A direct synthesis of neocryptolepine and isocryptolepine

Article abstract of DOI:10.1016/j.tetlet.2010.05.141

A formal synthesis of indolequinoline alkaloid neocryptolepine and isocryptolepine is described which employed a common intermediate and used an intramolecular Wittig reaction followed by regioselective methylation in excellent yield.

Full text of DOI:10.1016/j.tetlet.2010.05.141

Tetrahedron Letters 51 (2010) 4137–4139
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A direct synthesis of neocryptolepine and isocryptolepine
*
George A. Kraus , Haitao Guo
Department of Chemistry, Iowa State University, Iowa 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of indolequinoline alkaloid neocryptolepine and isocryptolepine is described which
employed a common intermediate and used an intramolecular Wittig reaction followed by regioselective
methylation in excellent yield.
Received 12 March 2010
Revised 27 May 2010
Accepted 29 May 2010
Available online 2 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
thesis of isocryptolepine 3 in 28% overall yield involving an indole
synthesis as the key step.12 We recently reported a synthesis of 3
More than 2.5 million people die annually from malaria, one of
the most serious parasitic diseases in developing and industrial-
ized nations.1,2 The root of the west African plant Cryptolepis san-
guinlenta has been traditionally used to treat a variety of health
disorders, including malaria, rheumatism, urinary tract infections,
and other diseases.3,4 The linear indolequinoline alkaloids cryptol-
epine 1, neocryptolepine 2 (also called cryptotackieine), and iso-
cryptolepine 3 (also called cryptosanguinolentine) were isolated
from C. sanguinlenta in 1996 by two groups (Fig. 1).5 All of these
compounds can function as DNA-intercalating agents, inhibiting
DNA replication and transcription. These compounds also exhibit
potent antiplasmodial activity. However, compound 1 has a 10-
fold higher affinity for DNA than the other alkaloids and also shows
stronger inhibition of human topoisomerase II.6 Consequently,
compounds 2 and 3 are more promising leads for new anti-malar-
ial agents.
from 2-(2-nitrophenyl)indole which was prepared using our re-
cently reported indole synthesis.20
2. Results and discussion
The most common approach involves organometallic coupling
of substituted quinolines. We report herein a direct and distinctly
different strategy. Our retrosynthetic analysis of intermediate 4
showed that it could be prepared in one pot by intermediate 5
by an intramolecular Wittig reaction. Keto amide 5 could be made
by a coupling reaction using commercially available Wittig salt 6
(Scheme 1). The target molecules neocryptolepine 2 and isocry-
ptolepine 3 could be prepared via the same intermediate 4.
In our initial approach, the reaction of isatin with ethyl chloro-
formate in THF with triethyl amine, followed by sodium carbonate,
gave the acid 7 in 95% yield (Scheme 2). With acid 7, Steglich–Has-
ser esterification with commercially available phosphonium salt 6,
followed by an intramolecular Wittig reaction in the presence of
potassium tert-butoxide, gave a very complex reaction. We also
tried to prepare the acid chloride in situ first and then couple it
with phosphonium salt 6, followed the same intramolecular Wittig
reaction. This also failed. After careful study, we found that the
intermediate 8 did not form under these conditions. Instead of
using the unstable intermediate 8, we decided to introduce an
azide as the nitrogen source in the o-position because azides are
generally stable groups under acid or base conditions. The new
In the past decade, the significant biological activity and chal-
lenging structure of this class of natural products have drawn syn-
thetic chemists’ attention. Several syntheses for compounds 27–10
and 311–19 have been reported.
In 1997, Alajarin reported a formal synthetic route to compound
2 using an aza-Wittig-type reaction in three steps with an overall
yield of 15%.7 In 2001, Molina reported a total synthesis of com-
pound 2 in 10 steps in 9% yield and compound 3 in 11 steps in
17% yield, which used an intramolecular aza-Wittig reaction under
microwave-assisted conditions as the key reaction.8 Pieters and co-
workers reported a total synthesis of compound 2 in five steps in
2002 using a diradical cyclization as the key step.9 More recently,
Tilve and co-workers have reported a direct synthesis of compound
2 via double reductive cyclization. The overall yield for this synthe-
sis is 42% over four steps, which is the highest yield reported so
far.10 In 2006, Mohan and co-workers reported a three-step syn-
* Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294 0108.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.141

