Total synthesis of calothrixin B and its analogs

Article abstract of DOI:10.1002/ejoc.201301524

The total synthesis of calothrixin B and its analogs was achieved starting from 2-methylindole. The synthesis involved an electrocyclization of 2-nitroarylvinyl-3-phenylsulfonylvinylindoles as a key step to give 2-nitroaryl-4-methoxy-3-methylcarbazoles. Oxidation of these compounds followed by reductive cyclization led to N-phenylsulfonylquinocarbazoles. These quinocarbazoles underwent hydrolysis and aerial oxidation in one pot to give the target compounds. A linear synthesis of calothrixin B and its analogs has been established from commercially available 2-methylindole. The thermal electrocyclization of 2-nitroarylvinyl-3-phenylsulfonylindole was a key step in the synthesis. The synthesis of calothrixin B and its analogs was achieved in 12-22 % overall yield over twelve steps. Copyright

Full text of DOI:10.1002/ejoc.201301524

FULL PAPER
DOI: 10.1002/ejoc.201301524
Total Synthesis of Calothrixin B and Its Analogs
Velu Saravanan,[a] Bose Muthu Ramalingam,[a] and Arasambattu K. Mohanakrishnan*[a]
Keywords: Total synthesis / Natural products / Alkaloids / Nitrogen heterocycles / Electrocyclic reactions / Cyclization
The total synthesis of calothrixin B and its analogs was
achieved starting from 2-methylindole. The synthesis in-
volved an electrocyclization of 2-nitroarylvinyl-3-phenylsulf-
onylvinylindoles as a key step to give 2-nitroaryl-4-methoxy-
3-methylcarbazoles. Oxidation of these compounds followed
by reductive cyclization led to N-phenylsulfonylquinocarb-
azoles. These quinocarbazoles underwent hydrolysis and
aerial oxidation in one pot to give the target compounds.
dole-3-carbaldehyde.[6] Two years later, Chai and co-
workers reported[7] a simple and concise route to cal-
othrixin B involving a Friedel–Crafts reaction between N-
magnesium indole and methyl 3-(chlorocarbonyl)quinoline-
2-carboxylate, followed by cyclization using the lithiation
procedure. Compared to Kelly’s method, the procedure de-
veloped by Chai and co-workers gave calothrixin B in a
better yield.
Hibino and co-workers[8] reported a multi-step synthesis
of calothrixin B in which the key intermediate, 4-methoxy-
2-nitroarylcarbazole, was obtained by an allene-mediated
electrocyclization. Hibino and co-workers[9] also achieved
the synthesis of calothrixin B by stepwise oxidations of 6-
methylindolo[2,3-b]carbazole using DDQ (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone) and CAN [cerium(IV) ammo-
nium nitrate].
Sissouma et al. reported[10] an efficient synthesis of cal-
othrixin B. In their synthesis, an imino-Diels–Alder reac-
tion between 3-bromocarbazole-1,4-dione and N,N-di-
methyl-NЈ-(4-oxocyclohex-2-enyl)formamide was used to
assemble the core skeleton of the natural product. A synthe-
sis of calothrixin B involving an intramolecular radical cy-
clization of a 3-(3-quinolyl)methyl-2-indolylacyl selenoester
followed by aerial oxidation under basic conditions was re-
alized by Bennasar and co-workers.[11]
Introduction
The synthesis and biological activities of carbazole alk-
aloids were extensively reviewed by Knölker and co-
workers.[1] Calothrixin A (1) and calothrixin B (2), two of
these carbazole alkaloids, are classified as quinolino[3,4-b]-
carbazole-1,4-quinone alkaloids (Figure 1). The calothrix-
ins were isolated from photoautotrophic cultures of
Calothrix cyanobacteria by Rickards et al. in 1999,[2] and
the unique pentacyclic indolo[3,2-j]phenanthridine ring
structure was confirmed by single-crystal analysis of cal-
othrixin A (1). Calothrixins A (1) and B (2) inhibit human
HeLa cancer cells and Plasmodium falciparum at nanomo-
lar concentrations. Recently, Matsumoto et al. reported the
synthesis and antimalarial activity of calothrixins as well as
their N-alkyl derivatives.[3] To elucidate the mechanism of
action of the calothrixins, several structurally related quin-
ones were synthesized and tested for their cytotoxicity.[4]
However, the precise mode of action for the cytotoxic ac-
tivity of calothrixins has not been fully explained.[5]
Moody and co-workers outlined a biomimetic approach
to calothrixin B starting from indigo and involving an oxi-
dative transformation of 6-hydroxyindolo[2,3-a]carbazole-
5-carbaldehyde to give the indolo[3,2-j]phenathridine.[12]
Abe et al. reported[13] a synthesis of calothrixin B involving
an indole-based triene intermediate obtained by a Pd-cata-
lyzed tandem cyclization/cross-coupling reaction followed
by a Cu(OTf)2-mediated 6π-electrocyclization. The re-
sulting indolo[3,2-j]phenanthridine core gave, after success-
ive oxidations, calothrixin B.
Figure 1. Calothrixins A and B.
In 2000, Kelly et al. described the first synthesis of
calothrixins involving a one-pot double-lithiation protocol
in which the crucial indolo[3,2-j]phenanthridine framework
was constructed from N,N-diethyl-quinolinolin-4-carbox-
amide and MOM-protected (MOM = methoxymethyl) in-
[a] Department of Organic Chemistry, University of Madras,
Guindy Campus,
The partial synthesis of calothrixin B was achieved by
Kusurkar and co-workers.[14] Their route involved a Pd-me-
diated intramolecular arylation of 1,4-(dimethoxycarbazol-
3-yl)methyl-N-(2-iodophenyl)acetamide. Very recently,
Chennai 600025, Tamil Nadu, India
E-mail: mohanakrishnan@unom.ac.in
www.unom.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301524.
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Total Synthesis of Calothrixin B and Its Analogs
Nagarajan and Ramkumar reported[15] a synthesis of cal-
othrixin B in which the crucial indolo[3,2-j]phenanthridine
core was achieved by Pd-mediated intramolecular arylation
of N-(2-iodophenyl)-4-methoxycarbazole-3-carboxamide.
Results and Discussion
As part of our studies of Lewis-acid-mediated domino
reactions,[16] we recently reported a synthesis of calothrixin
B and its analogs involving an FeCl3-mediated domino re-
action of enamines.[17] Prior to this report on calothrixin B,
syntheses of quino[4,3-b]carbazole[18] and indolo[2,3-a]-
carbazole[19] using a thermal electrocyclization strategy
were also achieved in our lab. In this paper, we report a
linear synthesis of calothrixin B and its analogs using the
thermal electrocyclization of 2-nitroarylvinyl-3-phenylsulf-
onylvinylindole as a key step.
Scheme 2. Synthesis of 4-methoxy-2-nitrophenylcarbazoles.
Our strategy for the synthesis of calothrixin B is shown
in Scheme 1. Thermal electrocyclization of 2,3-divinylindole
4, with concomitant loss of the phenylsulfonyl unit, leads
to 4-methoxy-2-nitroarylcarbazole 5. A chemoselective for-
mylation of the carbazole 5 followed by reductive cycliza-
tion and hydrolysis may give calothrixin B and its analogs
6.
as a single product in better yield. We also reasoned that
the transformation of 3-methylcarbazole 10a into the corre-
sponding aldehyde may be easier than the regioselective for-
mylation of carbazole 11 proposed in Scheme 1. Accord-
ingly, the selective N-phenylsulfonylation of 2-methylindole
(12) was achieved using N-phenylsulfonylbenzotriazole
(13)[21] as a phenylsulfonylating agent with NaH in dry
THF. Next, to our surprise, the known propionylation of 2-
methyl-1-phenylsulfonylindole (14) using propionic an-
hydride (15) in the presence of AlCl3 at 0 °C following the
published procedure[22] led to the formation of 3-prop-
ionylindole 16 and chlorovinylindole 17 in a 3:1 ratio
(Scheme 3).
