Total synthesis of ellipticine quinones, olivacine, and calothrixin b

Article abstract of DOI:10.1021/jo402593w

A direct route to the synthesis of biologically active ellipticine quinones, olivacine, and calothrixin B is described. The prominent key steps involved are Friedel-Crafts hydroxyalkylation followed by oxidation and directed ortho-lithiation reactions of readily available indole-2-carboxylate esters with appropriately substituted pyridine and quinoline carboxaldehydes.

Full text of DOI:10.1021/jo402593w

Article
pubs.acs.org/joc
Total Synthesis of Ellipticine Quinones, Olivacine, and Calothrixin B
Nagarajan Ramkumar and Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
*
S Supporting Information
ABSTRACT: A direct route to the synthesis of biologically active ellipticine quinones, olivacine, and calothrixin B is described.
The prominent key steps involved are Friedel−Crafts hydroxyalkylation followed by oxidation and directed ortho-lithiation
reactions of readily available indole-2-carboxylate esters with appropriately substituted pyridine and quinoline carboxaldehydes.
INTRODUCTION
have highlighted the synthesis and biological activities of
16
■
calothrixin B.
Several natural and synthetic heterocyclic quinones have
important biological activities such as antitumoral, antiproto-
zoan, and antibiotic activities. Many of these molecules possess
antineoplastic chemotherapeutic properties. Quinones are a
class of compounds found in many drugs that are used in the
Friedel−Crafts hydroxyalkylation reaction of aromatic
compounds with carbonyl compounds is one of the best
methods for the synthesis of pyridyl aryl/heteroaryl carbinols
1
2
1
7
and their derivatives. Directed ortho-metalation (DoM)
3
reaction is widely used in modern organic synthesis of natural
clinical therapy of solid tumors. Among them, carbazolequi-
18
products. In this paper, we explored the utility of these
reactions in synthesizing biologically important heterocyclic
quinones such as ellipticine quinones, calothrixin B, and further
few steps to olivacine.
none alkaloids (Figure 1) display notable biological properties
such as cardiotonic, antituberclosis, and neutronal cell-
4
protecting activities. Pyrido and quinolinocarbazole alkaloids
(
Figure 1) are well-known for their wide range of potent
5
biological activities. Ellipticine (5,11-dimethyl-6H-pyrido[4,3-
RESULTS AND DISCUSSION
6
■
b]carbazole) 3 and 9-methoxyellipticine 4 were isolated from
The synthesis of ellipticine quinone 15 is summarized in
Scheme 1. After several screening conditions, we treated
commercially available ethyl 1H-indole-2-carboxylate 11 with
the leaves of Ochrosia elliptica Labill by Goodwin et al. in 1959.
The biological activity of ellipticine was considered to be based7
mainly on DNA intercalation and topoisomerase II inhibition.
pyridine-3-carboxaldehyde 12 in presence of 1.1 equiv of AlCl3
at 0 °C to room temperature followed by oxidation using 1.2
The first clinical success of celiptium 7 led to extensive studies
into the synthesis of ellipticinium derivatives, and several of
these progressed to clinical trials. Since the commercialization
of some ellipticine derivatives and their successful clinical uses
prompted tremendous development in the chemistry and
biology of pyridocarbazole alkaloids. Olivacine 8 was isolated
from different members of the Apocynaceae family, and
limited reports are available for its synthesis. The synthesis
and biological activity of ellipticine and its congeners have been
8
equiv of IBX in DMSO, giving ketone 14 in 94% yield. The
carbinol formed 13 was not isolated from the reaction mixture,
and subsequently we carried out oxidation after the reaction
work up. The ketone 14 was then subjected to directed o-
lithiation reaction using 5 equiv of LiTMP (lithium
tetramethylpiperidide) as a base to afford a single regioisomer
7
,8
9
10
15 in 72% yield. Thus, ellipticine quinone 15 was obtained in 3
1
1
steps and 67.6% overall yield.
covered by several comprehensive reviews.
