A synthetic study of magallanesine by cyclization of a benzamidoacrylate intermediate

Article abstract of DOI:10.1016/j.tetlet.2015.04.085

Cyclization of a benzamidoacrylate intermediate has been applied for the synthesis of magallanesine rings. Heck reaction for the five-membered ring and the following Friedel-Crafts reaction provided the azocine central rings of the alkaloid. The precursor

Full text of DOI:10.1016/j.tetlet.2015.04.085

Accepted Manuscript
A synthetic study of magallanesine by cyclization of a benzamidoacrylate in-
termediate
Seong-Ye Seo, Guncheol Kim
PII:
S0040-4039(15)00731-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.085
TETL 46224
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 March 2015
16 April 2015
21 April 2015
Please cite this article as: Seo, S-Y., Kim, G., A synthetic study of magallanesine by cyclization of a
benzamidoacrylate intermediate, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.085
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A synthetic study of magallanesine by
cyclization of a benzamidoacrylate
intermediate
Leave this area blank for abstract info.
∗
Seong-Ye Seo, Guncheol Kim
O
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EtO
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magallanesine

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Tetrahedron Letters
journal homepage: www.els evier.com
A synthetic study of magallanesine by cyclization of a benzamidoacrylate
intermediate
∗
Seong-Ye Seo and Guncheol Kim
Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejon 305-764, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Cyclization of a benzamidoacrylate intermediate has been applied for the synthesis of
magallanesine rings. Heck reaction for the 5-membered ring and the following Friedel-Crafts
reaction provided the azocine central rings of the alkaloid. The precursor obtained by
cyclizations from a properly funtionalized benzamidoacrylate has been converted successfully to
magallanesine via the final oxidation with DDQ.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Magallanesine
Benzamidoacrylate
Heck reaction
Friedel-Crafts reaction
Polycyclic alkaloids are frequently encountered in natural
compounds, and the structurally related products containing
synthetic drugs have shown numerous physiological activities.
For the construction of the core skeleton of 1, we planned to
try two cyclization reactions from intermediate 3: Heck reaction
for 5-membered ring first and Friedel-Crafts acylation for 8-
membered ring next. Compound 3 would be prepared by Michael
type reaction of amide 2 with an alkyl propiolate. Heck reaction
of aryliodide with the vinyl group of acrylate group would yield
the 5-membered ring and the following Friedel-Crafts acylation
reaction with or without olefin group would be tried to construct
the required central ring skeleton (Scheme 1).
1
Especially, medium ring sized azocine or azepine compounds
arranged with other rings around have been attracted by many
synthetic chemists because of skeletal attraction as well as
2
,3
biological applications. As an extension of our interests on the
synthesis of the natural alkaloid products containing medium
4
sized ring, we want to explore cyclization reactions using
benzamidoacrylate intermediates for the synthetic study of
magallanesine containing an 8-membered ring (Figure 1). The
product is the first known isoindolobenzazocine alkaloid isolated
5
from Berberis Darwin, which has been synthesized only by a
few groups. For a new synthetic approach, we wanted to explore
6
benzamidoacrylate precursors providing proper carbon number as
well as functional groups, however, these intermediates have
been rarely applied in natural alkaloid synthesis.
Scheme 1.
Figure 1.
For the first cyclization trial using Heck reaction from 3, we
prepared iodoarylamide 6 via a coupling reaction of 5 and 2-
iodobenzoic acid in 99% yield. And addition reaction of 6 with
—
——
∗
Corresponding author. Tel.: +82-42-821-5475; fax: +82-42-821-8896; e-mail: guncheol@cnu.ac.kr

