An efficient synthesis of indoloquinoline alkaloid - Neocryptolepine (cryptotackieine)

Article abstract of DOI:10.1016/j.tetlet.2011.09.135

A short and convenient method for the synthesis of neocryptolepine (cryptotackieine) is described using Wittig reaction and one-pot reduction-cyclization-dehydration approach as the key steps.

Full text of DOI:10.1016/j.tetlet.2011.09.135

Tetrahedron Letters 52 (2011) 6594–6596
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Tetrahedron Letters
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An efficient synthesis of indoloquinoline alkaloid—neocryptolepine
(cryptotackieine)
Prakash T. Parvatkar, Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and convenient method for the synthesis of neocryptolepine (cryptotackieine) is described using
Wittig reaction and one-pot reduction–cyclization–dehydration approach as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 August 2011
Revised 27 September 2011
Accepted 29 September 2011
Available online 6 October 2011
Keywords:
Alkaloid
Indoloquinoline
Neocryptolepine
Cryptotackieine
One-pot and Wittig reaction
Plants are still the important resources for the discovery of
new drugs. The roots of the West African plant Cryptolepis sangu-
inolenta have long been used by Ghanaian healers to treat a vari-
ety of disorders such as infectious diseases, amebiasis, and fever
including malaria1–3 and have proved to be a rich source of indo-
loquinoline alkaloids. Neocryptolepine 1 (also named cryptotac-
kieine) is one of the thirteen characterized alkaloids isolated
synthesis in two steps with an overall yield of 19% using aza-Wittig
reaction. In the same year, Timari et al.10 reported the total synthe-
sis in five steps with an improved overall yield of 24% using Suzuki
coupling as the key step. Molina and co-workers11,12 developed
two routes using aza-Wittig reaction—one involving eight steps
with 26% overall yield (in 1999)11 while the other route involves
nine steps with 9% overall yield (in 2001).12 Wang and co-work-
ers13 in 1999 prepared 1 in four steps via biradical pathway with
an overall yield of 5%. Pieters and co-workers14 reported the five
step synthesis in 2002 using a diradical cyclization approach. In
the same year, Ho and Jou15 prepared 1 in five steps with an overall
yield of 33% using DCC coupling and Favorskii rearrangement as
the main steps. In 2004, Ila and co-workers16 reported its synthesis
in five steps with an overall yield of 27% via heterocyclization ap-
proach. Mohan and co-workers17 in 2006 reported the synthesis of
1 via photocyclization reaction with an overall yield of 40% in three
steps. In 2007, we prepared neocryptolepine in three steps with an
overall yield of 42% using double reduction–double cyclization ap-
proach.18 Sharma and Kundu19 reported its synthesis in three steps
via C–N bond formation using SnCl2Á2H2O with 24% overall yield
(in 2008). We reported the formal synthesis of neocryptolepine
in one-pot using iodine as a catalyst in 45% yield (in 2009).20 Re-
cently in 2010, Kraus and Guo21 reported the synthesis of 1 in five
steps with an overall yield of 24% via intramolecular Wittig reac-
tion. In the same year, Haddadin et al.22 prepared neocryptolepine
in three steps using reduction as the key step with 28% overall
yield. More recently in 2011, Hostyn et al.23 reported its synthesis
in three steps using Pd-catalyzed intramolecular direct arylation as
the key reaction with an overall yield of 88%, which is the highest
yield reported so far.
from C. sanguinolentine4,5 and has
a considerable structural
resemblance to the highly potent alkaloid ellipticine 2.
H3C
N
N
N
H
N
CH3
2
1
CH3
Neocryptolepine 1 is a tetracyclic heteroaromatic alkaloid con-
taining linear indolo[2,3-b]quinoline ring system and displays a
strong antiplasmodial activity6 in addition to antimicrobial and
cytotoxic activity.7,8 Novel structural features and wide biological
activity profile of neocryptolepine attracted both synthetic and
medicinal chemists. It was first synthesized in 1994 by
Peczynska-Czoch and co-workers7 before its isolation from natural
source in four steps with an overall yield of 9% via Graebe–Ullmann
reaction. Later on in 1997, Alajarin et al.9 reported its formal
⇑
Corresponding authors.
E-mail addresses: pparvatker@yahoo.com (P.T. Parvatkar), stilve@unigoa.ac.in
(S.G. Tilve).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.135