12
Also, we tested the stability of ester groups present in the
indole moiety by introducing methyl and t-butyl groups in
Scheme 2. Because of the high mobility of t-butyl group, we
obtained 20 as acid under Friedel−Crafts hydroxyalkylation
reaction. The acid 20 was directly converted into 15 by LiTMP
in 43% yield. Thus, we synthesized 9-methoxy ellipticine
Ellipticine quinone 15 is a pivotal synthetic intermediate in
the early Gribble syntheses of ellipticines that shows activity
1
3
against antitumors. The only known quinolino[4,3-b]-
carbazole alkaloid, calothrixin B 10 (7H-indolo[3,2-j]-
phenanthridine-7,13(12H)-dione), was first obtained from a
blue-green algae Calothrix cyanobacteria by Rickards group in
1
4
1
999. It is a pentacyclic quinone that exhibits antimalarial
activity as well as activity against human HeLa cancer cells and
inhibition of RNA polymerase. Several recent publications
Received: November 19, 2013
Published: December 27, 2013
15
©
2013 American Chemical Society
736
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Article
Figure 1. Examples of carbazolequinone, pyrido, and quinolinocarbazole alkaloids.
Scheme 1. Synthesis of Ellipticine Quinone (15)
derivative 32 (confirmed by a single crystal XRD, see
Supporting Information) was isolated as indicated in Scheme 4.
Therefore, we switched to base-mediated reaction to form
18
indolyl/pyridyl or quinolyl methanols. Treatment of 11 with
2
1
-methylnicotinaldehyde 31 in the presence of 1.5 equiv of
,1,3,3,-tetramethylguanidine (TMG) in MeOH at room
temperature for 8 h followed by oxidation using IBX afforded
the ketone 33 in 84% yield. Wolff−Kishner reduction of the
ketone 33 gave reduced compound 34. The cyclized compound
3
5 was obtained by treating 34 with LDA/HMPA at −78 °C
for 3 h. Finally, the addition of MeMgI into 35 followed by
treatment upon NaBH /AlCl (3:1) in dry THF at room
4
3
temperature for 3 h produced 8 in 58% yield. Thus, olivacine 8
was obtained in 6 steps and 15.6% overall yield as shown in
Scheme 4.
The synthesis of calothrixin B 10 is outlined in Scheme 5.
The reaction of 11 with quinoline-3-carboxaldehyde 36 in the
presence of 1.5 equiv of TMG in MeOH followed by oxidation
with 1.5 equiv of Dess−Martin periodinane (DMP) in DCM/
AcOH (9:1) at room temperature for 6 h gave the ketone 37 in
quinone 22, which can be considered as a key intermediate in
synthesizing 9-methoxyellipticine 4.
By employing our route, isoellipticines 5 and 6 can also be
prepared, which are the known isomeric structures of
ellipticines. Hence, isoellipticine quinones 26 and 27 can be
obtained by varying pyridine part 23 as shown in Scheme 3.
Also the other isomer of ellipticine quinone 30 was synthesized
by using pyridine-2-carboxaldehyde 28. The ketones obtained
8
3
0% yield. Then intramolecular directed o-lithiation reaction of
7 in the presence of LiTMP afforded 10 in 48% yield. Thus,
calothrixin B 10 was obtained in three steps and 38.4% overall
yield.
CONCLUSIONS
19, 25, and 29 were confirmed by a single crystal XRD (see
■
Supporting Information).
In summary, we demonstrated a novel and concise total
synthesis of biologically important ellipticine quinone and
calothrixin B in three-step sequences of 67 and 38% good
overall yields, respectively. Also, we have extended this route to
the synthesis of olivacine in 16% overall yield over 6 steps. It is
We have successfully applied our synthetic route to the
synthesis of olivacine 8 and calothrixin B 10. In both cases, we
surprisingly observed the formation of bisindolylmethane
derivatives under Lewis acid conditions, and one of the
Scheme 2. Stability of Indole-2-carboxylate Esters and Synthesis of 9-Methoxyellipticine Quinone (22)
7
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The Journal of Organic Chemistry
Article
Scheme 3. Synthesis of Isomeric Ellipticine Quinones
Scheme 4. Synthesis of Olivacine 8
Scheme 5. Synthesis of Calothrixin B 10
worth mentioning that our synthetic approach for these
compounds is superior to that of previously reported methods
in terms of availability of starting materials, overall yields, and
the number of steps used. We are screening suitable reagents to
convert ellipticine quinones into ellipticines, and these results
will be reported in due course.
reagents and solvents were used without further purification and
were purchased. Melting points were determined using open capillary
tubes and are uncorrected.