Scheme 1. Proposed synthetic pathway to calothrixin B and its ana-
logs.
We started our synthesis of calothrixin B from the known
1-phenylsulfonyl-2-nitrophenylvinylindole 7.[17] α-Bromin-
ation of 2-nitroaryl-3-acetylindole 7 using phenyltrimeth-
ylammonium tribromide (PTT)[20] in dry THF gave bromo
compound 8. The reaction of bromo compound 8 with so-
dium phenylsulfinate in DMF gave sulfone 9 as a pale yel-
low solid. Further reaction of β-keto sulfone 9 with di-
methyl sulfate in the presence of K2CO3 in dry THF, fol-
lowed by thermal electrocyclization of the resulting 2,3-di-
vinylindoles in xylenes at reflux, led to the formation of a
mixture of carbazoles 10a and 11 (Scheme 2).
Scheme 3. Synthesis of 2-bromomethyl-3-propionylindole.
The formation of chlorovinylindole 17 under Friedel–
All our attempts to perform a selective O/C-methylation Crafts conditions is surprising. However, a similar chlorin-
of β-keto sulfone 9 by changing the solvent and the methyl- ation during the Friedel–Crafts reaction of anisole with 4-
ating agent were unsuccessful. Furthermore, separation of methoxyphenylacetyl chloride using ZnCl2/SiO2 has been
carbazoles 10a and 11 by column chromatography was also reported.[23] Finally, a straightforward 3-propionylation of
found to be tedious. Hence, we decided to slightly modify 14 to give 2-methyl-1-phenylsulfonylindole 16 without the
the route shown in Scheme 2 to produce the carbazole 10a undesired formation of 17 was achieved by using BF3·OEt2
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FULL PAPER
as the catalyst. Next, benzylic bromination of 2-methylind- carbazoles 23a–23e, upon oxidation[24] using bis(tetrabutyl-
ole 16 using NBS (N-bromosuccinimide) and a catalytic ammonium) dichromate (TBAD) in refluxing CHCl3, gave
amount of AIBN (azobisisobutyronitrile) in CCl4 led to the the respective carbazole-3-aldehydes (i.e., 24a–24e;
formation of bromomethylindole 18[22] in excellent yield Scheme 5). Next, reductive cyclization of 2-nitroaryl-3-
(Scheme 3).
carbazole aldehyde 24a using Raney Ni in refluxing acetone
The further transformation of 2-bromomethyl-3-prop- gave quinocarbazole 25 (Scheme 5). Unfortunately, the fur-
ionylindole 18 into carbazoles 10a–10e is shown in ther demethylation of quinocarbazole 25 could not be car-
Scheme 4. The reaction of bromo compound 18 with tri- ried out, due its poor solubility in CH2Cl2.
phenylphosphine, followed by Wittig reaction of the re-
sulting phosphonium salt with 2-nitroaryl aldehydes 19a–
19e[17] in the presence of K2CO3 in CH2Cl2 at room tem-
perature, gave 2-nitroarylvinyl-3-propionyl indoles 20a–20e
in excellent yields.
Scheme 5. Synthesis of 2-nitroarylcarbazole-3-carbaldehyde and
quinocarbazole.
The structures of representative 2-nitroarylcarbazoles
10b (Figure 2) and 24b (Figure 3) were confirmed by single-
crystal X-ray analysis.
Scheme 4. Synthesis of 2-nitroaryl-4-methoxy-3-methylcarbazoles.
As expected, α-bromination of 3-propionoylindoles 20a–
20e, followed by reaction of resulting bromo compounds
21a–21e with sodium phenyl sulfinate, gave the respective
sulfones (i.e., 22a–22e). Next, O-methylation of β-keto sulf-
ones 22a–22e using dimethyl sulfate in the presence of
K2CO3 in THF, followed by thermal electrocyclization of
the resulting trienes in xylenes at reflux, led to the isolation
Figure 2. X-ray crystal structure of compound 10b.
of
2-nitroaryl-4-methoxy-3-methylcarbazoles
10a–10e
(Scheme 4).
The insoluble nature of quinocarbazole 25 prompted us
With the required 2-nitroaryl-4-methylcarbazoles (i.e., to cleave the methyl ether of carbazole aldehydes 24a–24e
10a–10e) in hand, we continued with the synthetic sequence before the formation of the quinocarbazole framework. As
towards calothrixin B. Benzylic bromination of carbazoles expected, carbazole aldehydes 24a–24e underwent straight-
10a–10e using NBS (3 equiv.) in the presence of AIBN in forward demethylation upon treatment with BBr3 (1 m) in
refluxing CCl4 gave the corresponding 3-bromomethylcarb- CH2Cl2 at 0 °C to give 4-hydroxy-2-nitroarylcarbazole-3-
azoles (i.e., 23a–23e) in excellent yields. (Bromomethyl)- carbaldehydes 26a–26e[17] (Scheme 6). N-Phenylsulfonyl-
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Total Synthesis of Calothrixin B and Its Analogs
The formation of calothrixins A (1) and B (2) can be
envisaged to occur via the respective quinocarbazoles (i.e.,
30 and 31; Scheme 7). The intermediacy of quinocarbazole
structures 30 and 31 was supported by HRMS data (see
Exp. Section).
Figure 3. X-ray crystal structure of compound 24b.
carbazole aldehyde 26a was then desulfonylated using
NaOH (50% aq.) in DMSO to give known carbazole alde-
hyde 27[8] in 95% yield. Next, we planned to convert carb-
azole aldehyde 27 into calothrixin B (2) was planned by
using Hibino’s procedure.[8] To our surprise, reductive cycli-
zation of carbazole aldehyde 27 in the presence of Pd/C
(10%) under H2 (balloon), followed by oxidation of the re-
sulting 13-hydroxyquinocarbazoles using CAN in CH3CN/
H2O, led to the formation of calothrixins A (1) and B (2)
in a 1:1 ratio (Scheme 6). Alternatively, reductive cyclization
of 27 under Hibino’s conditions [Pd/C (10%) under H2],
followed by oxidation of the 13-hydroxyquinocarbazoles
using Frémy’s[25] salt, also gave a mixture of calothrixins A
(1) and B (2).
Scheme 7. Proposed mechanism for the formation of calothrixins
A and B.
To overcome the partial reduction of the nitro group, the
reductive cyclization of 4-hydroxy-2-nitroarylcarbazole-3-
[26]
carbaldehydes 26a–26e was carried out using Fe/CaCl2
in EtOH/H2O at reflux to give quinocarbazoles 32a–32e in
72–88% yields (Scheme 8). To complete the total synthesis
of calothrixin B (2) and its analogs 33b–33e, quinocarb-
azoles 32a–32e were subjected to a one-pot hydrolysis/oxi-
dation using NaOH (25% aq.) under an O2 atmosphere.
Scheme 6. Synthesis of calothrixins A and B.
Scheme 8. Synthesis of calothrixin B and its analogs.
