Friedel-crafts cyclodehydration approach toward the synthesis of ellipti-cine and 9-methoxyellipticine

Article abstract of DOI:10.1055/s-0034-1379305

An expedient synthesis of biologically important pyrido[4,3-b]carbazole alkaloids, ellipticine and 9-methoxyellipticine, is reported. Our synthetic approach applies a key H₃PO₄-mediated Friedel-Crafts cyclodehydration to construct the pyridine core.

Full text of DOI:10.1055/s-0034-1379305

LETTER
▌2791
letter
Friedel–Crafts Cyclodehydration Approach toward the Synthesis of Ellipti-
cine and 9-Methoxyellipticine
Friedel–Crafts Cyclodehydration
Nagarajan Ramkumar, Medishetty S. Raghavendra, Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Fax +91(40)23012460; E-mail: rnsc@uohyd.ernet.in
Received: 21.08.2014; Accepted after revision: 21.09.2014
Previous syntheses of ellipticine and 9-methoxyellipticine
Abstract: An expedient synthesis of biologically important pyri-
have been accomplished from known 1,4-dimethylcarba-
do[4,3-b]carbazole alkaloids, ellipticine and 9-methoxyellipticine,
zole-3-aldehyde precursors using a Pomeranz–Fritsch cy-
is reported. Our synthetic approach applies a key H3PO4-mediated
Friedel–Crafts cyclodehydration to construct the pyridine core.
clization as key step; reported individually by Saxton,9
Jackson,10 Chern,11 and Dračínský.12 However, acid-cata-
lyzed Friedel–Crafts-type cyclodehydration reactions
have been less explored in the total synthesis of natural
products.13
Key words: alkaloids, nitrogen heterocycles, natural products, total
synthesis, cyclization
We herein describe a novel route to the synthesis of ellip-
ticine and 9-methoxyellipticine, starting from N-benzyl-
1,4-dimethylcarbazole-3-aldehyde precursors. Our syn-
thesis commenced with the preparation of 9-benzyl-1,4-
dimethylcarbazoles 7 and 8 from the corresponding 1,4-
dimethylcarbazoles, which can be readily prepared by lit-
erature methods7 (Scheme 1). N-Benzylation of 5 and 6
afforded 7 and 8 in excellent yields. Next, Vilsmeier–
Haack formylation of 7 and 8 with DMF and POCl3 at
70 °C furnished aldehydes 9 and 10. Subsequent Pinnick
oxidation, using 30% aqueous H2O2, NaClO2, and
KH2PO4 in THF–H2O (2:1), transformed 9 and 10 into ac-
ids 11 and 12 in 94% and 97% yields, respectively. Acids
11 and 12 were converted into the corresponding acid
chlorides using SOCl2, followed by amidation with 2-am-
Natural products belonging to the pyrido[4,3-b]carbazole
family of alkaloids are well represented in the chemical
literature.1–12 Examples of such pyridocarbazole alkaloids
are depicted in Figure 1, each of which possesses a pyri-
dine ring fused to a carbazole moiety. Since the initial iso-
lation of ellipticine (1) and 9-methoxyellipticine (2) in
1959 by Goodwin et al.,2 several other compounds in this
family have been isolated from Apocynaceae plants.3 The
interesting structures of these molecules, and their wide
biological properties,4,6 have prompted a number of syn-
thetic investigations.5,8 The antineoplastic property of el-
lipticine was established to be largely due to DNA
intercalation and inhibition of topoisomerase II.6 Success-
ful clinical trials and commercialization of derivatives
have provoked significant interest in the chemistry and bi-
ology of pyrido[4,3-b]carbazole alkaloids.7 This is high-
lighted by several reviews covering the synthesis and
biological properties of ellipticine derivatives.8
R
R
DMF, POCl3
70 °C, 2 h
NaOH, BnCl
DMSO, r.t., 1 h
N
R
N
H
N
N
Bn
5 R = H
6 R = OMe
7 R = H, 84%
8 R = OMe, 86%
N
H
N
H
R
COOH
R
CHO
30% aq H2O2
NaClO2, KH2PO4
R = H, ellipticine (1)
R = OMe, 9-methoxyellipticine (2)
olivacine (3)
THF–H2O (2:1)
r.t., 1 h
N
N
Bn
Bn
NH
9 R = H, 71%
10 R = OMe, 78%
11 R = H, 94%
12 R = OMe, 97%
O
N
H
O
R
R
O
NH
janetine (4)
(i) SOCl2, CHCl3
3–5 h, reflux
+
Figure 1 Representative pyrido[4,3-b]carbazole alkaloids 1–4
N
N
NH2
OH
(ii) 2-aminoethanol
DIPEA, CH2Cl2
Bn
Bn
0 °C to r.t., 4–6 h
minor
major
13 R = H, 86%
14 R = OMe, 88%
15 R = H, 9%
16 R = OMe, 6%
SYNLETT 2014, 25, 2791–2793
Advanced online publication: 20.10.2014
DOI: 10.1055/s-0034-1379305; Art ID: st-2014-d0706-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 Synthesis of 9-benzyl-N-(2-hydroxyethyl)-1,4-dimethyl-
9H-carbazole-3-carboxamides 13 and 14