General Procedure for the Synthesis of Ketones 14, 19−21,
4, 25, and 29. To the solution of desired indole carboxylate ester (1
2
mmol) in dry DCM (20 mL) was added anhydrous AlCl (1.1 mmol),
3
and the mixture was stirred at room temperature for 30 min under
nitrogen atomsphere. Appropriate pyridine carboxaldehyde (1 mmol)
was added to the mixture at 0 °C, which was brought back to room
temperature and stirred for 2−4 h. The completion of the reaction was
monitored by TLC. The mixture was then quenched with ice cold
water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The
organic layer was dried over anhydrous Na SO and concentrated to
EXPERIMENTAL SECTION
■
General Information and Materials. The NMR experiments
were performed with 400 or 500 MHz spectrometer, and chemical
shifts are expressed in ppm (δ) with TMS as an internal reference.
Coupling constant J values are given in Hz. IR spectra were recorded
by using KBr pellets or neat. ESI-TOF mass analyzer type was used for
the HRMS measurements. Reactions were carried out under an inert
atmosphere, referring to the use of nitrogen, and monitored by TLC.
Column chromatography was performed on silica gel (100−200
mesh) in glass columns to purify the compounds. Solvents
tetrahydrofuran (THF), methanol, and dichloromethane were dried
by using standard distillation methods. Commercially available
2
4
give solid material. The solid obtained was dissolved in DMSO (7 mL)
followed by the addition of IBX (1.2 mmol). The reaction mixture was
then stirred at room temperature for 2−4 h. After completion of
reaction, ice cold water (75 mL) was added to the mixture. The
aqueous layer was extracted with ethyl acetate, washed with brine, and
dried over anhydrous Na SO . After the removal of the solvent, the
2
4
7
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Article
crude compound was purified by silica gel column chromatography
using hexanes/ethyl acetate as eluent to afford the title compounds.
126.2, 125.8, 123.2, 122.6, 122.1, 117.4, 111.9, 61.4, 13.5; HRMS
+
(ESI) [M + H] calcd for C H N O 295.1083, found 295.1085.
17
14
2
3
Ethyl 3-nicotinoyl-1H-indole-2-carboxylate (14). R = 0.41
General Procedure for the Synthesis of Ellipticine Quinones
and Its Isomers. A schlenck tube was charged with tetramethylpiper-
idine (5 mmol) in dry THF and sealed by rubber septum. 1.6 M n-
BuLi in hexanes (10 mmol) was added to it under nitrogen
atmosphere at −78 °C and stirred for 15 min. The respective ketone
f
(
°
hexanes:EtOAc, 4:6); light yellow solid (146 mg, 94%): mp 152−154
−1 1
C; IR (KBr) 3418, 2854, 1653, 1545 cm ; H NMR (400 MHz,
CDCl ) δ 9.92 (s, br, 1H), 9.03 (s, 1H), 8.79 (d, J = 3.2 Hz, 1H), 8.22
3
(
7
(
d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H),
.46−7.38 (m, 2H), 7.27−7.23 (m, 1H), 4.07 (q, J = 7.2 Hz, 2H), 0.90
t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl ) δ 191.3, 160.8,
(1 mmol) in dry THF was added to the mixture at the same
temperature and stirred for 2−3 h. After completion of the reaction,
3
the mixture was poured into saturated aqueous solution of NH Cl (30
1
1
52.8, 150.8, 136.4, 135.6, 135.1, 127.3, 127.0, 126.4, 123.4, 122.7,
4
21.9, 118.7, 112.1, 61.7, 13.5; HRMS (ESI) [M + H]+ calcd for
mL). The whole solution was then extracted with ethyl acetate (3 × 30
mL), dried over anhydrous Na SO , and concentrated. The crude
C H N O 295.1083, found 295.1085.
2
4
17
14
2
3
material was purified by silica gel column chromatography using ethyl
acetate/hexanes as eluent.