P. T. Parvatkar, S. G. Tilve / Tetrahedron Letters 52 (2011) 6594–6596
6595
N
N
N
N
N
N
H
H
H
1
3
OH 4a
CH3
H2N
FGI
NH2
O
O
N
H
N
H
4b
4c
O2N
O
Br
+
Ph3P
+
O
O
O2N
N
H
N
H
6
7
5
Scheme 1. Retrosynthetic analysis of neocryptolepine 1.
O2N
O
Br
+
Ph3P
Et3N, CHCl3
+
O
O
5
stir, r.t.
O2N
N
N
H
7
6
H
3h, 92%
Fe / HCl
AcOH
CH3I
stir at 1200C
24h, 77%
THF, reflux
12h, 96%
N
N
N
H
N
1
3
CH3
Scheme 2. Synthesis of neocryptolepine 1.
In continuation of our interest18,20,24 in indoloquinoline alka-
loids, we herein report a new synthesis of neocryptolepine. Our
retro-synthetic analysis of 6H-indolo[2,3-b]quinoline 3 (precursor
to neocryptolepine) showed that it could be prepared in one-pot
from intermediate 5 via reduction–cyclization–dehydration ap-
proach. The intermediate 5 in turn could be obtained by Wittig
reaction from easily available starting materials (Scheme 1).
Thus, condensation of (2-nitrobenzyl)triphenylphosphonium
bromide 7 with isatin 6 in the presence of triethyl amine yielded
the corresponding Wittig product 5 in 92% yield.25 Reduction of 5
with Fe/AcOH in the presence of a catalytic amount of HCl afforded
6H-indolo[2,3-b]quinoline 3 in 77% yield.26 In this step, reduction
of nitro group, isomerization of C–C double bond, cyclization, and
then dehydration took place in one-pot to give the aromatized
product 3 via intermediate 4c–a. Finally, the compound 3 is con-
verted to neocryptolepine
(Scheme 2). The overall yield of 1 in this three step sequence is
68%.
In conclusion, we have developed a short, simple, and high
yielding method for the synthesis of neocryptolepine. The new pro-
tocol has advantage in terms of number of steps, overall yield, and
efficiency over most of the other reported methods. We are cur-
rently evaluating the possibility to extend the range of compounds
to be prepared with the synthetic pathway presented in this Letter.
These results will be presented in due course.
Acknowledgments
We are grateful to the DST, New Delhi for financial assistance
and Prakash T. Parvatkar thanks the UGC, New Delhi for the award
of Dr. D.S. Kothari Postdoctoral Fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.135.
References and notes
1. Boye, G. L.; Ampofo, O. In Proceeding of the First International Symposium on
Cryptolepine; Boakye-Yiadom, K., Bamgbose, S. O. A., Eds.; University of Science
and Technology: Ghana, 1983; p 37.
2. Oliver-Bever, B. In Medicinal Plants in Tropical West Africa; Cambridge
University Press: Cambridge, 1986; Vol. 131, p 18.
3. Boakye-Yiadom, K. Q. J. Crude Drug Res. 1979, 17, 78.
4. Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A. Tetrahedron Lett.
1996, 37, 1703.
5. Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C. H., Jr.; Martin, G. E. J.
Heterocycl. Chem. 1996, 33, 239.
6. Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J. J. Nat. Prod. 1997, 60, 688.
7. Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski, J. J. Med. Chem.
1994, 37, 3503.
8. Kaczmarek, L.; Balicki, R.; Nantka-Namirski, P.; Peczynska-Czoch, W.;
Mordarski, M. Arch. Pharm. 1998, 321, 463.
1
via regioselective methylation15

