Study of aza-cyclization of α,β-unsaturated carbonyl moieties and synthetic application to hexahydroapoerysopine

Article abstract of DOI:10.1016/j.tetlet.2013.01.093

Aza-cyclization of α,β-unsaturated carbonyl moieties with free amine has been studied. An azepine alkaloid, hexahydroapoerysopine, has been synthesized from an enone-ester in a concise manner through the aza-cyclization followed by reductions.

Full text of DOI:10.1016/j.tetlet.2013.01.093

Tetrahedron Letters 54 (2013) 1765–1767
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Tetrahedron Letters
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Study of aza-cyclization of a,b-unsaturated carbonyl moieties and
synthetic application to hexahydroapoerysopine
⇑
Hee Dong Kim, Guncheol Kim
Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejon 305-764, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Aza-cyclization of a,b-unsaturated carbonyl moieties with free amine has been studied. An azepine alka-
loid, hexahydroapoerysopine, has been synthesized from an enone-ester in a concise manner through the
aza-cyclization followed by reductions.
Received 7 January 2013
Revised 22 January 2013
Accepted 23 January 2013
Available online 31 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aza-cyclization
Polycyclic alkaloid
Hexahydroapoerysopine
Azepine
Polycyclic hetero-compounds containing nitrogen are frequently
encountered in natural alkaloid compounds, and the structurally re-
lated products containing synthetic drugs have shown numerous
physiological activities.1 Especially, the azepine compounds ar-
ranged with other rings around have been attracted by many syn-
thetic chemists because of skeletal challenges as well as biological
applications.2,3 Most of the approaches toward the azepine com-
pounds have been focused on the efficient formation of the central
seven-membered ring (Fig. 1). As an extension of our interests on
the synthesis of the azepine natural products,4 we want to explore
an aza-cyclization reaction by free amine. The free amine addition
O
O
O
O
O
O
N
N
OMe
OMe
OMe
OMe
HO
O
1: lennoxamine
2: chilenine
Figure 1.
MeO
MeO
MeO
MeO
NH2
b
path a
NH
to the carbonyl or olefin of
a,b-unsaturated carbonyl derivatives
a
toluene,reflux
7 min.
for the formation of azepine ring has been rarely applied in natural
O
4
alkaloid synthesis.5
O
3
Preliminarily, we tested the selectivity of cyclization pathways
on compound 3, condensation to intermediate 5, or addition to 4.
Compound 3 would be obtained by the deprotection of N-Boc
protected precursor of 3. The precursor could be readily prepared
by the known Suzuki coupling reaction pathway.6,7 Upon refluxing
the precursor with CF3CO2H in toluene followed by addition of
K2CO3 and concentration, an unstable intermediate was obtained,
and the crude product was reduced readily with NaCNBH3 to enam-
ine compound 6 in quantitative yield in three steps. We assumed
that the product would be formed from intermediate 5 via pathway
b. However, the product 6 might be also formed from intermediate 4
via pathway a through reduction of ketone to alcohol followed by
elimination (Scheme 1).
NaCNBH3
MeOH
toluene,reflux
path b
MeO
7 min.
MeO
MeO
NaCNBH3
MeOH
N
NH
MeO
6
5
Scheme 1.
In order to confirm the reaction route, we tried to synthesize a
known azepine compound,5 hexahydroapoerysopine 11 using
enone-ester 9 which could induce a sequential cyclization. The
compound 9 was synthesized from 76,8 by the Suzuki coupling
reaction with vinyl iodide 8 in 78% yield. The iodide compound 8
was prepared from the corresponding enone by iodination
⇑
Corresponding author. Tel.: +82 42 821 5475; fax: +82 42 821 8896.
E-mail address: guncheol@cnu.ac.kr (G. Kim).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.093