Methyl 3-nicotinoyl-1H-indole-2-carboxylate (19). R = 0.40
f
(
°
(
(
7
1
1
hexanes:EtOAc, 3:7); light yellow solid (145 mg, 91%): mp 156−158
−1
1
5H-Pyrido[4,3-b]carbazole-5,11(6H)-dione (Ellipticine Qui-
C; IR (KBr) 3426, 1675 cm ; H NMR (400 MHz, CDCl ) δ 9.69
3
none) (15). R = 0.53 (hexanes:EtOAc, 6:4); red solid (60 mg,
f
s, br, 1H), 9.03 (s, 1H), 8.81 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.76
d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.46−7.41 (m, 2H),
−
1 1
7
2%): mp >300 °C; IR (KBr) 3387, 1615 cm ; H NMR (400 MHz,
CDCl +DMSO-d ) δ 12.54 (s, br, 1H), 9.30 (s, 1H), 8.89 (d, J = 4.8
1
3
3
6
.28−7.25 (m, 1H), 3.61 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 4.4 Hz, 1H), 7.48 (d, J
91.2, 161.0, 152.8, 150.6, 136.3, 135.5, 134.9, 127.2, 126.8, 126.5,
23.4, 122.8, 121.9, 119.1, 112.1, 52.3; HRMS (ESI) [M + H] calcd
1
3
+
= 8.4 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.29−7.22 (m, 1H);
C
NMR (100 MHz, CDCl +DMSO-d ) δ 181.2, 180.4, 154.4, 148.0,
3
6
for C H N O 281.0927, found 281.0929.
16
12
2
3
1
1
46.8, 136.4, 134.3, 131.9, 127.6, 127.4, 125.1, 124.2, 123.3, 118.1,
3
-Nicotinoyl-1H-indole-2-carboxylic acid (20). Rf = 0.66
+
13.7; HRMS (ESI) [M + H] calcd for C H N O 249.0665, found
15
8
2
2
(
°
hexanes:EtOAc, 5:5); yellow solid (106 mg, 87%): mp 182−184
C; IR (KBr) 3415, 1672, 1564 cm ; H NMR (400 MHz,
−1
1
249.0664.
9-Methoxy-5H-pyrido[4,3-b]carbazole-5,11(6H)-dione (22).
CDCl +DMSO-d ) δ 8.98 (s, br, 1H), 7.73 (d, J = 8.0 Hz, 1H),
3
6
R = 0.46 (hexanes:EtOAc, 6:4); orange red solid (66 mg, 78%): mp
f
7
.64−7.55 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.39−7.35 (m, 2H), 7.27
−
1
1
13
>300 °C; IR (KBr) 3356, 1651 cm ; H NMR (400 MHz,
CDCl +DMSO-d ) δ 12.53 (s, br, 1H), 9.06 (s, 1H), 8.67 (d, J =
(
(
1
m, 1H), 7.20−7.11 (m, 2H); note −COOH not observed; C NMR
3
6
100 MHz, CDCl +DMSO-d ) δ 190.9, 163.4, 152.7, 150.7, 137.1,
3
6
4
.4 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J = 8.8 Hz,
37.0, 135.8, 128.3, 127.0, 124.2, 123.1, 121.8, 119.9, 112.3, 107.6;
13
+
1H), 6.74 (d, J = 8.8 Hz, 1H), 3.59 (s, 3H); C NMR (125 MHz,
CDCl +DMSO-d ) δ 187.0, 185.8, 155.2, 154.3, 149.7, 147.5, 136.3,
HRMS (ESI) [M + H] calcd for C H N O 267.0770, found
15
10
2
3
3
6
2
67.0767.
Ethyl 5-methoxy-3-nicotinoyl-1H-indole-2-carboxylate (21).
R = 0.50 (hexanes:EtOAc, 4:6); bright yellow solid (139 mg, 94%):
1
35.9, 130.9, 126.9, 123.1, 119.1, 117.0, 114.7, 113.9, 54.8; HRMS
+
(ESI) [M + H] calcd for C H N O 279.0769, found 279.0768.
16 10 2 3
f
5
H-Pyrido[3,4-b]carbazole-5,11(10H)-dione (26). R = 0.51
−1
1
f
mp 188−190 °C; IR (KBr) 3382, 1678, 1338, 1116 cm ; H NMR
(
3
9
hexanes:EtOAc, 5:5); red solid (57 mg, 64%): mp >300 °C; IR (KBr)
396, 1665 cm ; H NMR (400 MHz, DMSO-d ) δ 12.32 (s, br, 1H),
.34 (s, 1H), 9.07 (d, J = 4.8 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.03
(
400 MHz, CDCl ) δ 10.32 (s, br, 1H), 9.04 (d, J = 1.2 Hz, 1H),
−1 1
3
6
8
.80−8.79 (m, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.46−7.42 (m, 1H), 7.37
(
d, J = 8.8 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.05−7.02 (dd, J = 1.6
1
(
d, J = 5.2 Hz, 1H), 7.65 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.39 (t, J =
Hz, J = 7.2 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 0.85 (t, J =
13
2
7
1
1
2
.6 Hz, 1H); C NMR (100 MHz, CDCl +DMSO-d ) δ 178.0, 176.2,
13
3 6
7
1
1
.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ 191.5, 160.8, 156.3,
3
59.6, 154.4, 149.2, 137.4, 135.6, 129.6, 128.3, 126.1, 123.1, 122.9,
52.5, 150.6, 136.4, 135.6, 131.0, 128.1, 127.9, 123.4, 118.5, 117.9,
+
21.5, 118.0, 112.8; HRMS (ESI) [M + H] calcd for C H N O
13.2, 101.3, 61.6, 55.6, 13.4; HRMS (ESI) [M + H]+ calcd for
15
8
2
2
49.0665, found 249.0658.
