Double reductive cyclization: a facile synthesis of the indoloquinoline alkaloid cryptotackieine

Article abstract of DOI:10.1016/j.tetlet.2007.08.126

A new synthesis of the indoloquinoline alkaloid cryptotackieine, isolated from Cryptolepis sanguinolenta, is described which involves a Perkin reaction, a tandem double reduction-double cyclization reaction followed by regioselective methylation at the quinoline nitrogen.

Full text of DOI:10.1016/j.tetlet.2007.08.126

Tetrahedron Letters 48 (2007) 7870–7872
Double reductive cyclization: a facile synthesis
of the indoloquinoline alkaloid cryptotackieine
P. T. Parvatkar,a,b P. S. Parameswarana,* and S. G. Tilveb,*
aNational Institute of Oceanography, Dona Paula, Goa 403 207, India
bDepartment of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India
Received 22 June 2007; revised 21 August 2007; accepted 30 August 2007
Available online 4 September 2007
Abstract—A new synthesis of the indoloquinoline alkaloid cryptotackieine, isolated from Cryptolepis sanguinolenta, is described
which involves a Perkin reaction, a tandem double reduction–double cyclization reaction followed by regioselective methylation
at the quinoline nitrogen.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Two independent groups reported the isolation of a new
indoloquinoline alkaloid in 1996 from the ethanolic ex-
tracts of Cryptolepis sanguinolenta, a shrub indigenous
to tropical West Africa, which was named as cryptotac-
kieine 1 by one group,1 and neocryptolepine by the
other group.2 Cryptotackieine (neocryptolepine), which
displays strong antiplasmodial activity against chloro-
quine-resistant Plasmodium falciparum strains3 was
found to be the N-methyl derivative of the linear indo-
lo[2,3-b]quinoline ring system. It has been reported that
cryptotackieine (neocryptolepine) and various methyl
derivatives of such systems display biological properties
such as antimuscarinic, antibacterial, antiviral, antimi-
cotic, antihyperglycemic, and cytotoxic activities
in vivo, and significant antitumor properties in vitro.4
polyheteroatomic ring systems such as 6H-indolo[2,3-b]-
quinoline, the precursor to cryptotakieine (neocrypto-
lepine).5 In 1997, Alajarin et al.6 reported the synthesis
of cryptotackieine 1 in three steps using an aza-Wittig
reaction with an overall yield of 15%.
In the same year, Timari et al. reported a synthesis in
five steps with an improved overall yield of 24%. The
key reaction of this method was the Suzuki coupling
reaction between 3-bromoquinoline and N-piv-
aloylaminophenylboronic acid.7 In 1999, Molina et al.
described an iminophosphorane mediated approach to
obtain 1 in 26% overall yield, which involved eight
steps.8 Molina has also prepared 1 in nine steps in 9%
overall yield using an intramolecular aza-Wittig
reaction9 as the key step. Wang and co-workers
reported the synthesis of 1 in four steps via a biradical
pathway10 with an overall yield of 5%. In 2004, Ila
and co-workers reported a five-step synthesis of 1 with
an overall yield of 27%, which involved heterocycliza-
tion as the key step.11 More recently, Mohan and co-
workers reported the synthesis of 1 via three steps using
a photocyclization reaction as the key step with an over-
all yield of 40%.12
N
N
CH3
1
The interesting biological activity of 1 has generated
an interest in developing a new synthetic pathway to
In continuation of our interest13 in domino reactions,
we report herein a facile synthesis of 6H-indolo[2,3-b]-
quinoline 3, the immediate chemical precursor of the
alkaloid cryptotackieine (neocryptolepine). Our retro-
synthetic analysis of 3 indicated that it should be possi-
ble to prepare 3 via a one-pot double reduction,
isomerization, and double cyclization (Scheme 1). The
Keywords: Indoloquinoline alkaloid; Perkin reaction; Cryptotackieine;
Neocryptolepine; Tandem; Reductive cyclization.
*
Corresponding authors. Tel.: +91 832 2451345/2450458; fax: +91
832 2451184 (S.G.T.);
stilve@unigoa.ac.in
e-mail addresses: param@nio.org;
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.126