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G. A. Kraus, H. Guo / Tetrahedron Letters 51 (2010) 4137–4139
Scheme 1. Retrosynthetic analysis.
Scheme 2. Unsuccessful approach to 9.
Scheme 3. Reagent and conditions: (a) SOCl2, benzene, reflux, 1 h; (b) (COCl)2, CH2Cl2, rt, 3 h; (c) compound 6, CH2Cl2, rt, 12 h; (d) t-BuOK, THF, rt, 5 h, 62% from compound
10; (e) MeI, K2CO3, DMF, 60 °C, 8 h, 98%.
approach started from the known acid 10, which can easily be
made from isatin in one step in 92% yield (Scheme 3).21 The acid
chloride 11 was prepared from compound 10 by two different
methods, one using oxalyl chloride in methylene chloride solution
and the other using thionyl chloride. The resultant solid was di-
rectly used for the next step without further purification. Conden-
sation of (2-aminobenzyl) triphenylphosphonium bromide with
compound 11 in methylene chloride, followed by intramolecular
Wittig reaction with potassium tert-butoxide at room temperature,
led to lactam 13 in 62% yield in three steps and one pot from com-
pound 10.22 Methylation of 13 with methyl iodide in the presence
of potassium carbonate in DMF gave the known intermediate 14 in
98% yield.23 The overall yield of 14 was 60% over 4 steps in two
pots compared to the 22% yield over 9 steps according to the liter-
ature.8 Neocryptolepine 2 can be made in one step from 14 using
an intramolecular aza-Wittig reaction under microwave-assisted
conditions and isocryptolepine 3 can be made in two steps via nit-
rene insertion, followed by Red-Al reduction.8
isocryptolepine 3, employing a common intermediate 14, and
using an intramolecular Wittig reaction, followed by regioselective
methylation in excellent yield.
Acknowledgment
We thank the Iowa State University Department of Chemistry
for partial support of this work.
References and notes
1. O’Neill, P. M.; Bray, P. G.; Hawley, S. R.; Ward, S. A.; Park, B. K. Pharmacol. Ther.
1998, 77, 29–58.
2. Rang, H. P.; Dale, M. M.; Ritter, J. M. Pharmacology, 4th ed.; Churchill
Livingstone: Edinburgh, U.K., 1999. Chapter 46 (Antiprotozoal Drugs).
3. Boye, G. L.; Ampofo, O. Proceedings of the First International Symposium on
Cryptolepine; University of Science and Technology: Kumasi, Ghana, 1983.
4. Oliver-Bever, B. Medicinal Plants in Tropical West Africa; Cambridge University
Press: Cambridge, 1986, p 41.
5. (a) Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C. H., Jr.; Martin, G. E.
J. Heterocycl. Chem. 1996, 33, 239; (b) Cimanga, K.; De Bruyne, T.; Pieters, L.;
Claeys, M.; Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703.
In conclusion, we have established
a new, efficient, and
straightforward formal total synthesis of neocryptolepine 2 and