-Methoxy-5H-pyrido[3,4-b]carbazole-5,11(10H)-dione (27).
R = 0.44 (hexanes:EtOAc, 6:4); orange red solid (61 mg, 71%): mp
C H N O 325.1189, found 325.1188.
18
16
2
4
7
Ethyl 3-isonicotinoyl-1H-indole-2-carboxylate (24). R = 0.48
f
f
(
°
hexanes:EtOAc, 3:7); pale yellow solid (143 mg, 92%): mp 182−184
−1
1
>
300 °C; IR (KBr) 3383, 1661 cm ; H NMR (400 MHz,
−1 1
C; IR (KBr) 3387, 1645, 1564 cm ; H NMR (400 MHz, CDCl ) δ
3
CDCl +DMSO-d ) δ 12.87 (s, br, 1H), 9.39 (s, 1H), 9.02 (d, J =
3
6
9
7
7
.86 (s, br, 1H), 8.51 (d, J = 4.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H),
.41−7.40 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.15−7.11 (m, 1H),
.01−6.97 (m, 1H), 3.75 (q, J = 7.2 Hz, 2H), 0.62 (t, J = 7.2 Hz, 3H);
5
8
.2 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H), 7.71−7.57 (m, 1H), 7.51 (d, J =
13
.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H); C NMR (100
MHz, CDCl +DMSO-d ) δ 175.6, 174.3, 155.2, 152.3, 149.7, 147.5,
3
6
1
3
C NMR (100 MHz, CDCl ) δ 191.7, 160.8, 150.3 (2C), 146.1,
3
135.9, 130.9, 126.9, 126.5, 123.1, 119.1, 117.0, 114.7, 113.9, 55.1;
+
1
1
2
35.6, 127.5, 127.3, 126.4, 122.8, 122.3 (2C), 121.9, 118.0, 112.1, 61.7,
HRMS (ESI) [M + H] calcd for C H N O 279.0769, found
16
10
2
3
+
3.4; HRMS (ESI) [M + H] calcd for C H N O 295.1083, found
17
14
2
3
279.0768.
H-Pyrido[3,2-b]carbazole-5,11(6H)-dione (30). Rf = 0.48
hexanes:EtOAc, 6:4); red solid (52 mg, 62%): mp >300 °C; IR
95.1082.
Ethyl 3-isonicotinoyl-5-methoxy-1H-indole-2-carboxylate
25). R = 0.50 (hexanes:EtOAc, 5:5); bright yellow solid (140 mg,
5
(
(
9
−1 1
f
(KBr) 3411, 1661 cm ; H NMR (400 MHz, CDCl +DMSO-d ) δ
3 6
−1 1
5%): mp 180−182 °C; IR (KBr) 3383, 1645 cm ; H NMR (400
1
2.27 (s, br, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.75 (d, J = 6.0 Hz, 1H),
MHz, CDCl ) δ 9.72 (s, br, 1H), 8.82 (s, 2H), 8.04−7.97 (m, 1H),
7
8
3
8.27 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 4.8 Hz, 1H), 7.63−7.61 (m, 1H),
.70 (d, J = 4.0 Hz, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.10−7.07 (dd, J =
.4 Hz, J = 2.4 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 0.89
13
1
7.43 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H); C NMR (100
2
MHz, CDCl +DMSO-d ) δ 180.0, 178.6, 157.1, 149.6, 137.8, 136.3,
3
6
13
(
t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ 191.7, 160.7,
3
129.9, 128.5, 127.1, 126.8, 124.1, 123.5, 123.0, 118.3, 112.8; HRMS
+
1
1
56.6, 149.8 (2C), 147.0, 141.5, 132.8, 130.7, 128.2, 127.9, 122.5,
18.7 (2C), 113.1, 61.8, 55.6, 13.4; HRMS (ESI) [M + H] calcd for
(
ESI) [M + H] calcd for C H N O 249.0665, found 249.0661.