P. T. Parvatkar et al. / Tetrahedron Letters 48 (2007) 7870–7872
7871
O
NH
N
H
N
N
H
NH2
O
NH2
3
NO2
O
OR
COOEt
NO2
NH2
NH2
2
Scheme 1.
NO2
COOEt
NO2
CHO
NO2
COOH
NO2
a
b
+
2
d
c
or
e
N
N
N
N
H
CH3
3
1
Scheme 2. Reagents and conditions: (a) Ac2O, Et3N, reflux, 5 h; (b) EtOH, H2SO4, reflux, 24 h, 71%; (c) Fe/AcOH:EtOH:H2O/HCl, 120 ꢁC, 24 h,
74%; (d) MW, Me2SO4/DMF, 140 ꢁC, 5 min, 75%; (e) Me2SO4, CH3CN, reflux, 6 h, K2CO3, 80%.
required unsaturated ester 2 could be easily assembled
from commercially available o-nitrobenzaldehyde and
o-nitrophenylacetic acid using the Perkin reaction.
In conclusion, we have developed a new and efficient
three-step synthesis of the alkaloid cryptotackieine
(neocryptolepine) using a Perkin reaction followed by
a ‘one-pot’ double reduction, double cyclization and
isomerization in excellent yield. Due to the easy
availability of the starting materials and high yields
realized in the different steps, this approach represents
an efficient synthesis of the title compound.
Thus, condensation of o-nitrobenzaldehyde and o-nitro-
phenylacetic acid in the presence of Ac2O and Et3N
yielded the corresponding a,b-unsaturated acid, which
on esterification afforded the required ester 2 in 71%
yield.14 Reduction of 2 with Fe/AcOH in presence of
HCl provided 6H-indolo[2,3-b]quinoline 3 in 74% in a
single step.15 In this step, four reactions had taken place
in a tandem manner, that is, reduction of both the nitro
groups, cyclization, isomerization of the intermediate E-
amide to the Z-amide followed by a second cyclization.
In the final step, compound 3 was subjected to regiose-
lective methylation on the quinoline nitrogen as re-
ported8,12 to give cryptotackieine (neocryptolepine) 1
in 80% yield. The overall yield of 1 was found to be
42% over the three steps and is comparable with those
reported (Scheme 2). The spectral data for compound
1 were identical with those reported1 for the natural
product.
Acknowledgments
We thank IISc, Bangalore, for HRMS and the CSIR,
New Delhi, for the financial support. One of us
(P.T.P.) thanks the CSIR, New Delhi, for the award
of a Junior Research Fellowship.
References and notes
1. Sharaf, M. H.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C.
H., Jr.; Martin, G. E. J. Heterocycl. Chem. 1996, 33, 239.