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V. Saravanan, B. Muthu Ramalingam, A. K. Mohanakrishnan
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sulfone 9 (0.52 g, 94%) as a pale yellow solid, m.p. 204–206 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 8.1 Hz, 1 H, Ar), 8.13
(d, J = 7.8 Hz, 1 H, Ar), 7.96 (d, J = 7.5 Hz, 1 H, Ar), 7.85–7.72
(m, 4 H, Ar), 7.66–7.50 (m, 6 H, Ar), 7.43–7.31 (m, 6 H, Ar), 7.04
(d, J = 15.9 Hz, 1 H, vinylic), 4.80 (s, 2 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 186.2, 147.8, 141.4, 138.6, 137.6, 136.0,
135.7, 134.7, 134.3, 134.1, 131.3, 130.2, 129.5, 129.4, 129.0, 128.2,
127.8, 126.8, 126.7, 125.5, 125.3, 123.0, 122.0, 121.6, 114.4,
66.6 ppm. DEPT-135 (75 MHz, CDCl3): δ = 136.0, 134.7, 134.4,
134.1, 130.2, 129.5, 129.4, 129.1, 128.2, 126.8, 126.7, 125.5, 125.3,
123.0, 121.6, 114.4, 66.5 ppm. HRMS (EI): calcd. for
C30H22N2O7S2 [M]+ 586.0868; found 586.0860.
Conclusions
In summary, we have achieved the linear synthesis of cal-
othrixin B and its analogs from commercially available 2-
methylindole. The thermal electrocyclization of 2-nitroaryl-
vinyl-3-phenylsulfonylvinylindole was a key step in the syn-
thesis. The method described in this paper, using 2,3-divin-
ylindoles bearing an easily removed phenylsulfonyl unit,
gave the 2-nitroarylcarbazoles in better yields than those
obtained with our earlier procedure,[18,19] in which the ther-
mal electrocyclization of 2,3-divinylindoles was carried out
in the presence of Pd/C. The synthesis of calothrixin B and
its analogs was achieved in 12–22% overall yield over
twelve steps.
4-Methoxy-3-methyl-2-(2-nitrophenyl)-9-(phenylsulfonyl)-9H-carb-
azole (10a) and 4-Methoxy-2-(2-nitrophenyl)-9-(phenylsulfonyl)-9H-
carbazole (11): A mixture of sulfone 9 (0.2 g, 0.34 mmol), dimethyl
sulfate (0.47 g, 3.41 mmol), and K2CO3 (0.21 g, 1.70 mmol) in dry
THF (10 mL) was stirred at room temperature for 24 h. After the
reaction was complete (monitored by TLC), the mixture was
poured onto crushed ice (100 g). The resulting solid was filtered
and dried (CaCl2) to give the enol ether. Then, the crude enol ether
was dissolved in xylenes (20 mL) and the mixture was heated at
reflux for 24 h. Removal of xylenes in vacuo followed by column
chromatographic purification (silica gel; hexane/ethyl acetate, 9:1)
gave carbazoles 10a and 11.
Experimental Section
General Methods: Solvents were dried by standard procedures. All
the reactions were carried out under a nitrogen atmosphere unless
otherwise stated. The progress of all the reactions was monitored
by TLC using hexane/ethyl acetate mixtures as eluent. Column
chromatography was carried out on silica gel (100–200 mesh,
Acme) or silica gel (230–400 mesh, Merck) using eluents of increas-
ing polarity. 1H, 13C, DEPT-90, and DEPT-135 NMR spectra were
recorded in CDCl3, CDCl3/[D]TFA, or [D6]DMSO, using tet-
ramethylsilane as an internal standard, with a 300 MHz spectrome-
ter at room temperature. Chemical shift (δ) values are quoted in
parts per million (ppm), and coupling constants (J) are quoted in
Hertz (Hz). IR spectra were recorded with an ABB MB3000 series
FTIR spectrometer. Elemental analysis data was recorded with an
Elementar Vario Series Analyser (IISER, Pune) instrument.
HRMS spectra were recorded with Waters-Q-Top premier-Hab 213
(ESI), GC Mate II (EI), and Varian FTMS (ESI) instruments. The
required bis(tetrabutylammonium) dichromate, N-phenylsulfonyl
benzotriazole (13), PTT, 2-nitroaryl-3-acetylindole (7), and 2-
nitroaryl aldehydes 19a–19e were prepared following reported pro-
cedures.[17,20,21,24]
Data for 10a: Colorless solid (80 mg, 52%), m.p. 174–176 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.34 (d, J = 8.1 Hz, 1 H, Ar), 8.14
(d, J = 7.2 Hz, 1 H, Ar), 8.05 (d, J = 7.8 Hz, 1 H, Ar), 7.95 (s, 1
H, Ar), 7.76 (d, J = 7.5 Hz, 2 H, Ar), 7.69 (t, J = 7.5 Hz, 1 H, Ar),
7.58 (t, J = 7.5 Hz, 1 H, Ar), 7.52–7.31 (m, 6 H, Ar), 3.90 (s, 3 H,
OCH3), 2.11 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
153.5, 149.3, 138.4 (2 C), 137.5, 137.1, 136.2, 134.0, 132.7, 132.2,
129.1, 128.7, 127.2, 126.5, 125.0 (2 C), 124.5, 124.2, 122.8, 119.7,
115.1, 111.4, 60.3, 12.7 ppm. DEPT-90 (75 MHz, CDCl3): δ =
134.0, 132.7, 132.2, 129.1, 128.7, 127.2, 126.5, 124.5, 124.2, 122.8,
115.1, 111.4 ppm. HRMS (EI): calcd. for C26H20N2O5S [M]+
472.1093; found 472.1088.
Data for 11: Thick liquid (30 mg, 22 %). 1H NMR (300 MHz,
CDCl3): δ = 8.34 (d, J = 8.4 Hz, 1 H, Ar), 8.21 (d, J = 7.5 Hz, 1
H, Ar), 7.94 (s, 1 H, Ar), 7.91 (d, J = 8.1 Hz, 1 H, Ar), 7.82 (d, J
= 7.8 Hz, 2 H, Ar), 7.68 (t, J = 7.65 Hz, 1 H, Ar), 7.58–7.53 (m, 2
H, Ar), 7.48 (t, J = 7.65 Hz, 2 H, Ar), 7.37 (t, J = 7.5 Hz, 3 H,
Ar), 6.77 (s, 1 H, Ar), 4.01 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 155.5, 149.7, 139.5, 138.0, 137.5, 137.4,
136.6, 133.9, 132.2, 132.1, 129.1, 128.4, 126.8, 126.6, 125.4, 124.2,
124.0, 123.3, 115.6, 114.6, 107.6, 105.4, 55.7 ppm. DEPT-90
(75 MHz, CDCl3): δ = 133.9, 132.2, 132.1, 129.2, 128.4, 126.8,
126.6, 124.2, 124.0, 123.3, 114.6, 107.6, 105.4 ppm. HRMS (EI):
calcd. for C25H18N2O5S [M]+ 458.0936; found 458.0930.
(E)-2-Bromo-1-[2-(2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-
ethanone (8): A solution of 2-nitrophenylvinyl-3-acetylindole 7 (1 g,
2.29 mmol) and PTT (0.92 g, 2.46 mmol) in dry THF (20 mL) was
stirred at 10 °C for 1 h. After the reaction was complete (monitored
by TLC), the mixture was poured onto crushed ice (100 g). The
resulting solid was filtered and washed with MeOH (10 mL) to give
bromo compound 8 (0.92 g, 78 %) as a yellow solid, m.p. 184–
186 °C. 1H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 7.8 Hz, 1
H, Ar), 8.12 (d, J = 7.8 Hz, 1 H, Ar), 7.95 (t, J = 6.3 Hz, 2 H, Ar),
7.80–7.72 (m, 4 H, Ar), 7.62–7.53 (m, 2 H, Ar), 7.44–7.34 (m, 4 H,
Ar), 7.19 (d, J = 15.9 Hz, 1 H, vinylic), 4.34 (s, 2 H, CH2) ppm.