15 8 2 2
+
Synthesis of Diethyl 3,3′-((2-methylpyridin-3-yl)methylene)-
C H N O 325.1189, found 325.1188.
bis(1H-indole-2-carboxylate) (32). To a solution of 11 (1 mmol)
18
16
2
4
Ethyl 3-picolinoyl-1H-indole-2-carboxylate (29). R = 0.53
in dry DCM (20 mL) was added anhydrous AlCl (1.1 mmol), and the
f
3
(
hexanes:EtOAc, 6:4); yellow solid (141 mg, 91%): mp 160−162 °C;
mixture was stirred for 30 min at room temperature under nitrogen
atmosphere. 2-Methylnicotinaldehyde 31 (1 mmol) in dry DCM (10
mL) was added to the mixture and stirred for 2 h at room temperature.
After completion of the reaction, ice cold water was added, extracted
with ethyl acetate (3 × 50 mL), and dried over anhydrous Na SO .
−1 1
IR (KBr) 3378, 1671 cm ; H NMR (400 MHz, CDCl ) δ 9.55 (s, br,
3
1
2
1
H), 8.63−8.62 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.95−7.89 (m,
H), 7.47−7.41 (m, 2H), 7.35−7.31 (m, 1H), 7.23 (d, J = 8.0 Hz,
13
H), 3.96 (q, J = 7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H); C NMR (100
2
4
MHz, CDCl ) δ 191.8, 161.3, 156.2, 148.6, 136.9, 135.4, 129.0, 127.6,
The solvent was removed, and crude material was purified by column
3
7
39
dx.doi.org/10.1021/jo402593w | J. Org. Chem. 2014, 79, 736−741

The Journal of Organic Chemistry
Article
chromatography to afford the title compound. Rf = 0.33
125.4, 122.6, 120.8, 111.9, 108.8, 36.8, 20.6; HRMS (ESI) [M + H]+
calcd for C H N O 249.1028, found 249. 1030.
(
1
9
hexanes:EtOAc, 5:5); pale yellow solid (208 mg, 82%): mp 192−
16
12
2
−1 1
94 °C; IR (KBr) 3349, 1567 cm ; H NMR (400 MHz, CDCl ) δ
Synthesis of 1,5-Dimethyl-6H-pyrido[4,3-b]carbazole (Oliva-
cine) (8). To a freshly prepared MeMgI (about 2−3 mmol) in dry
THF (10 mL), the compound 35 (1 mmol) in dry THF (5 mL) was
added at 0 °C, and after 30 min at room temperature, the solution was
3
.08 (s, br, 2H), 8.43 (d, J = 4.4 Hz, 1H), 7.45 (s, 1H), 7.39 (t, J = 7.6
Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.26−7.24 (m, 1H), 7.18 (t, J = 7.6
Hz, 1H), 7.04−7.01 (m, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.73−6.65 (m,
then refluxed for 6 h. Then, saturated aqueous NH Cl solution (30
1
1
H), 6.52 (d, J = 8.4 Hz, 1H), 4.31−4.21 (m, 4H), 2.38 (s, 3H), 1.28−
4
.21 (m, 6H); note aliphatic methine proton (CH) not observed; 13
mL) was added and extracted with ethyl acetate (3 × 20 mL). The
organic layer was concentrated and gave a brown oil, which was again
C
NMR (100 MHz, CDCl ) δ 162.0, 161.6, 157.6, 146.8 (2C), 138.0,
3
dissolved in dry THF (7 mL). To this, NaBH (3 mmol) followed by
136.3 (2C), 135.9, 135.7, 128.0, 127.8, 125.2, 125.0, 124.8, 124.4,
4
AlCl (1 mmol) were added and stirred for 3 h at room temperature.