6596
P. T. Parvatkar, S. G. Tilve / Tetrahedron Letters 52 (2011) 6594–6596
9. Alajarin, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60, 747.
10. Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067.
product 5 (0.50 g, 92%) as a bright red solid. Mp = 228–232 °C; IR (KBr):
m
max = 3175 (–NH), 1705 (–C@O), 1616, 1522, 1340, 1232, 866, 735 cmÀ1
.
11. Molina, P.; Fresneda, P. M.; Delgado, S. Synthesis 1999, 326.
12. Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron 2001, 57, 6197.
13. Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64, 925.
14. Jonckers, T. H. M.; van Miert, S.; Cimanga, K.; Bailly, C.; Colson, P.; De Pauw-
Gillet, M.-C.; Van den Heuvel, H.; Claeys, M.; Dommisse, R.; Lemiere, G. L. F.;
Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45, 3497.
15. Ho, T.-L.; Jou, D.-G. Helv. Chim. Acta 2002, 85, 3823.
16. Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2004, 69, 5760.
1H NMR (DMSO-d6, 400 MHz): (geometrical isomers in 2:1 ratio)
d
10.69
[10.52]⁄ (s, 1H, –NH), 8.31 [8.29]⁄ (d, J = 7.6 Hz, 1H), 7.83 [8.16]⁄ (s, 1H), 7.64–
7.89 (m, 4H), 6.72–7.25 (m, 4H).
⁄Values in the square brackets are for the minor isomer.
13C NMR (DMSO-d6, 75 MHz):
d 111.2 (110.6), 121.4 (121.7), 122.2 (122.3), 123.3 (124.1), 125.2 (126.1), 128.8
(129.4), 129.6 (129.8), 130.7 (130.9), 130.9 (131.4), 131.6 (131.9), 132.4
(132.3), 135.5 (134.2), 143.9 (142.5), 148.4 (147.9), 168.9 (167.6).
Values in the brackets are for the minor isomer.
17. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron 2006, 62, 6258.
18. Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron Lett. 2007, 48,
7870.
HRMS: m/z [M+Na]+ calcd for C15H10N2O3, 289.0589; found, 289.0589.
26. Experimental procedure for the preparation of 3: Fe powder (3.01 g) was added
over
a period of 30 min to a stirred solution of compound 5 (0.3574 g,
19. Sharma, S.; Kundu, B. Tetrahedron Lett. 2008, 49, 7062.
20. Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. J. Org. Chem. 2009, 74, 8369.
21. Kraus, G. A.; Guo, H. Tetrahedron Lett. 2010, 51, 4137.
22. Haddadin, M. J.; Zerdan, R. M. B.; Kurth, M. J.; Fettinger, J. C. Org. Lett. 2010, 12,
5502.
23. Hostyn, S.; Tehrani, K. A.; Lemiere, F.; Smout, V.; Maes, B. U. W. Tetrahedron
2011, 67, 655.
24. Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Curr. Org. Chem. 2011, 15, 1036.
25. Experimental procedure for the preparation of 5: To a mixture of isatin 6 (0.30 g,
1.34 mmol) in AcOH (30 mL). To this mixture 5 drops of concd HCl were added
and the suspension was stirred at 120 °C for 24 h. 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 (4 Â 25 mL). The combined
organic extract was washed with 10% aqueous NaHCO3 (25 mL) and H2O
(3 Â 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 (0.23 g, 77%) as a yellow solid.
Mp >300 °C; Lit.9 346 °C.
2.04 mmol) and 2-nitrobenzyl triphenylphosphonium bromide
7
(1.17 g,
Spectral data (IR, 1H and 13C NMR) were identical to those reported18,20 for the
6H-indolo[2,3-b]quinoline.
2.45 mmol) in CHCl3 (10 mL) was added Et3N (0.5 mL) and stirred at room
temp for 3 h. The solid which comes out was filtered and dried to give the