13C NMR (75 MHz, CDCl3): δ = 190.8, 147.8, 140.2, 137.5, 135.9,
134.8, 134.6, 134.1, 131.3, 129.9, 129.4, 129.3, 128.0, 126.8, 126.5,
125.4, 125.1, 122.9, 121.6, 120.1, 114.5, 33.7 ppm. DEPT-135
(75 MHz, CDCl3): δ = 129.6, 129.5, 129.0, 124.8, 124.3, 124.1,
121.6, 121.4, 120.2, 120.0, 117.7, 116.5, 109.3, 28.6 ppm. HRMS
(EI): calcd. for C24H17BrN2O5S 524.0042; found 524.0040.
2-Methyl-1-(phenylsulfonyl)-1H-indole (14): NaH (7.6 g, 190 mmol)
was washed with hexane (25 mL) and suspended in dry THF
(50 mL) at 0 °C under N2. A solution of 2-methylindole (12; 10 g,
76 mmol) in dry THF (75 mL) was added dropwise. The mixture
was heated at reflux for 1 h, and then it was allowed to cool to
room temperature. A solution of N-sulfonyl benzotriazole (13;[21]
23.72 g, 91 mmol) in dry THF (150 mL) was added dropwise to
(E)-1-[2-(2-Nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-2-(phenyl- this mixture at 10 °C over 15 min, and then the resulting mixture
sulfonyl)ethanone (9): Sodium phenyl sulfinate (0.32 g, 1.90 mmol)
was added to a solution of α-bromomethylindole 8 (0.5 g,
0.95 mmol) in DMF (10 mL), and the mixture was stirred at room
temperature for 3 h. After the reaction was complete (monitored
by TLC), the mixture was poured onto crushed ice (100 g). The
resulting solid was filtered and washed with MeOH (10 mL) to give
was stirred at room temperature for a further 10 min. After the
reaction was complete (monitored by TLC), the mixture was
poured into ice-water (200 g) containing NH4Cl (10 g). It was then
extracted with CH2Cl2 (300 mL), and the organic extract was
washed with water (3ϫ 150 mL) and dried (Na2SO4). The solvent
was removed in vacuo, and the crude product was purified by col-
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Total Synthesis of Calothrixin B and Its Analogs
umn chromatography (silica gel; hexane/ethyl acetate, 95:5) to give
14 (19.8 g, 96 %) as a colorless solid, m.p. 48–50 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.16 (d, J = 8.1 Hz, 1 H, Ar), 7.77 (d, J =
7.5 Hz, 2 H, Ar), 7.51 (t, J = 7.5 Hz, 1 H, Ar), 7.43–7.38 (m, 3 H,
General Procedure for Wittig Reactions: A solution of 2-
(bromomethyl)indole 18 (5 g, 12.31 mmol) and triphenylphosphine
(3.5 g, 13.54 mmol) in dry THF (100 mL) was heated at reflux for
6 h. After consumption of the starting material, the solvent was
Ar), 7.28–7.17 (m, 2 H, Ar), 6.34 (s, 1 H, Ar), 2.59 (s, 3 H, CH3) removed in vacuo, and the solid was washed with diethyl ether to
ppm. 13C NMR (75 MHz, CDCl3): δ = 139.3, 137.3, 137.0, 133.7,
129.7, 129.3, 126.3, 123.8, 123.5, 120.0, 114.5, 109.8, 15.8 ppm.
give the phosphonium salt. Then, a mixture of the phosphonium
salt (8 g, 11.97 mmol), 2-nitroarylaldehydes 19a–19e (13.17 mmol),
and K2CO3 (3.30 g, 23.95 mmol) in CH2Cl2 (70 mL) was stirred at
room temperature. After the reaction was complete (monitored by
TLC), the mixture was diluted using CH2Cl2 (30 mL), washed with
water (2ϫ 100 mL), and dried (Na2SO4). Removal of the solvent
in vacuo followed by trituration of the crude product with MeOH
(20 mL) gave 20a–20e.
1-[2-Methyl-1-(phenylsulfonyl)-1H-indol-3-yl]propan-1-one (16) and
(Z)-3-(1-Chloroprop-1-enyl)-2-methyl-1-(phenylsulfonyl)-1H-indole
(17)
AlCl3 (1.47 g, 11.07 mmol) and propionic anhydride (15; 0.71 mL,
5.53 mmol) were added to a solution of indole 14 (1 g, 3.69 mmol)
in dry CH2Cl2 (20 mL) at 0 °C, and the mixture was stirred for 3 h.
Then, the reaction mixture was washed with NaHCO3 (saturated
(E)-1-[2-(2-Nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]propan-1-
aq.; 2ϫ 10 mL) and water (3ϫ 10 mL), and dried (Na2SO4). Re- one (20a): Wittig reaction of phosphonium salt [prepared using
moval of the solvent followed by purification by column
chromatography (silica gel; hexane/ethyl acetate, 95:5) gave 17. Fur-
ther elution of the column (silica gel; hexane/ethyl acetate, 9:1) gave
16.[22]
Data for 16: Colorless solid (0.75 g, 62%), m.p. 130–132 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.30–8.28 (m, 1 H, Ar), 7.86–7.81
(m, 3 H, Ar), 7.55 (t, J = 7.5 Hz, 1 H, Ar), 7.43 (t, J = 7.65 Hz, 2
H, Ar), 7.36–7.28 (m, 2 H, Ar), 2.93 (q, J = 7.3 Hz, 2 H, CH2),
2.88 (s, 3 H, CH3), 1.20 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 199.5, 142.5, 138.9, 136.1, 134.3, 129.6,
126.9, 126.5, 124.7, 124.4, 120.8, 114.6, 37.3, 14.3, 8.2 ppm (only
15 carbon signals appeared).
Data for 17: Colorless solid (0.25 g, 20%), m.p. 114–116 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 8.1 Hz, 1 H, Ar), 7.80
(d, J = 7.5 Hz, 2 H, Ar), 7.54 (t, J = 6.9 Hz, 2 H, Ar), 7.43 (t, J =
7.65 Hz, 2 H, Ar), 7.32–7.22 (m, 2 H, Ar), 5.81 (q, J = 6.6 Hz, 1
H, CH), 2.60 (s, 3 H, CH3), 1.96 (d, J = 6.6 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.1, 135.8, 135.0, 133.9, 129.4,
128.8, 128.1, 126.4, 124.7, 124.5, 123.7, 121.0, 119.6, 114.4, 14.7,
13.6 ppm. HRMS (EI): calcd. for C18H16ClNO2S [M]+ 345.0590;
found 345.0600.
