeleton to a functionalized
By establishing a synthetic route to the basic skeleton of
the natural product, we started the synthesis of bulgaramine
as follows. Our synthesis was launched with the preparation
of the known acid chloride 7.14
Treatment of tetrahydroisoquinoline derivative 4 with 2,3-
methylenedioxybenzoyl chloride 7 in THF in the presence
of NaHMDS in THF afforded the 1-benzoyl derivative 8 in
83% yield. Reductive carbon-nitrogen bond cleavage reac-
tion of 8 with SmI2 (4 equiv) in THF in the presence of
MeOH (3 equiv) as the proton source at room temperature
for 30 min gave a secondary amine, which on treatment with
p-TsOH monohydrate (0.1 equiv) in refluxing toluene
furnished the desired benzindenoazepine-type compound 9
directly in 68% yield from 8.
(5) Blasko, G. Acta Chim. Hung. 1991, 128, 819–822.
It is noteworthy that the bond-cleaved compound was
converted to benzindenoazepin-6-one 9 by treatment with
p-TsOH in reasonable yield, probably due to the presence
of an electron-donatng methylenedioxy group on the D-ring,
which might facilitate the cyclization of a relatively unstable
enamino-ester to the more stable tetracyclic compound 9
(Scheme 3). Actually, when this cyclization was attempted
in toluene in the absence of p-TsOH, enamino-ester 10 was
isolated in 40% yield as the major product, which could be
transformed to 9 in refluxing toluene containing p-TsOH in
81% yield. The plausible reaction mechanism is depicted in
Scheme 4.
(6) (a) For transformation to protopine alkaloid, see: Orito, K.; Itoh, M.
J. Chem. Soc., Chem. Commun. 1978, 812–813. Orito, K.; Kurokawa, Y.;
Itoh, M. Tetrahedron 1980, 36, 617–621. Wada, Y.; Kaga, H.; Uchiito, S.;
Kumazawa, E.; Tomiki, M.; Onozaki, Y.; Kurono, N.; Tokuda, M.; Ohkuma,
T.; Orito, K. J. Org. Chem. 2007, 72, 7301–7306. (b) For transformation
to rhoeadine alkaloid, see: Orito, K.; Manske, R. H.; Rodrigo, R. J. Am.
Chem. Soc. 1974, 96, 1944–1945. Hanaoka, M.; Inoue, M.; Kobayashi, N.;
Yasuda, S. Chem. Pharm. Bull. 1987, 35, 980–985.
(7) Giese, M. W.; Moser, W. H. J. Org. Chem. 2005, 70, 6222–6229.
(8) (a) For photochemical synthesis of benzindenoazepine ring system,
see: Fidalgo, J.; Castedo, L.; Dominguez, D. Heterocycles 1994, 39, 581–
589. (b) For a radical cyclization approach, see ref 2. (c) For transformation
of protoberberines to benzindenoazepines, see: Hanaoka, M.; Iwasaki, M.;
Sakurai, S.; Mukai, C. Tetrahedron Lett. 1983, 24, 3845–3848. Hanaoka,
M.; Ashimori, A.; Yamagishi, H.; Yasuda, S. Chem. Pharm. Bull. 1983,
31, 2172–2175. Hanaoka, M.; Kim, S. K.; Inoue, M.; Nagami, K.; Shimada,
Y.; Yasuda, S. Chem. Pharm. Bull. 1985, 33, 1434–1443.
Finally, reduction of the carbonyl group of 9 at the
6-position was investigated under various reaction conditions.
Usually, reduction of enaminones with various hydride
donors, such as lithium borohydride, sodium borohydride,
zinc borohydride, sodium acetoxyborohydride, or lithium
aluminum hydride, provides the corresponding carbon-carbon
double bond reduced ketones or corresponding alcohols,15
(9) Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065–1066.
(10) (a) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925–3927. (b) Katoh,
M.; Matsune, R.; Nagase, H.; Honda, T. Tetrahedron Lett. 2004, 45, 6221–
6223. (c) Honda, T.; Takahashi, R.; Namiki, H. J. Org. Chem. 2005, 70,
499–504. (d) Katoh, M.; Mizutani, H.; Honda, T. Tetrahedron Lett. 2005,
46, 5161–5163. (e) Katoh, M.; Inoue, H.; Suzuki, A.; Honda, T. Synlett
2005, 2820–2822. (f) fKatoh, M.; Hisa, C.; Honda, T. Tetrahedron Lett.
2007, 48, 4691–4694.
(11) Matsuo, I.; Takahashi, T.; Oki, S. Yakugaku Zasshi 1964, 84, 711–
715.
(12) Zala´n, Z.; Martinek, T. A.; La´za´r, L.; Sillanpa¨a¨, R.; Fu¨lo¨p, F.
Tetrahedron 2006, 62, 2883–2891.
(14) Mitscher, L. A.; Flynn, D. L.; Gracey, H. E.; Drake, S. D. J. Med.
Chem. 1979, 22, 1354–1357.
(13) The deethoxycarbonyl analogue of 6 was generated as a byproduct
under these reaction conditions.
(15) Palmieri, G.; Cimarelli, C. ARKIVOC 2006, Vi, 104–126.
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Org. Lett., Vol. 11, No. 8, 2009

yield, together with the isomer 125,7 in 67% yield. Further
transformation of 11 to 2 was achieved by treatment with
10% NaOH in EtOH at room temperature for 19 h in 95%
yield (Scheme 5).
Scheme 3. Sml2-Promoted Ring Transformation of 8
Scheme 5. Synthesis of Bulgaramine 2
The spectroscopic data of the synthesized compound
including its melting point, 205-206 °C (lit.4 mp 209 °C),
were identical to those reported in the literature.4
but the attempted reduction of 9 under similar reaction
conditions did not give any reduced products. Fortunately,
we are able to find a practical route for the conversion of 9
to the target compound 2 in which DIBAL was employed
as the reducing agent.
Thus, the reduction of ketone 9 with DIBAL (5 equiv) in
toluene at -78 °C for 24 h afforded bulgaramine 2, in 24%
In summary, we were able to establish a facile and entirely
new route for construction of a benzindenoazepine ring
skeleton in a small number of steps with reasonably high
yield,inwhichaSmI2-promotedregioselectivecarbon-nitrogen
bond cleavage reaction, followed by acid-catalyzed formation
of a benzindenoazepin-6-one ring system, was involved as
the key step. By exploiting this strategy, we succeeded in a
concise synthesis of a benzindenoazepine alkaloid, bulgar-
amine, starting from the known tetrahydroisoquinoline
derivative 4 in 4 or 5 steps in 50% overall yield. Further
utilization of this strategy in the synthesis of other types of
biologically active alkaloids is in progress in our laboratory.
Scheme 4. Plausible Reaction Mechanism for Formation of 9
Acknowledgment. This research was supported financially
in part by a grant for The Open Research Center Project
and a Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
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