1766
H. D. Kim, G. Kim / Tetrahedron Letters 54 (2013) 1765–1767
O
to proceed at rt to afford seven-membered azepine ring products
15a12 or 15b as a single isomer in 99% or 70% yield respectively
(Table 1: entries 1 and 2). However, for imide derivatives, 14c or
14d, six-memberedring compounds 15c or15c0 containing a quater-
nary center were formed favorably via 6-exo addition mode over the
seven-membered ring compound 15d or 15d0 in 2:1 ratio (entries 3
and 4) in 98% combined yields.13 As expected, ester or imide moie-
ties allowed only Michael type addition reactions differently from
I
OEt
MeO
MeO
MeO
MeO
NHBoc
NHBoc
O
O
O
8
B(OH)2
Pd(PPh3)4, Na2CO3
PhH:EtOH (2:1), reflux
3hr, 78%
OEt
7
9
i. TFA/toluene, 150°C
10 mins
ii. NaCNBH3 / MeOH
80%
a,b-unsaturated carbonyl compounds.
In summary, we could synthesize a tricyclic azepine compound,
MeO
MeO
MeO
MeO
i. H2 (1 atm)
Pd/C / MeOH
O
N
hexahydroapoerysopine 11 via an aza-cyclization reaction through
free amine–carbonyl condensation of ,b-unsaturated ketone
N
H
a
H
ii. LiAlH4 / THF
97%
followed by sequential reduction. The cyclization of conjugate esters
and imides has been investigated under the same condition. In the
H
H
H
11
10
case of
a
,b-unsaturated esters, Michael type addition was exclusive
Scheme 2.
to afford the seven-membered ring, however,
a,b-unsaturated imi-
des have afforded six-membered ring compounds dominantly via
exo-type Michael addition. Further synthetic application is under
study.
followed by elimination.9 Application of the same conditions to 9
provided 10 in 80% yield, which showed that the initial cyclization
should be carried out by amine–carbonyl condensation. Hydroge-
nation followed by hydride reduction of 10 provided the known
11 in 97% yield (Scheme 2).10
Acknowledgment
This work was supported by the Korea Research Foundation
Grant Funded by Korean Government (KRF-2011-0015865).
Additionally we want to examine the amine cyclization with con-
jugate ester and imide moieties. First, we prepared a few substrates
to figure out the addition reaction aspects on the a,b-unsaturated
References and notes
carbonyl compounds. The substrates 14 could be readily prepared
through Suzuki coupling between 7 and vinyl bromide 13 in moder-
ate yields. Although the yields were not satisfactory, we just wanted
to find the results of the next reaction instead of optimizing the reac-
tion with vinyl iodide derivatives of 13. Upon treatment of 14a or
14b with CF3COOH in CH2Cl2 at rt followed by concentration and
basification with K2CO3 in CH2Cl2, Michael addition has been found
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. (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.
Table 1
Study of cyclization 1411
O
MeO
MeO
MeO
NHBoc
Br
NHBoc
Z
Y
MeO
X
cyclization
Z
15
13
O
Y
12: X: Br
i. n-BuLi
ii. B(OMe)3
7
: X: B(OH)2
14
Pd(0)
Entry13
1
13
14
15
O
MeO
MeO
NHBoc
MeO
Br
NH
H
O
O
MeO
H
14a
(37%)
O
13a
15a
(99%)
MeO
O
O
O
MeO
MeO
NHBoc
Br
O
NH
H
O
MeO
15b
(70%)
MeO
2
3
H
O
O
14b
(25%)
13b
O
O
MeO
MeO
NHBoc
MeO
MeO
Br
O
NH
H
NH
O
NMe
MeO
H
O
O
NMe
14c
(28%)
13c
NMe
15c'
15c
N
O
Me
O
O
2 : 1 (98%)
O
O
MeO
MeO
NHBoc
MeO
MeO
MeO
Br
NH
O
NH
O
H
NPh
MeO
H
O
4
NPh
O
14d
(56%)
13d
15d
N
15d'
2 : 1 (98%)
NPh
O
Ph
O