G. A. Kraus, H. Guo / Tetrahedron Letters 51 (2010) 4137–4139
4139
6. Bailly, C.; Laine, W.; Baldeyrou, B.; De Pauw-Gillet, M.-C.; Colson, P.; Houssier,
C.; Cimanga, K.; Van Miert, S.; Vlietinck, A. J.; Pieters, L. Anti-Cancer Drug Des.
2000, 15, 191.
7. Alajarin, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60, 747.
8. Fresneda, M. P.; Molina, P.; Delgado, S. Tetrahedron 2001, 57, 6197.
9. Jonckers, H. M. T.; Miert, V. S.; Cimanga, K.; Bailly, C.; Colson, P.; Pauw-Gillet, D.
M.; Heuvel, H.; Claeys, M.; Lemiere, F.; Esmans, L. E.; Rozenski, J.; Quirijnen, L.;
Maes, L.; Dommisse, R.; Lemiere, L. F. G.; Vlietinck, A.; Pieters, L. J. Med. Chem.
2002, 45, 3497.
10. Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron Lett. 2007, 48,
7870.
11. Miki, Y.; Kuromatsu, M.; Miyatake, H.; Hamamoto, H. Tetrahedron Lett. 2007,
48, 9093.
12. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron 2006, 62, 6258.
13. Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron Lett. 2005, 46, 4509.
14. Jonckers, T. H. M.; Maes, B. U. W.; Lemière, G. L. F.; Rombouts, G.; Pieters, L.;
Haemers, A.; Dommisse, R. A. Synlett 2003, 615.
15. Kumar, R. N.; Suresh, T.; Mohan, P. S. Tetrahedron Lett. 2002, 43, 3327.
16. Molina, P.; Alajarn, M.; Vidal, A.; Sanchez-Andrada, P. J. Org. Chem. 1992, 57,
929.
B: oxalyl chloride (0.41 g, 3.24 mmol) was slowly added under an inert
atmosphere to an ice-cold solution of compound 10 (0.5 g, 2.7 mmol) in 5 mL
of dry CH2Cl2. The resulting mixture was treated with a catalytic amount of
DMF and allowed to react at rt for 3 h. The solvent and excess reagent were
evaporated. The resultant brown solid was directly used in the next step
without any purification. The acid chloride 11 (0.1 g, 0.48 mmol) was
redissolved in 5 mL of CH2Cl2 and phosphonium salt 6 (0.214 g, 0.48 mmol)
was added. The resulting mixture was stirred at rt for 12 h. The solvent was
removed under vacuum. THF (5 mL) was added to the resultant orange solid,
followed slowly by 0.57 mL of a t-BuOK (1 M, 0.57 mmol) solution in THF at rt.
After 5 h at rt, the reaction was quenched by the addition of an aqueous NH4Cl
solution. The product was extracted twice with ethyl acetate and the combined
organic layers were washed with brine. Evaporation of the solvent, followed by
column chromatography gave compound 13 (75 mg, 62% for three steps) as
yellow powder; mp = 201–202 °C; 1H NMR (400 MHz, DMSO-d6) 11.94 (s, 1H),
7.91 (s, 1H), 7.68–7.70 (d, J = 7.6 Hz, 1H), 7.47–7.54 (m, 2H), 7.33–7.39 (m, 3H),
7.24–7.28 (m, 1H), 7.18–7.22 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
161.1, 140.0, 139.2, 138.4, 132.1, 130.9, 130.7, 130.0, 129.3, 128.6, 125.3, 122.4,
119.54, 119.49, 115.3; HRMS electrospray (m/z) calcd for C15H10N4O, 262.0855;
found, 262.0858.
17. Holt, S. J.; Petrow, V. J. Chem. Soc. 1948, 922.
23. Experimental procedure for the preparation of 3-(2-Azidophenyl)-1-
18. Kaczmarek, L.; Balicki, R.; Nantka-Namirski, P.; Peczynska-Czoch, W.;
Modarsski, M. Arch. Pharm. (Weinheim) 1988, 321, 463.
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1994, 37, 3503.
20. Kraus, G. A.; Guo, H.; Kumar, G.; Pollock, G., III; Carruthers, H.; Chaudhary, D.;
Beasley, J. Synthesis 2010, 8, 1386.
21. Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187.
22. Experimental procedure for the preparation of 3-(2-Azidophenyl)quinolin-2-one
13: Method A: To a suspension of acid 10 (1.0 g, 5.4 mmol) in 10 mL of benzene
was added thionyl chloride (3.86 g, 32.4 mmol). The mixture was boiled with
stirring for 1 h and was concentrated under reduced pressure. The residue was
recrystallized from benzene to give acid chloride 11 as a brown solid. Method
methylquinolin-2(1H)-one 14: To a mixture of compound 13 (60 mg,
0.23 mmol) in 4 mL of dry DMF and anhydrous K2CO3 (191 mg, 1.38 mmol),
methyl iodide (49 mg, 0.345 mmol) was added dropwise under argon. The
resultant mixture was stirred at 60 °C for 8 h. The reaction was quenched by
the addition of 10 mL of water. The product was extracted twice with ethyl
acetate and the combined organic layers were washed with brine. Evaporation
of the solvent, followed by column chromatography, gave compound 14
(62 mg, 98%) as yellow solid; mp = 168–170 °C (lit. mp = 169 °C)8; 1H NMR
(400 MHz, CDCl3) 7.67 (s, 1H), 7.54–7.58 (m, 2H), 7.34–7.42 (m, 3H), 7.16–7.25
(m, 3H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) 161.1, 140.0, 138.8, 138.6,
131.6, 130.7, 130.3, 129.6, 129.0, 124.7, 122.3, 120.3, 118.6, 114.2, 30.0; HRMS
electrospray (m/z) calcd for C16H12N4O, 276.1011; found, 276.1017.