2792
N. Ramkumar et al.
LETTER
inoethanol afforded the desired amides 13 and 14 along overall yields, respectively. For the first time, we have uti-
with esters 15 and 16 in smaller amounts.
lized the H3PO4-mediated Friedel–Crafts cyclodehydra-
tion as a key step to construct these pyrido[4,3-
b]carbazole alkaloids and observed in situ aerial oxidation
during the course of the reaction.
Following access to amides 13 and 14, we explored the
critical Friedel–Crafts cyclodehydration and ensuing pyr-
idine ring formation, as summarized in Scheme 2. We
were delighted to find that treatment of 13 or 14 with
H3PO4 in air at 150 °C furnished dihydropyridocarbazolo-
nes 17 and 18 in 73% and 71% yields, respectively. Under
these rather forcing conditions, we also observed the for-
mation of the oxidative cleavage products 7 or 8 in trace
amounts.
Acknowledgment
We gratefully acknowledge DST for financial support (Project No
SR/S1/OC-70/2008). N.R. thanks CSIR, India for a Senior Rese-
arch Fellowship and contingency grant.
Supporting Information for this article is available online
O
at
http://www.thieme-connect.com/products/ejournals/journal/
R
NH
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
H3PO4
trace amounts of
13 or 14
+
7 or 8
air, 150 °C
3–5 h
N
References and Notes
Bn
(1) (a) Knölker, H.-J.; Reddy, K. R. In The Alkaloids; Vol. 65;
Cordell, G. A., Ed.; Elsevier Science: Amsterdam, 2008, 1–
430. (b) Álvarez, M.; Joule, J. A. In The Alkaloids; Vol. 57;
Cordell, G. A., Ed.; Academic Press: New York, 2001, 235.
(c) Gribble, G. W. In Advances in Heterocyclic Natural
Product Synthesis; Vol. 1; Pearson, W. H., Ed.; JAI Press:
Greenwich, CT, 1990, 43. (d) Gribble, G. W. In The
Alkaloids; Vol. 39; Brossi, A., Ed.; Academic Press: New
York, 1990, 239.
(2) Goodwin, S.; Smith, A. F.; Horning, E. C. J. Am. Chem. Soc.
1959, 81, 1903.
(3) (a) Woodward, R. B.; Iacobucci, G. A.; Hochstein, F. A.
J. Am. Chem. Soc. 1959, 81, 4434. (b) Svoboda, G. H.;
Poore, G. A.; Montfort, M. L. J. Pharm. Sci. 1968, 57, 1720.
(c) Kilminster, K. N.; Sainsbury, M.; Webb, B.
17 R = H, 73%
18 R = OMe, 71%
Scheme 2 The key H3PO4-mediated Friedel–Crafts cyclodehydra-
tion
Having assembled the tetracyclic scaffold of the natural
products, two simple transformations remained in order to
access ellipticine (1) and 9-methoxyellipticine (2). This
would involve conversion of the amide group into an
imine followed by the cleavage of the N-benzyl group in
the intermediates 17 and 18.
As shown in Scheme 3, the first of these challenges was