1-[2-Methyl-1-(phenylsulfonyl)-1H-indol-3-yl]propan-1-one (16):[22]
BF3·OEt2 (10.43 mL, 83 mmol) was slowly added to a stirred solu-
tion of 1-phenylsulfonylindole 14 (15 g, 55.35 mmol) and propionic
anhydride (15; 10.7 mL, 83 mmol) in dry CH2Cl2 (200 mL) at 0–
10 °C. The reaction mixture was stirred at room temperature for
8 h. After the reaction was complete (monitored by TLC), the mix-
ture was washed with NaHCO3 (saturated aq.; 2ϫ 100 mL) and
water (3ϫ 200 mL), and dried (Na2SO4). Removal of the solvent
followed by trituration of the crude product with MeOH (50 mL)
gave 16 (16.65 g, 92%) as a colorless solid, m.p. 130–132 °C.
bromo compound 18 (5 g, 12.31 mmol) and triphenylphosphine
(3.5 g, 13.54 mmol)] with 2-nitrobenzaldehyde (19a; 1.99 g,
13.17 mmol) using K2CO3 (3.30 g, 23.95 mmol) in CH2Cl2 (70 mL)
at room temperature for 24 h, followed by work-up as described
above gave 20a (4.30 g, 76%) as a yellow solid, m.p. 168–170 °C. IR
(KBr): ν = 1666, 1520, 1373, 1342, 1173 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 8.18–8.15 (m, 1 H, Ar), 8.03–8.00 (m, 1 H, Ar), 7.83
(d, J = 7.8 Hz, 1 H, Ar), 7.75 (d, J = 7.8 Hz, 1 H, Ar), 7.71–7.68
(m, 3 H, Ar), 7.63 (d, J = 15.9 Hz, 1 H, vinylic), 7.52–7.43 (m, 2
H, Ar), 7.36–7.23 (m, 4 H, Ar), 7.08 (d, J = 15.9 Hz, 1 H, vinylic),
2.76 (q, J = 7.3 Hz, 2 H, Ar, CH2), 1.03 (t, J = 7.35 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 201.2, 147.8, 138.6, 137.6,
136.0, 134.4, 134.0, 133.9, 131.6, 129.6, 129.4, 129.2, 128.0, 126.8,
126.2, 125.0, 123.6, 123.2, 121.4, 114.6, 36.2, 8.6 ppm (only 22 car-
bon signals appeared). DEPT-135 (75 MHz, CDCl3): δ = 134.5,
134.1, 134.0, 129.6, 129.4, 129.3, 126.9, 126.2, 125.1 (2CH), 123.2,
121.4, 114.6, 36.3, 8.7 ppm. HRMS (EI): calcd. for C25H20N2O5S
[M]+ 460.1093; found 460.1090.
(E)-1-[2-(4,5-Dimethoxy-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-
3-yl]propan-1-one (20b): Wittig reaction of phosphonium salt [pre-
pared using bromo compound 18 (5 g, 12.31 mmol) and tri-
phenylphosphine (3.5 g, 13.54 mmol)] with 2-nitroveratraldehyde
(19b; 2.78 g, 13.17 mmol) using K2CO3 (3.30 g, 23.95 mmol) in
CH2Cl2 (70 mL) at room temperature for 40 h, followed by work-
up as described above gave 20b (4.73 g, 74%) as a yellow solid,
m.p. 156–158 °C. IR (KBr): ν = 1666, 1520, 1381, 1335, 1281, 1219,
˜
1
1180 cm–1. H NMR (300 MHz, CDCl3): δ = 8.22 (d, J = 8.4 Hz,
1 H, Ar), 7.85 (d, J = 7.8 Hz, 1 H, Ar), 7.76 (d, J = 8.1 Hz, 2 H,
Ar), 7.70 (s, 1 H, Ar), 7.61 (d, J = 15.9 Hz, 1 H, vinylic), 7.53 (t,
J = 7.2 Hz, 1 H, Ar), 7.42–7.35 (m, 3 H, Ar), 7.32–7.25 (m, 3 H,
Ar), 4.11 (s, 3 H, OCH3), 4.01 (s, 3 H, OCH3), 2.88 (q, J = 7.2 Hz,
2 H, CH2), 1.12 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 201.0, 153.6, 149.3, 140.3, 139.0, 137.5,
135.9, 134.9, 134.4, 129.3, 128.1, 126.7, 126.0, 125.0, 123.3, 122.0,
121.4, 114.5, 110.2, 107.9, 56.6, 56.5, 36.1, 8.6 ppm (only 24 carbon
signals appeared). DEPT-135 (75 MHz, CDCl3): δ = 135.0, 134.4,
129.4, 126.8, 126.1, 125.1, 122.1, 121.5, 114.6, 110.2, 108.0, 56.7,
56.6, 36.2, 8.6 ppm. C27H24N2O7S (520.13): calcd. C 62.30, H 4.65,
N 5.38, S 6.16; found C 62.14, H 4.41, N 5.21, S 6.02.
1-[2-(Bromomethyl)-1-(phenylsulfonyl)-1H-indol-3-yl]propan-1-one
(18):[22] A mixture of indole 16 (15 g, 45.87 mmol) and NBS (9.8 g,
55 mmol) in dry CCl4 (250 mL) containing a catalytic amount of
AIBN (50 mg) was heated at reflux for 3 h. Then, the reaction mix-
ture was cooled to room temperature and filtered through an
Na2SO4 pad to remove undissolved succinimide, washing with CCl4
(20 mL). Removal of the solvent from the filtrate followed by tritu-
ration of the crude product with MeOH (50 mL) gave 2-bromo-
methyl indole 18 (17.13 g, 92 %) as a colorless solid, m.p. 120–
122 °C. 1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 7.8 Hz, 1
H, Ar), 7.92 (d, J = 7.2 Hz, 2 H, Ar), 7.81 (d, J = 7.2 Hz, 1 H,
Ar), 7.53 (t, J = 7.5 Hz, 1 H, Ar), 7.43–7.35 (m, 2 H, Ar), 7.33–
7.28 (m, 2 H, Ar), 5.36 (s, 2 H, CH2), 2.94 (q, J = 7.1 Hz, 2 H,
CH2), 1.19 (t, J = 7.2 MHz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 198.9, 140.5, 138.3, 136.2, 134.6, 129.5, 127.2, 126.2,
126.1, 124.8, 121.7, 121.5, 115.0, 37.6, 22.2, 8.1 ppm.
(E)-1-[2-(4-Chloro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-
propan-1-one (20c): Wittig reaction of phosphonium salt [prepared
using bromo compound 18 (5 g, 12.31 mmol) and triphenylphos-
phine (3.5 g, 13.54 mmol)] with 4-chloro-2-nitrobenzaldehyde (19c;
2.45 g, 13.17 mmol) using K2CO3 (3.30 g, 23.95 mmol) in CH2Cl2
(70 mL) at room temperature for 24 h, followed by work-up as de-
scribed above gave compound 20c (5.15 g, 84%) as a yellow solid,
m.p. 180–182 °C. IR (KBr): ν = 1690, 1520, 1373, 1342, 1173 cm–1.