H. D. Kim, G. Kim / Tetrahedron Letters 54 (2013) 1765–1767
1767
3. (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, 527–540; (g) Sahakitpichan, P.; Ruchirawat, S.
Tetrahedron 2004, 60, 4169–4172; (h) Honda, T.; Sakamaki, Y. Tetrahedron
Lett. 2005, 46, 6823–6825; (i) Tomasevich, L. L.; Kennedy, N. M.; Zitelli, S. M.;
Hull, R. T., II.; Gillen, C. R.; Lam, S. K.; Baker, N. J.; 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, 599–602; (j) Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5,
1849–1853; (k) Kim, G.; Lee, K. Y.; Yoo, C.-H. Synth. Commun. 2008, 38, 3251–
3259; (l) Fuwa, H.; Sasaki, M. Heterocycles 2008, 76, 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,
1981–1982.
8. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, B. W.; Wovkulich, P. M.;
Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917–918.
9. Dubé, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295–2298.
10. Spectral data of 11 were identical to those of the known.5
11. Reaction conditions for 14: A mixture of 7 and 4 in dioxane:H2O (3:1) containing
Pd(PPh3)4 (4%) and Na2CO3 (2 equiv.) was heated at 150 °C in a sealed tube for
7 min. 15: a solution of 14 in TFA: CH2Cl2 (1:1) was stirred at rt for 30 min.
Concentration and treatment with excess K2CO3 in CH2Cl2 at rt were followed
by routine work-up and purification.
12. Compound 15a has been characterized more cleanly after acylation of amine, Ac-
15a: 1H NMR (400 MHz, CDCl3) 1.95 (s, 3H), 2.80–3.08 (m, 4H), 3.59 (m, 2H),
3.86 (s, 3H), 3.87 (s, 3H), 4.46 (dd, 1H, J = 10.9, 2.1 Hz), 4.67 (dd, 1H, J = 10.9,
7.6 Hz), 5.95 (dd, 1H, J = 9.2, 7.6 Hz), 6.66 (s, 1H), 6.73 (s, 1H); 13C NMR
(100 MHz, CDCl3) 21.94, 31.62, 41.25, 48.79, 50.29, 55.92, 56.07, 69.95, 113.54,
115.42, 123.86, 127.75, 148.05, 149.03, 171.12, 176.36, EIMS 306.34 (M+).
13. The ratio has been detected by 1H NMR, because pure separation of the two
isomers was hard. Compound 15d has also been characterized more cleanly
after acylation of amine, Ac-15d: 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.83
(ddd, 1H, J = 12.0, 4.0, 4.0 Hz), 3.15 (ddd, 1H, J = 12.0, 8.0, 4.0 Hz), 3.18 (d, 1H,
J = 17.9 Hz), 3.40 (d, 1H, J = 17.9 Hz), 3.52 (ddd, 1H, J = 12.0, 8.0, 4.0 Hz), 3.82 (s,
3H), 3.89 (s, 3H), 4.03 (ddd, 1H, J = 12.0, 4.0, 4.0 Hz), 6.62 (s, 1H), 6.71 (s, 1H);
7.34–7.50 (m, 5H) 13C NMR (100 MHz, CDCl3) 23.02, 30.10, 44.26, 45.25, 56.33,
56.47, 63.57, 107.10, 112.03, 126.53, 126.99, 128.37, 129.06, 129.62, 132.80,
149.21, 149.43, 170.94, 174.54, 176.03.
4. (a) Kim, G.; Jung, P.; Tuan, L. A. Tetrahedron Lett. 2008, 49, 2391–2392; (b) Oh, K.
R.; Kim, G. Bull. Korean Chem. Soc. 2012, 33, 3933–3934.
5. (a) Iida, H. I.; Takarai, T.; Kibayashi, C. J. Org. Chem. 1978, 43, 975–979; (b) Iida,
H. I.; Takarai, T.; Kibayashi, C. J. Chem. Soc., Chem. Commun. 1977, 644–645.
6. Pandey, G.; Balakrishnan, M. J. Org. Chem. 2008, 73, 8128–8131.
7. Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Comb. Chem. High Throughput
Screening 2007, 10, 790–801.