7872
P. T. Parvatkar et al. / Tetrahedron Letters 48 (2007) 7870–7872
2. Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.;
heated at reflux for 5 h. The mixture was allowed to cool
and poured into water (50 mL). This was then extracted
with CHCl3 (3 · 15 mL) and the combined organic
extracts were washed with aqueous satd Na2CO3 solution
(3 · 15 mL). The combined Na2CO3 washings were acid-
ified with 6 N HCl. The resulting solid was filtered, dried,
redissolved in EtOH (15 mL), H2SO4 (five drops) were
added, and refluxed for 24 h. The reaction mixture was
cooled to room temp and after 6 h, the a,b-unsaturated
ester 2 (1.71 g, 71%) precipitated as a crystalline white
solid and was isolated by filtration. IR (KBr, cmÀ1): m
1524, 1570, 1611, 1701; 1H NMR (CDCl3, 300 MHz) d
(ppm): 1.28 (t, 3H, J = 7.2 Hz, –OCH2CH3), 4.29 (q, 2H,
J = 7.2 Hz, –OCH2CH3), 7.02–7.08 (m, 2H, Ar-H), 7.28–
7.41 (m, 3H, Ar-H), 8.12–8.16 (m, 3H, Ar-H), 8.22 (s, 1H,
@CH); 13C NMR (CDCl3, 75 MHz) d (ppm): 13.99, 61.84,
76.60, 77.03, 77.45, 124.56, 124.66, 129.26, 129.37, 131.00,
131.58, 131.68, 133.01, 133.10, 133.55, 133.58, 137.25;
HRMS m/z: [M+Na]+ calcd for C17H14N2O6, 365.0750;
found, 365.0746.
Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703.
3. Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.;
Turger, C. A. J. Nat. Prod. 1997, 60, 688.
4. Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Bora-
tynski, J. J. Med. Chem. 1994, 37, 3503; Cimanga, K.; De
Bruyne, T.; Lasure, A.; Van Poel, B.; Pieters, L.; Claeys,
M.; Vanden Berghe, D.; Kambu, K.; Tona, L.; Vlietinck,
A. J. Planta Med. 1996, 62, 22; Cimanga, K.; De Bruyne,
T.; Pieters, L.; Totte, J.; Tona, L.; Kambu, K.; Berghe,
D.-V.; Vlietinck, A. J. Phytomed. 1998, 5, 209; Bierer, D.
E.; Fort, D. M.; Mendez, C. D.; Luo, J.; Imbach, P. A.;
Dubenko, L. G.; Jolad, S. D.; Gerber, R. E.; Litvak, J.;
Lu, Q.; Zhang, P.; Reed, M. J.; Waldeck, N.; Bruening, R.
C.; Noamesi, B. K.; Hector, R. F.; Calrson, T. J.; King, S.
R. J. Med. Chem. 1998, 41, 894; Abblordeppey, S. Y.;
Fan, P.; Clark, A. M.; Nimrod, A. Bioorg. Med. Chem.
1999, 7, 343; Arzel, E.; Rocca, P.; Grellier, P.; Labaeid,
M.; Frappier, F.; Gueritte, F.; Gaspard, C.; Marsais, F.;
Godard, A.; Queguiner, G. J. Med. Chem. 2001, 44, 949.
5. Molina, P.; Alajarin, M.; Vidal, A. J. Chem. Soc., Chem.
Commun. 1990, 1277; Molina, P.; Alajarin, M.; Vidal, A.;
Sanchez-Andrada, P. J. Org. Chem. 1992, 57, 929; Chen,
Y. L.; Hung, H. M.; Lu, C. M.; Li, K. C.; Tzeng, C. C.
Bioorg. Med. Chem. 2004, 12, 6539; Sundaram, G. S. M.;
Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H.
J. Org. Chem. 2004, 69, 5760.
6. Alajarin, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60,
747.
7. Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067.
8. Molina, P.; Fresnsda, P. M.; Delgado, S. Synthesis 1999,
326.
9. Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron
Lett. 1999, 40, 7275.
10. Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64,
925.
11. Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar, U. K.;
Ila, H.; Junjappa, H. J. Org. Chem. 2004, 69, 5760.
12. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron
2006, 62, 6258.
13. Patre, R. E.; Gawas, S.; Sen, S.; Parameswaran, P. S.;
Tilve, S. G. Tetrahedron Lett. 2007, 48, 3517.
14. Experimental procedure for the preparation of a,b-unsatu-
rated ester derivative 2: A mixture of o-nitrobenzaldehyde
(1.06 g, 7.01 mmol), o-nitrophenylacetic acid (1.27 g,
7.01 mmol), Et3N (1.1 mL), and Ac2O (15 mL) were
15. Experimental procedure for the preparation of 6H-indo-
lo[2,3-b]quinoline 3: Ester derivative 2 (0.55 g, 1.61 mmol)
and Fe powder (3.6 g) were added to a mixture of EtOH
(10 mL), acetic acid (10 mL), and H2O (5 mL). To this
mixture five drops of concd HCl were added and the
suspension was heated at 120 ꢁC while stirring for 24h.
The mixture was allowed to cool to room temp and then
filtered through Celite. The filtrate was diluted with water
(50 mL) and then extracted with CHCl3 (3 · 15 mL). The
combined organic extract was washed with 10% aqueous
NaHCO3 (25 mL) and H2O (3 · 15 mL), dried over
anhydrous Na2SO4, and concentrated to dryness to give
a yellow solid. The solid was washed with Et2O and air
dried to give 6H-indolo[2,3-b]quinoline 3 (0.26 g, 74%).
Mp > 300 ꢁC (Lit.16 mp: 346 ꢁC); IR (KBr, cmÀ1): m 1231,
1406, 1460, 1614, 3144; 1H NMR (DMSO-d6, 300 MHz) d
(ppm): 7.27 (tm, 1H, H-9), 7.46–7.57 (m, 3H, H-2, H-7, H-
8), 7.72 (ddd, 1H, J = 8.1, 7.2, 0.9 Hz, H-3), 7.98 (d, 1H,
J = 8.4 Hz, H-9), 8.11 (d, 1H, J = 8.1 Hz, H-1), 8.27 (d,
1H, J = 7.8 Hz, H-10), 9.05 (s, 1H, H-11), 11.70 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d (ppm): 111.39 (C-
7), 118.37 (C-10b), 120.14 (C-9), 120.76 (C-11a), 122.29
(C-10), 123.20 (C-2), 124.15 (C-10a), 127.45 (C-1), 128.01
(C-11), 128.67 (C-4), 129.13 (C-8 + C-3), 141.93 (C-6a),
146.79 (C-4a), 153.36 (C-5a).
16. Holt, S. J.; Petrow, V. J. J. Chem. Soc. 1948, 922.