achieved by reductive amination using mild reagents Tf2O
and Et3SiH. This generated N-benzylellipticines 1914 and
20 in good yields. Next, the N-benzyl group was removed
from 19 and 20 by using 10% palladium on carbon to fur-
nish ellipticines 1 and 2 with analytical data consistent
with those previously reported in literatures in all as-
pects.8
Phytochemistry 1972, 11, 389. (d) Ahond, A.; Fernandez,
H.; Julia-Moore, M.; Poupat, C.; Sanchez, V.; Potier, P.;
Kan, S. K.; Sevenet, T. J. Nat. Prod. 1981, 44, 193. (e) Lin,
Y.-M.; Juichi, M.; Wu, R.-Y.; Lee, K.-H. Planta Med. 1985,
51, 545.
(4) (a) Juret, P.; Tanguy, A.; Girard, A.; Le Talaer, J. Y.;
Abbatucci, J. S.; Dat-Xuong, N.; Le Pecq, J. B.; Paoletti, C.
Eur. J. Cancer 1978, 14, 205. (b) Paoletti, C.; Le Pecq,
L.-B.; Dat-Xuong, N.; Juret, P.; Garnier, H.; Amiel, J.-L.;
Rouesse, J. Recent Res. Cancer Res. 1980, 74, 107.
(c) Dodion, P.; Rozencweig, M.; Nicaise, C.; Piccart, M.;
Cumps, E.; Crespeigne, N.; Kisner, D.; Kenis, Y. Eur. J.
Cancer Clin. Oncol. 1982, 18, 519. (d) Juret, P.; Heron, J. F.;
Couette, J. E.; Delozier, T.; Le Talaer, J. Y. Cancer Treat.
Rep. 1982, 66, 1909. (e) Clarysse, A.; Brugarolas, A.;
Siegenthaler, P.; Abele, R.; Cavalli, F.; de Jager, R.; Renard,
G.; Rozencweig, M.; Hansen, H. H. Eur. J. Cancer Clin.
Oncol. 1984, 20, 243.
R
N
Tf2O, pyridine
CH2Cl2
17 or 18
–40 °C to r.t., 1 h
then
Et3SiH, r.t., 5 h
N
Bn
19 R = H, 87%
20 R = OMe, 84%
R
N
(5) (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303. (b) Kansal, V. K.; Potier, P. Tetrahedron 1986, 42,
2389. (c) Sainsbury, M. Synthesis 1977, 437. (d) Barone, R.;
Chanon, M. Heterocycles 1981, 16, 1357. (e) Hewlins, M. J.
E.; Oliveira-Campos, A.-M.; Shannon, P. V. R. Synthesis
1984, 289. (f) Gribble, G. W.; Saulnier, M. G. Heterocycles
1985, 23, 1277. (g) Gribble, G. W. Synlett 1991, 289.
(h) Potier, P. Chem. Soc. Rev. 1992, 21, 113. (i) Gribble, G.
W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.; Ketcha, D. M.
J. Org. Chem. 1992, 57, 5891.
H2, Pd/C, MeOH
reflux, 6 h
N
H
1 R = H, 75%
2 R = OMe, 73%
Scheme 3 Synthesis of ellipticine (1) and 9-methoxyellipticine (2)
In summary, we have completed an expedient synthesis
of the pyrido[4,3-b]carbazole alkaloids, ellipticine (1) and
9-methoxyellipticine (2) over seven steps from known
1,4-dimethylcarbazoles (5 and 6) with 23% and 25%
(6) (a) Stiborová, M.; Bieler, C. A.; Wiessler, M.; Frei, E.
Biochem. Pharmacol. 2001, 62, 1675. (b) Stiborová, M.;
Sejbal, J.; Borek-Dohalská, L.; Aimová, D.; Poljaková, J.;
Synlett 2014, 25, 2791–2793
© Georg Thieme Verlag Stuttgart · New York