3
1
23.7, 122.3, 122.2, 121.0, 120.8 (2C), 120.3, 112.1, 111.8, 60.9, 37.8,
+
Then, the solution was poured into ice water, extracted with ethyl
32.3, 14.1; HRMS (ESI) [M + H] calcd for C H N O 482.2081,
29
27
3
4
acetate, washed with brine, and dried over anhydrous Na SO . After
2
4
found 482.2079.
removal of the solvent, the crude was purified by silica gel column
Synthesis of Ethyl 3-(2-methylnicotinoyl)-1H-indole-2-car-
boxylate (33). To a solution of 11 (1 mmol) and 31 (1 mmol) in
MeOH (30 mL), TMG (1.5 mmol) was added, and the mixture was
stirred for 8 h at room temperature. After completion of the reaction,
distilled water (100 mL) was added and extracted with ethyl acetate (3
chromatography afforded the title compound. R = 0.43 (hexanes:E-
f
tOAc, 7:3); dark yellow solid (43 mg, 58%): mp >300 °C; IR (KBr)
−
1 1
3
8
1
362, 1345 cm ; H NMR (400 MHz, DMSO-d ) δ 9.91 (s, br, 1H),
6
.39 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 6.4 Hz, 1H), 7.82 (d, J = 6.4 Hz,
H), 7.54−7.52 (m, 2H), 7.26 (ddd, J = 7.6, 5.2, and 1.6 Hz, 2H), 3.05
×
60 mL). After removal of the solvent, crude material obtained was
(
s, 3H), 2.93 (s, 3H); 13C NMR (100 MHz, DMSO-d ) δ 156.6, 147.9,
6
dissolved in DMSO (10 mL), and IBX was added (1.5 mmol). The
whole mixture was stirred at room temperature for 4 h. The reaction
was monitored by TLC. Then water (75 mL) was added, extracted
1
1
2
43.8, 138.8, 132.9, 127.7, 126.4, 123.8, 122.8, 120.8, 119.2, 116.9,
+
16.3, 110.5, 110.4, 21.4, 13.2; HRMS (ESI) [M] calcd for C H N
1
7
14
2
46.1157, found 246.1156.
Synthesis of Ethyl 3-(quinoline-3-carbonyl)-1H-indole-2-
with ethyl acetate (3 × 40 mL), and washed with saturated aq. NH Cl
4
solution. After removal of the solvent, the crude was purified by silica
carboxylate (37). We followed the same procedure used for the
compound 32 except oxidation step. Instead of IBX, DMP (1.5 mmol)
gel column chromatography to give the title compound. R = 0.58
f
(
°
(
hexanes:EtOAc, 6:4); pale yellow solid (683 mg, 84%): mp 162−164
in DCM/AcOH (9:1) was used. R = 0.56 (hexanes:EtOAc, 2:8); red
f
−1 1
C; IR (KBr) 3381, 1673 cm ; H NMR (400 MHz, CDCl ) δ 10.52
−1 1
3
solid (145 mg, 80%): mp 212−214 °C; IR (KBr) 3385, 1650 cm ; H
NMR (400 MHz, CDCl ) δ 9.83 (s, br, 1H), 8.95 (s, 1H), 8.51 (s,
s, br, 1H), 8.85 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.17 (d,
3
J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.50−7.48 (m, 1H), 7.45−
.42 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.05 (q, J = 7.6 Hz, 2H), 2.33
s, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl ) δ
1
H), 8.23 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 8.0
7
Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.45 (t, J =
6.8 Hz, 1H), 7.39 (d, J = 4.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 4.12 (q,
J = 7.2 Hz, 2H), 1.26 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
(
3
1
1
91.2, 160.8, 157.8, 154.4, 136.4, 135.1, 131.3, 127.2, 127.1, 126.2,
23.4, 122.5, 121.7, 118.5, 112.1, 61.5, 32.4, 13.4; HRMS (ESI) [M +
CDCl ) δ 192.9, 161.9, 150.4, 149.9, 147.5, 144.7, 143.3, 136.7, 130.2,
3
+
H] calcd for C H N O 309.1240, found 309.1243.
130.0, 129.6, 129.4, 129.3, 128.3, 126.4, 125.8, 124.4, 123.8, 121.8,
18
16
2
3
+
Synthesis of 3-((2-Methylpyridin-3-yl)methyl)-1H-indole-2-
carboxylic acid (34). To a solution of 32 (1 mmol) in 25 mL of
ethylene glycol (EG), KOH (2.5 mmol) and hydrazine hydrate (3
mmol) were added. The mixture was refluxed for 2 h and diluted with
water (100 mL). The aqueous layer was treated with 1 N HCl and
brought up to pH 1. Then, the reaction mixture was extracted with
ethyl acetate (3 × 30 mL), washed with brine, and dried over
anhydrous Na SO . The crude material obtained was purified by silica
60.9, 14.2; HRMS (ESI) [M + H] calcd for C H N O 345.1234,
21
16
2
3
found 345.1239.