˜
Eur. J. Org. Chem. 2014, 1266–1279
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1271

V. Saravanan, B. Muthu Ramalingam, A. K. Mohanakrishnan
1H NMR (300 MHz, CDCl3): δ = 8.16 (d, J = 8.1 Hz, 1 H, Ar), 9 mmol) using PTT (3.72 g, 9.9 mmol) in dry THF (100 mL) at
FULL PAPER
8.02–8.01 (m, 1 H, Ar), 7.79 (d, J = 8.4 Hz, 1 H, Ar), 7.74 (d, J =
7.5 Hz, 1 H, Ar), 7.68–7.59 (m, 4 H, Ar), 7.46 (t, J = 7.5 Hz, 1 H,
Ar), 7.37–7.23 (m, 4 H, Ar), 7.02 (d, J = 15.9 Hz, 1 H, vinylic),
2.75 (q, J = 7.4 Hz, 2 H, CH2), 1.04 (t, J = 7.35 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 201.0, 148.0, 138.1, 137.6,
136.1, 135.4, 134.5, 134.0, 132.6, 130.2, 130.1, 129.4, 128.0, 126.8,
room temperature for 3 h, followed by work-up as described above
gave 21a (4.41 g, 91%) as a pale yellow solid, m.p. 162–164 °C. H
NMR (300 MHz, CDCl3): δ = 8.16 (d, J = 8.4 Hz, 1 H, Ar), 8.03
(d, J = 8.1 Hz, 1 H, Ar), 7.88 (d, J = 7.8 Hz, 1 H, Ar), 7.77–7.66
(m, 5 H, Ar), 7.54–7.44 (m, 2 H, Ar), 7.38–7.29 (m, 4 H, Ar), 7.06
(d, J = 15.9 Hz, 1 H, vinylic), 5.12 (q, J = 6.6 Hz, 1 H, CH), 1.73
1
126.3, 125.2, 125.1, 123.9, 123.8, 121.4, 114.7, 36.4, 8.6 ppm. (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
DEPT-135 (75 MHz, CDCl3): δ = 134.5, 134.0, 132.6, 130.3, 129.4, 193.2, 147.9, 138.8, 137.6, 136.1, 134.6, 134.2, 134.1, 131.3, 129.9,
126.8, 126.3, 125.2, 125.1, 123.8, 121.4, 114.7, 36.4, 8.6 ppm. 129.5, 129.3, 128.6, 126.8, 126.5, 125.3, 125.1, 123.2, 121.5, 120.9,
HRMS (EI): calcd. for C25H19ClN2O5S [M]+ 494.0703; found
494.0700.
114.6, 46.4, 20.0 ppm. HRMS (EI): calcd. for C25H19BrN2O5S
[M]+ 538.0198; found 538.0190.
(E)-1-[2-(4-Fluoro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-
propan-1-one (20d): Wittig reaction of phosphonium salt [prepared
using bromo compound 18 (5 g, 12.31 mmol) and triphenylphos-
phine (3.5 g, 13.54 mmol)] with 4-fluoro-2-nitrobenzaldehyde (19d;
2.24 g, 13.17 mmol) using K2CO3 (3.30 g, 23.95 mmol) in CH2Cl2
(70 mL) at room temperature for 22 h, followed by work-up as de-
scribed above gave 20d (4.80 g, 81%) as a yellow solid, m.p. 164–
(E)-2-Bromo-1-[2-(4,5-dimethoxy-2-nitrostyryl)-1-(phenylsulfonyl)-
1H-indol-3-yl]propan-1-one (21b): Bromination of 3-propionylin-
dole 20b (4.68 g, 9 mmol) using PTT (3.72 g, 9.9 mmol) in dry THF
(100 mL) at room temperature for 3 h, followed by work-up as de-
scribed above gave 21b (4.68 g, 87%) as a pale yellow solid, m.p.
126–128 °C. 1H NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 8.1 Hz,
1 H, Ar), 7.79–7.77 (m, 1 H, Ar), 7.68–7.65 (m, 2 H, Ar), 7.62 (s,
1 H, Ar), 7.58 (d, J = 15.9 Hz, 1 H, vinylic), 7.44 (t, J = 7.35 Hz,
1 H, Ar), 7.35–7.24 (m, 5 H, Ar), 7.23 (d, J = 15.9 Hz, 1 H, vinylic),
5.21 (q, J = 6.6 Hz, 1 H, CH), 4.03 (s, 3 H, OCH3), 3.92 (s, 3 H,
OCH3), 1.74 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 193.0, 153.8, 149.6, 140.4, 139.2, 137.5, 136.0, 134.9,
134.6, 129.5, 128.7, 126.8, 126.5, 126.4, 125.3, 122.1, 121.5, 120.4,
114.6, 110.4, 108.0, 56.7, 56.6, 46.3, 19.9 ppm. HRMS (EI): calcd.
for C27H23BrN2O7S [M]+ 598.0409; found 598.0400.
166 °C. IR (KBr): ν = 1666, 1535, 1381, 1342, 1180 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 8.23 (d, J = 8.1 Hz, 1 H, Ar), 7.94–7.89
(m, 1 H, Ar), 7.81 (d, J = 8.1 Hz, 2 H, Ar), 7.76 (d, J = 7.5 Hz, 2
H, Ar), 7.65 (d, J = 15.9 Hz, 1 H, vinylic), 7.55–7.45 (m, 2 H, Ar),
7.42–7.29 (m, 4 H, Ar), 7.12 (d, J = 15.9 Hz, 1 H, vinylic), 2.83 (q,
J = 7.30 Hz, 2 H, CH2), 1.11 (t, J = 7.3 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 201.1, 162.1 (d, J = 254 Hz), 148.2
(d, J = 8.29 Hz), 138.3, 137.6, 136.0, 134.5, 132.9, 131.1 (d, J =
8.29 Hz), 129.4, 128.1 (d, J = 3.72 Hz), 128.0, 126.8, 126.3, 125.1,
123.8, 123.4, 121.5 (d, J = 21 Hz), 121.4, 114.7, 112.7 (d, J =
26.39 Hz), 36.3, 8.6 ppm. DEPT-135 (75 MHz, CDCl3): δ = 134.5,
132.9, 131.8 (d, J = 7.89 Hz), 129.4, 126.8, 126.3, 125.1, 123.4,
121.5 (d, J = 21 Hz), 121.4, 114.7, 112.7 (d, J = 26.69 Hz), 36.3,
8.6 ppm. HRMS (EI): calcd. for C25H19FN2O5S [M]+ 478.0999;
found 478.0990.
(E)-2-Bromo-1-[2-(4-chloro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-
indol-3-yl]propan-1-one (21c): Bromination of 3-propionylindole
20c (4.45 g, 9 mmol) using PTT (3.72 g, 9.9 mmol) in dry THF
(100 mL) at room temperature for 3 h, followed by work-up as de-
scribed above gave 21c (4.85 g, 94%) as a pale yellow solid, m.p.
178–180 °C. 1H NMR (300 MHz, CDCl3): δ = 8.23 (d, J = 8.4 Hz,
1 H, Ar), 8.09 (s, 1 H), 7.90 (d, J = 8.1 Hz, 1 H, Ar), 7.82 (d, J =
7.8 Hz, 1 H, Ar), 7.74 (d, J = 8.1 Hz, 4 H, Ar), 7.54 (t, J = 7.35 Hz,
1 H, Ar), 7.46–7.34 (m, 4 H, Ar), 7.09 (d, J = 15.9 Hz, 1 H, vinylic),
5.14 (q, J = 6.5 Hz, 1 H, CH), 1.82 (d, J = 6.6 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 193.1, 148.0, 138.4, 137.6, 136.1,
135.8, 134.6, 134.2, 132.7, 130.3, 129.8, 129.5, 128.5, 126.8, 126.6,
125.4, 125.3, 123.8, 121.5, 121.0, 114.6, 46.3, 20.0 ppm. HRMS
(EI): calcd. for C25H18BrClN2O5S [M]+ 571.9808; found 571.9800.
(E)-1-[2-(4,5-Dichloro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-
yl]propan-1-one (20e): Wittig reaction of phosphonium salt [pre-
pared using bromo compound 18 (5 g, 12.31 mmol) and tri-
phenylphosphine (3.5 g, 13.54 mmol)] with 4,5-dichloro-2-nitro-
benzaldehyde (19e; 2.88 g, 13.17 mmol) using K2CO3 (3.30 g,
23.95 mmol) in CH2Cl2 (70 mL) at room temperature for 24 h, fol-
lowed by work-up as described above gave 20e (5.06 g, 78%) as a
yellow solid, m.p. 186–188 °C. IR (KBr): ν = 1674, 1520, 1373,
˜
1
1342, 1173 cm–1. H NMR (300 MHz, CDCl3): δ = 8.24–8.22 (m,
(E)-2-Bromo-1-[2-(4-fluoro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-
indol-3-yl]propan-1-one (21d): Bromination of 3-propionylindole
20d (4.30 g, 9 mmol) using PTT (3.72 g, 9.9 mmol) in dry THF
(100 mL) at room temperature for 3 h, followed by work-up as de-
scribed above gave 21d (4.5 g, 90%) as a pale yellow solid, m.p.