2
Tetrahedron
ethyl propiolate in the presence of Cs
amidoacrylate 7 in 97% yield. Compound 7 under conventional
Heck reaction condition using Pd(OAc) and Bu NCl provided a
:1 mixture of 8 in 99% yield (Scheme 2). The mixture of 8
could be neither separated nor differentiated to show which
isomer should be E or Z in NMR spectrum. However, we expect
that any cyclzation attempt of 8 under acidic conditions might
reveal its potential aspects to the azocine ring.
2
CO
3
in DMF afforded
hydrolysis, has been applied to obtain compound 14 in three step
79% yield. Unlike 10, Friedel-Crafts reaction of 14 required a
particular condition, sequential treatment with trifluoroacetic
2
4
o
anhydride (TFAA) at 0 C and addition of BF
3
3
·OEt
o
2
followed by
heating the resulting solution for 6 hr at 50 C. This process
8
9
allowed 76% yield of 15 as a solid. Final oxidative condition
would result in the successful synthesis of magallanesine.
Optimal dehydrogenation reaction of 15 has been found to be
o
DDQ treatment under heating at 110 C to yield the final product
1
0
1
in 57% yield.
Scheme 2.
Friedel-Crafts reaction of 8 with acid such as AlCl
or HCl provided all the similar results yielding a single isomer of
recovered in 23% yield and 9 in 70% yield via Michael type
3 3 2
, BF ·OEt
8
Scheme 4.
7
alkylation reaction. Only one isomer has been found to be
reactive under the acidic condition toward Michael reaction and
the stereochemistry of the isomer recovered remains still
uncertain. For the formation of the 8-membered ring, the exo-C-
C double bond of 8 seemed to be removed first. Accordingly,
hydrogenation of 8 in the presence of Pd catalyst (97%) was
followed by hydrolysis with NaOH (82%) to provide compound
In summary, we could synthesize an azocine alkaloid,
magallanesine from the useful benzamidoacrylate precursor. Two
cyclization reactions, Heck and Friedel-Crafts reactions, using
the intermediate have been successfully applied for a concise
route to the final product.
1
1
0. The azocine ring could be formed under heating a solution of
o
0 in polyphosphoric acid (PPA) at 70 C in 75% yield of 11
(
Scheme 3).
Acknowledgments
This work was supported by Research Fund of Chungnam
National University.
References and notes
1
.
(a) Cordell, G. A.. In The Alkaloids: Chemistry and
Pharmacology; Academic Press: San Diego, 1998; Vol. 50; (b)
Weinstock, J.; Hieble, J. P.; Wilson, J. W. Drugs Future 1985, 10,
645-651; (c) Padwa, A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K.
J. J. Org. Chem. 2001, 66, 2414-2421.
2
3
.
.
(a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M.
Tetrahedron Lett. 1982, 23, 39-42. (b) Valencia, E.; Freyer, A. J.;
Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 599-602.
(a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C.
Tetrahedron 2000, 56, 1491-1499; (b) Padwa, A.; Beall, L. S.;
Eidel, Worsencroft, K. J. J. Org. Chem. 2001, 66, 2414-2421; (c)
Yoda, H.; Nakahama, A.; Koketsu, T.; Takabe, K. Tetrahedron
Lett. 2002, 43, 4667-4669; (d) Kim, G.; Kim, J. H.; Kim, W.; Kim,
Y. A. Tetrahedron Lett. 2003, 44, 8207-8209; (e) Yoda, H.; Inoue,
K.; Ujihara, Y.; Mase, N.; Takebe, K. Tetrahedron Lett. 2003, 44,
9057-9060; (f) Koseki, Y.; Katsura, S.; Kusano, S.; Sakata, H.;
Sato, H.; Monzene, Y.; Nagasaka, T. Heterocycles 2003, 59, 527-
Scheme 3.
In order to synthesize magallanesine, we prepared the
requisite precursor 13 from 3,4-methylenedioxyphenethylamine
2 through coupling with 6-iodo-2,3-dimethoxybenzoic acid
1
5
4
4
40; (g) Sahakitpichan, P.; Ruchirawat, S. Tetrahedron 2004, 60,
169-4172; (h) Honda, T.; Sakamaki, Y. Tetrahedron Lett. 2005,
6, 6823-6825; (i) Tomasevich, L. L.; Kennedy, N. M.; Zitelli, S.
using chloromethyltriazine and 4-methylmorphorine in 98% yield
and the following Michael reaction in 99% yield. The same
sequence, Heck reaction followed by hydrogenation and
M.; Hull, R. T., II; Gillen, C. R.; Lam, S. K.; Baker, N. J.;