Synthesis of 7H-Indolo[3,2-j ]phenanthridine-7,13(12H)-
dione (Calothrixin B) (10). We followed the same procedure used
for the synthesis of ellipticine quinones. R = 0.45 (hexanes:EtOAc,
f
8:2); red solid (41 mg, 48%): mp >300 °C; IR (KBr) 3389, 1653
−
1 1
cm ; H NMR (400 MHz, DMSO-d ) δ 12.94 (s, br, 1H), 9.63 (s,
6
1H), 9.47 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 6.4 Hz, 2H), 7.84 (t, J = 8.0
Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 7.41 (t, J =
7.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-
2
4
gel column chromatography to afford the title compound. R = 0.51
f
(
°
(
hexanes:EtOAc, 3:7); pale yellow solid (384 mg, 89%): mp 174−176
−1 1
C; IR (KBr) 3364, 1632 cm ; H NMR (400 MHz, CDCl ) δ 10.31
d
6
) δ 181.1, 180.7, 151.7, 147.9, 138.9, 138.4, 133.1, 132.1, 130.7,
30.3, 127.5, 125.3 (2C), 124.5, 123.7, 123.1, 122.8, 116.2, 114.4;
3
1
s, br, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.96 (d,
+
HRMS (ESI) [M + H] calcd for C H N O 299.0821, found
J = 8.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 5.2 Hz, 1H), 7.16
t, J = 8.0 Hz, 1H), 7.05−7.00 (m, 1H), 4.20 (s, 2H), 2.36 (s, 3H);
19 10
2
2
2
99.0823.
(
1
3
note −COOH not observed; C NMR (100 MHz, CDCl ) δ 163.9,
1
1
3
54.5, 150.6, 135.6, 135.2, 131.5, 127.3, 126.3, 124.2, 123.5, 122.6,
21.8, 118.6, 112.2, 35.8, 19.8; HRMS (ESI) [M + H] calcd for
ASSOCIATED CONTENT
+
■
*
S
Supporting Information
C H N O 267.1133, found 267.1113.
16
14
2
2
Characterization data ( H, 13C NMR, mass spectra, crystallo-
graphic structures). This material is available free of charge via
the Internet at http://pubs.acs.org.
1
Synthesis of 1-Methyl-6,11-dihydro-5H-pyrido[4,3-b]-
carbazol-5-one (35). A schlenck tube was charged with freshly
distilled diisopropylamine (5 mmol) in dry THF (20 mL) under
nitrogen atmosphere and fitted with rubber septum. 1.6 M n-BuLi in
hexanes (7.5 mmol) was added to it at −78 °C, followed by the
addition of HMPA (2.5 mmol) and stirred for 15 min. The acid 33 (1
mmol) in dry THF (5 mL) was added to the mixture via rubber
septum and maintained the same temperature for 3 h. After
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail: rnsc@uohyd.ernet.in.
completion, saturated aqueous NH Cl solution (30 mL) was added
4
Notes
and extracted with ethyl acetate (3 × 30 mL). The solvent was
removed and purified by silica gel column chromatography to give the
The authors declare no competing financial interest.
title compound. R = 0.41 (hexanes:EtOAc, 5:5); pale yellow solid
f
−
1
1
(
100 mg, 36%): mp 242−244 °C; IR (KBr) 3421, 1678 cm ; H
NMR (400 MHz, CDCl ) δ 9.16 (s, br, 1H), 8.16 (d, J = 7.2 Hz, 1H),
ACKNOWLEDGMENTS
■
3
We gratefully acknowledge DST for financial support (Project
No. SR/S1/OC-70/2008). N.R. thanks CSIR, New Delhi, for
senior research fellowship and contingency grant.
7
7
.45 (d, J = 8.0 Hz, 1H), 7.36−7.32 (m, 1H), 7.26−7.25 (m, 2H),
13
.19−7.15 (m, 1H), 3.67 (s, 2H), 2.21 (s, 3H); C NMR (100 MHz,
CDCl ) δ 177.4, 155.1, 151.7, 147.1, 142.4, 136.9, 131.9, 127.4, 127.1,
3
7
40
dx.doi.org/10.1021/jo402593w | J. Org. Chem. 2014, 79, 736−741

The Journal of Organic Chemistry
Article
(
14) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N.
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dx.doi.org/10.1021/jo402593w | J. Org. Chem. 2014, 79, 736−741