152–154 °C. 1H NMR (300 MHz, CDCl3): δ = 8.23 (d, J = 8.1 Hz,
1 H, Ar), 7.98–7.31 (m, 1 H, Ar), 7.86–7.81 (m, 2 H, Ar), 7.75 (d,
J = 7.8 Hz, 2 H, Ar), 7.70 (d, J = 15.9 Hz, 1 H, vinylic), 7.57–7.49
(m, 2 H, Ar), 7.46–7.34 (m, 4 H, Ar), 7.10 (d, J = 15.9 Hz, 1 H,
vinylic), 5.16 (q, J = 6.7 Hz, 1 H, CH), 1.81 (d, J = 6.9 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.1, 162.3 (d, J =
254 Hz), 148.2 (d, J = 8.37 Hz), 138.6, 137.6, 136.0, 134.6, 133.0,
131.2 (d, J = 8.07 Hz), 129.5, 128.5, 127.8 (d, J = 3.92 Hz), 126.8,
126.6, 125.4, 123.4, 121.7 (d, J = 22.5 Hz), 121.4, 120.9, 114.6,
112.8 (d, J = 26.61 Hz), 46.4, 20.0 ppm. HRMS (EI): calcd. for
C25H18BrFN2O5S [M]+ 556.0104; found 556.0100.
2 H, Ar), 7.95 (s, 1 H, Ar), 7.79 (d, J = 8.1 Hz, 1 H, Ar), 7.74 (d,
J = 7.8 Hz, 2 H, Ar), 7.69 (d, J = 15.9 Hz, 1 H, vinylic), 7.55 (t, J
= 7.35 Hz, 1 H, Ar), 7.43–7.38 (m, 3 H, Ar), 7.36–7.31 (m, 1 H,
Ar), 7.11 (d, J = 15.9 Hz, 1 H, vinylic), 2.82 (q, J = 7.3 Hz, 2 H,
CH2), 1.12 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 200.9, 145.8, 139.0, 137.6 (2 C), 136.1, 134.5, 133.7,
131.5, 131.4, 130.4, 129.5, 127.9, 127.0, 126.8, 126.4, 126.1, 124.7,
124.2, 121.4, 114.7, 36.5, 8.6 ppm. DEPT-135 (75 MHz, CDCl3): δ
= 134.5, 131.6, 130.4, 129.5, 127.0, 126.8, 126.5, 125.2, 124.7, 121.4,
114.7, 36.5, 8.6 ppm. HRMS (EI): calcd. for C25H18Cl2N2O5S
[M]+ 528.0313; found 528.0310.
General Procedure for the α-Bromination of Vinylindoles 20a–20e: A
solution of 3-propionylindole 20a–20e (9 mmol) and PTT (3.72 g,
9.9 mmol) in dry THF (100 mL) was stirred at room temperature
for 3 h. After the reaction was complete (monitored by TLC), the
mixture was poured onto crushed ice (300 g). The resulting solid
was filtered and washed with MeOH (25 mL) to give 21a–21e as
pale yellow solids.
(E)-2-Bromo-1-[2-(4,5-dichloro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-
indol-3-yl]propan-1-one (21e): Bromination of 3-propionylindole
20e (4.92 g, 9 mmol) using PTT (3.72 g, 9.9 mmol) in dry THF
(E)-2-Bromo-1-[2-(2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]- (100 mL) at room temperature for 3 h, followed by work-up as de-
propan-1-one (21a): Bromination of 3-propionylindole 20a (4.14 g, scribed above gave 21e (4.92 g, 90%) as a pale yellow solid, m.p.
1272
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1266–1279

Total Synthesis of Calothrixin B and Its Analogs
1
178–180 °C. H NMR (300 MHz, CDCl3): δ = 8.23–8.21 (m, 2 H,
134.3, 134.1, 130.4, 129.5, 129.4, 128.9, 128.8, 127.7, 126.8, 126.7,
125.5, 125.4, 123.8, 122.7, 121.6, 114.4, 68.9, 11.5 ppm (only 26
carbon signals appeared). HRMS (EI): calcd. for C31H23ClN2O7S2
[M]+ 634.0635; found 634.0630.
Ar), 8.00 (s, 1 H, Ar), 7.80 (d, J = 7.8 Hz, 1 H, Ar), 7.77–7.72 (m,
3 H, Ar), 7.55 (t, J = 7.5 Hz, 1 H, Ar), 7.46–7.34 (m, 4 H, Ar),
7.12 (d, J = 15.9 Hz, 1 H, vinylic), 5.10 (q, J = 6.70 Hz, 1 H, CH),
1.81 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 193.0, 145.8, 139.2, 138.0, 137.5, 136.1, 134.7, 134.0, 131.6,
131.1, 130.5, 129.5, 128.3, 127.1, 126.8, 125.4, 124.6, 121.4, 121.3,
114.7, 46.4, 20.1 ppm (only 22 carbon signals appeared). HRMS
(EI): calcd. for C25H17BrCl2N2O5S [M]+ 605.9419; found 605.9410.
(E)-1-[2-(4-Fluoro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-2-
(phenylsulfonyl)propan-1-one (22d): Reaction of α-bromoprop-
ionylindole 21d (4.18 g, 7.5 mmol) with sodium phenyl sulfinate
(2.49 g, 15 mmol) in DMF (30 mL) at room temperature for 3 h,
followed by work-up as described above gave sulfone 22d (4.13 g,
89 %) as a yellow solid, m.p. 168–170 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.17 (d, J = 8.1 Hz, 1 H, Ar), 7.98–7.97 (m, 1 H, Ar),
7.85 (dd, J = 8.1, J = 2.7 Hz, 1 H, Ar), 7.79 (d, J = 7.5 Hz, 1 H,
Ar), 7.72–7.69 (m, 2 H, Ar), 7.60 (d, J = 15.6 Hz, 1 H, vinylic),
7.56–7.50 (m, 5 H, Ar), 7.46–7.29 (m, 6 H, Ar), 7.00 (d, J =
15.9 Hz, 1 H, vinylic), 5.11 (q, J = 6.9 Hz, 1 H, CH), 1.55 (d, J =
6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 190.0,
162.4 (d, J = 255 Hz), 148.3 (d, J = 8.23 Hz), 140.7, 137.5, 136.6,
135.7, 134.7, 134.2 134.0, 131.2 (d, J = 8.07 Hz), 129.5, 128.9,
128.8, 127.7, 127.4 (d, J = 3.97 Hz), 126.7, 125.5, 123.5 (2 C), 122.5,
121.8 (d, J = 21.5 Hz), 121.6, 114.4, 112.9 (d, J = 26.61 Hz), 68.9,
11.5 ppm. HRMS (EI): calcd. for C31H23FN2O7S2 [M]+ 618.0931;
found 618.0930.
General Procedure for the Synthesis of β-Ketosulfones 22a–22e: So-
dium phenyl sulfinate (15 mmol) was added to a solution of α-
bromopropionylindoles 21a–21e (4.04 g, 7.5 mmol) in DMF
(30 mL), and the mixture was stirred at room temperature. After
the reaction was complete (monitored by TLC), the mixture was
poured onto crushed ice (300 g). The resulting solid was filtered
and washed with MeOH (30 mL) to give β-ketosulfones 22a–22e.