LETTER
Forsterová, K.; Rupertová, M.; Wiesner, J.; Hudeček, J.;
Friedel–Crafts Cyclodehydration
2793
736. (l) Watanabe, M.; Snieckus, V. J. Am. Chem. Soc. 1980,
102, 1457.
Wiessler, M.; Frei, E. Cancer Res. 2004, 64, 8374.
(7) (a) Miller, C. M.; McCarthy, F. O. RSC Adv. 2012, 2, 8883.
(b) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem. Rev.
2012, 112, 3193. (c) Deane, F. M.; O’Sullivan, E. C.;
Maguire, A. R.; Gilbert, J.; Sakoff, J. A.; McCluskey, A.;
McCarthy, F. O. Org. Biomol. Chem. 2013, 11, 1334.
(8) (a) Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007,
63, 3768. (b) Mal, D.; Senapati, B. K.; Pahari, P. Synlett
2005, 994. (c) Miki, Y.; Tsuzaki, Y.; Hibino, H.; Aoki, Y.
Synlett 2004, 2206. (d) Miki, Y.; Aoki, Y.; Tsuzaki, Y.;
Umemoto, M.; Hibino, H. Heterocycles 2005, 65, 2693.
(e) Bennasar, M. L.; Roca, T.; Ferrando, F. J. Org. Chem.
2005, 70, 9077. (f) Pedersen, J. M.; Bowman, W. R.;
Elsegood, M. R. J.; Fletcher, A. J.; Lovell, P. J. J. Org.
Chem. 2005, 70, 10615. (g) Ho, T.-L.; Hsieh, S.-Y. Helv.
Chim. Acta 2006, 89, 111. (h) Liu, C.-Y.; Knochel, P. J. Org.
Chem. 2007, 72, 7106. (i) Konakahara, T.; Kiran, Y. B.;
Okuno, Y.; Ikeda, R.; Sakai, N. Tetrahedron Lett. 2010, 51,
2335. (j) Yokoyama, Y.; Okuyama, N.; Iwadate, S.; Momoi,
T.; Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1990, 1319.
(k) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2014, 79,
(9) Cranwell, P. A.; Saxton, J. E. J. Chem. Soc. 1962, 3482.
(10) (a) Jackson, A. H.; Jenkins, P. R.; Shannon, P. V. R.
J. Chem. Soc., Perkin Trans. 1 1977, 1698. (b) Jackson, A.;
Wilson, N. D. V.; Gaskell, A. J.; Joule, J. A. J. Chem. Soc. C
1969, 2738.
(11) Lee, H.-Y.; Chen, G. S.; Chen, C.-S.; Chern, J.-W.
J. Heterocycl. Chem. 2010, 47, 454.
(12) Dračínský, M.; Sejbal, J.; Rygerová, B.; Stiborová, M.
Tetrahedron Lett. 2007, 48, 6893.
(13) (a) Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.
(b) Saito, S.; Sato, Y.; Ohwada, T.; Shudo, K. J. Am. Chem.
Soc. 1994, 116, 2312. (c) Saito, S.; Ohwada, T.; Shudo, K.
J. Am. Chem. Soc. 1995, 117, 11081. (d) Low, C.-E.;
Roberts, R. M. J. Org. Chem. 1973, 38, 1909. (e) Bailey, D.;
De Grazia, C. G. J. Org. Chem. 1970, 35, 4093. (f) Bradsher,
C. K. Chem. Rev. 1946, 38, 447.
(14) The CCDC deposition number for compound 19 is 994825.
Formula: C24H20N2. Unit cell parameters: a = 15.225 (8), b =
5.364 (3), c = 22.108 (12), α = 90, β = 101.789 (9), γ = 90,
Space group P21/c.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2791–2793

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.