3
Rohanna, J. C.; Conley, J. M.; Guerra, M. L.; Starr, M. L.; Sever, J.
B.; Carroll, P. J. ; Leonard, M. S. Tetrahedron Lett. 2007, 48,
5
1
2
7
99-602; (j) Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5,
849-1853; (k) Kim, G.; Lee, K. Y.; Yoo, C.-H. Synth. Commun.
008, 38, 3251-3259; (l) Fuwa, H.; Sasaki, M. Heterocycles 2008,
6, 521-539; (m) Onozaki, Y.; Kurono, N.; Senboku, H.; Tokuda,
M.; Orito, K. J. Org. Chem. 2009, 74, 5486-5495; (n) Piko, B. E.;
Keegan, A. L.; Leonard, M. S. Tetrahedron Lett. 2011, 52, 1981-
1
(a) Kim, G.; Jung, P.; Tuan, L. A. Tetrahedron Lett. 2008, 49,
982.
4
5
.
.
2
3
5
391-2392; (b) Oh, K. R.; Kim, G. Bull. Korean Chem. Soc. 2012,
3, 3933-3934; (c) Kim, H. D.; Kim, G. Tetrahedron Lett. 2013,
4, 1765-1767.
(a) Valencia, E.; Fajardo, V.; Freyer, A. J.; Shamma, M.
Tetrahedron Lett. 1985, 26, 993-996; (b) Several years before
isolation from natural sources, magallanesine 1 was obtained from
oxyberberine via dichlorocarbene adduct: Manikumar, G.;
Shamma, M. . J. Org. Chem. 1981, 46, 386-389; (c) It has been
reported that magallanesine may has been formed as an artifact of
the isolation process: Shamma, M.; Rahimizadeh, M. J. Nat. Prod.
1
986, 47, 398-405.
6
7
.
.
(a) Fang, F. G.; Feigelson, G. B.; Danishefsky, S. J. Tetrahedron
Lett. 1989, 30 , 2743-2746; (b) Yoneda, R.; Sakamoto, Y.; Oketo,
Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563-
1
4576.
One isomer of 8: H NMR (400MHz, CDCl
Hz), 2.87 (t, 2H, J = 8.0 Hz), 3.78 (s, 3H), 3.84 (s, 3H), 4.27 (q,
H, J = 8.0 Hz), 4.55 (t, 2H, J = 8.0 Hz), 5.89 (s, 1H), 6.76 – 6.83
m, 3H), 7.56 – 7.63 (m, 2H), 7.69 (d, 1H, J = 6.0 Hz), 7.82 (d, 1H,
1
3
) 1.34 (t, 3H, J = 8.0
2
(
1
J = 6.0 Hz). Compound 9: H NMR (400MHz, CDCl
J = 8.0 Hz), 2.76 (ddd, 1H, J = 12.0, 2.0, 2.0 Hz), 2.93 (m, 1H),
.25 (ABq, 2H, J = 12.0 Hz ), 3.45 (ddd, 1H, J = 8.0, 2.0, 2.0
Hz), 3.81 (q, 2H, J = 8.0 Hz), 3.85 (s, 3H), 3.93 (s, 3H), 4.65
3
) 0.88 (t, 3H,
3
(
ddd, 1H, J = 12.0, 8.0, 2.0 Hz), 6.59 (s, 1H), 7.16 (s, 1H), 7.49
dd, 1H, J = 8.0, 8.0 Hz), 7.63 (dd, 1H, J = 8.0, 8.0 Hz), 7.84 (d,
(
1
1
3
H, J = 8.0 Hz), 7.91 (d, 1H, J = 8.0 Hz) C NMR (100MHz,
) 13.76, 28.87, 35.02, 45.44, 55.96, 56.36, 60.60, 64.40,
09.36, 112.24, 122.99, 123.98, 126.33, 128.84, 129.45, 131.91,
32.07, 147.83, 147.95, 148.78, 167.88, 168.27 .
CDCl
3
1
1
8
9
.
.
Yasuda, S.; Yamamoto, Y.; Hanaoka, M. Chem. Pharm. Bull.
988, 26, 4229-4230.
Compound 15: mp 226-230 C, H NMR (400MHz, CDCl
1
o
1
3
) 2.98
dd, 1H, J = 14.6, 5.7 Hz), 3.26 (dd, 1H, J = 14.6, 1.5 Hz), 3.45
(
(
(
m, dd, 1H, J = 14.6, 5.7 Hz), 3.72 (td, 1H, J = 13.7, 6.1 Hz), 3.88
s, 3H), 3.89 (s, 3H), 4.53 (td, 1H, J = 13.7, 6.1 Hz), 4.83 (dd, 1H,
J = 6.1, 1.5 Hz), 5.95 (d, 1H, J = 1.0 Hz), 5.97 (d, 1H, J = 1.0
Hz), 6.72 (s, 1H), 7.11 (d, 1H, J = 8.4 Hz), 7.12 (s, 1H), 7.17 (d,
1
3
1
4
1
1
3
H, J = 8.4 Hz), 7.28 (s, 1H) C NMR (100MHz, CDCl ) 34.84,
0.05, 47.11, 56.52, 57.14, 62.46, 101.99, 109.31, 111.44, 116.36,
17.59, 123.88, 132.78, 134.75, 136.51, 146.95, 147.39, 151.95,
+
52.74, 166.25, 195.69, EIMS 381.12 (M ).
6
b
1
0. Spectral data of 11 were identical to those of the known.