(E)-1-[2-(2-Nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-2-(phenyl-
sulfonyl)propan-1-one (22a): Reaction of α-bromopropionylindole
21a (4.04 g, 7.5 mmol) with sodium phenyl sulfinate (2.49 g,
15 mmol) in DMF (30 mL) at room temperature for 3 h, followed
by work-up as described above gave sulfone 22a (4.05 g, 91%) as a
pale yellow solid, m.p. 210–212 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 8.16 (t, J = 7.95 Hz, 2 H, Ar), 8.09 (d, J = 8.4 Hz, 1
H, Ar), 7.96 (t, J = 7.35 Hz, 1 H, Ar), 7.87 (d, J = 7.8 Hz, 2 H,
Ar), 7.75–7.65 (m, 4 H, Ar), 7.61–7.46 (m, 6 H, Ar), 7.41 (d, J =
7.5 Hz, 1 H, Ar), 7.34 (t, J = 7.5 Hz, 2 H, Ar), 7.17 (d, J = 15.9 Hz,
1 H, vinylic), 5.20 (q, J = 6.3 Hz, 1 H, CH), 1.41 (d, J = 6.6 Hz, 3
H, CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 189.9, 147.8,
141.3, 136.7, 136.4, 135.9, 135.3, 134.7, 134.2, 134.0, 130.4 (2 C),
129.9, 129.3, 128.9, 128.2, 127.6, 126.7, 126.6, 125.2, 124.9, 122.3,
122.0, 120.9, 114.0, 67.8, 10.7 ppm. HRMS (EI): calcd. for
C31H24N2O7S2 [M]+ 600.1025; found 600.1020.
(E)-1-[2-(4,5-Dichloro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-
yl]-2-(phenylsulfonyl)propan-1-one (22e): Reaction of α-bromoprop-
ionylindole 21e (4.56 g, 7.5 mmol) with sodium phenyl sulfinate
(1.31 g, 7.87 mmol) in DMF (30 mL) at room temperature for
5 min followed by work-up as described above gave sulfone 22e
(4.11 g, 82 %) as a yellow solid, m.p. 180–182 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.24 (s, 1 H, Ar), 8.17 (d, J = 8.4 Hz, 1 H,
Ar), 8.00 (s, 1 H, Ar), 7.79 (d, J = 7.8 Hz, 1 H, Ar), 7.71 (d, J =
7.8 Hz, 2 H, Ar), 7.64 (d, J = 16.2 Hz, 1 H, Ar), 7.59–7.52 (m, 4
H, Ar), 7.47–7.32 (m, 6 H, Ar), 7.04 (d, J = 15.9 Hz, 1 H, vinylic),
5.04 (q, J = 6.80 Hz, 1 H, CH), 1.55 (d, J = 7.5 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 190.0, 145.8, 140.0, 139.3,
137.5, 136.6, 135.7, 134.7, 134.3, 134.1, 133.0, 130.8, 130.5, 129.5,
129.0, 128.8, 127.7, 127.1, 126.9, 126.7, 125.5, 124.6, 122.8, 121.6,
114.5, 69.0, 11.7 ppm. HRMS (EI): calcd. for C31H22Cl2N2O7S2
[M]+ 668.0245; found 668.0240.
(E)-1-[2-(4,5-Dimethoxy-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-
3-yl]-2-(phenylsulfonyl)propan-1-one (22b): Reaction of α-bromo-
propionylindole 21b (4.49 g, 7.5 mmol) with sodium phenyl sulfin-
ate (2.49 g, 15 mmol) in DMF (30 mL) at room temperature for
3 h, followed by work-up as described above gave sulfone 22b
(4.36 g, 88 %) as a yellow solid, m.p. 186–188 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.07 (d, J = 8.1 Hz, 1 H, Ar), 7.74 (d, J =
7.5 Hz, 1 H, Ar), 7.64 (d, J = 7.8 Hz, 2 H, Ar), 7.62 (s, 1 H, Ar),
7.50 (d, J = 15.9 Hz, 1 H, vinylic), 7.44–7.39 (m, 4 H, Ar), 7.35–
7.18 (m, 7 H, Ar), 7.11 (d, J = 15.9 Hz, 1 H, vinylic), 5.20 (q, J =
6.8 Hz, 1 H, CH), 4.04 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 1.46
(d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
189.9, 153.9, 149.8, 141.6, 140.4, 137.5, 136.4, 136.2, 135.6, 134.6,
134.0, 129.5, 129.0, 128.8, 127.9, 126.8, 126.6, 126.2, 125.5, 122.4,
122.2, 121.6, 114.4, 110.5, 108.1, 68.6, 56.8, 56.6, 11.5 ppm.
C33H28N2O9S2 (660.12): calcd. C 59.99, H 4.27, N 4.24, S 9.71;
found C 60.19, H 4.08, N 4.38, S 9.57.
General Procedure for the Synthesis of Carbazoles 10a–10e: A mix-
ture of β-ketosulfones 22a–22e (6 mmol), dimethyl sulfate
(2.86 mL, 30 mmol), and K2CO3 (8.28 g, 60 mmol) in THF
(100 mL) was stirred at room temperature for 18 h. After the reac-
tion was complete (monitored by TLC), the mixture was poured
onto crushed ice (100 g). The resulting solid was filtered and dried
(CaCl2) to give the enol ether. Then, the crude enol ether was dis-
solved in xylenes (100 mL), and the mixture was heated at reflux
for 24 h. Removal of xylenes in vacuo followed by column chroma-
tographic purification (silica gel; hexane/ethyl acetate) gave carba-
zoles 10a–10e.
4-Methoxy-3-methyl-2-(2-nitrophenyl)-9-(phenylsulfonyl)-9H-carb-
azole (10a): Preparation of the enol ether using β-ketosulfone 22a
(3.6 g, 6 mmol), dimethyl sulfate (2.86 mL, 30 mmol), and K2CO3
(8.28 g, 60 mmol) in THF (100 mL) at room temperature followed
by electrocyclization and subsequent column chromatographic pu-
rification (silica gel; hexane/ethyl acetate, 9:1) as described above
gave carbazole 10a (2.15 g, 76%) as a colorless solid, m.p. 174–
176 °C.
(E)-1-[2-(4-Chloro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-3-yl]-
2-(phenylsulfonyl)propan-1-one (22c): Reaction of α-bromoprop-
ionylindole 21c (4.30 g, 7.5 mmol) with sodium phenyl sulfinate
(2.49 g, 15 mmol) in DMF (30 mL) at room temperature for 3 h,
followed by work-up as described above gave sulfone 22c (4.57 g,
96 %) as a yellow solid, m.p. 192–194 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.17 (d, J = 8.1 Hz, 1 H, Ar), 8.09–8.08 (m, 1 H, Ar),
7.90 (d, J = 8.4 Hz, 1 H, Ar), 7.80–7.74 (m, 2 H, Ar), 7.70 (d, J =
7.5 Hz, 2 H, Ar), 7.64 (d, J = 15.9 Hz, 1 H, Ar), 7.55–7.49 (m, 4
2-(4,5-Dimethoxy-2-nitrophenyl)-4-methoxy-3-methyl-9-(phenylsulf-
H, Ar), 7.46–7.43 (m, 1 H, Ar), 7.41–7.37 (m, 2 H, Ar), 7.35–7.26 onyl)-9H-carbazole (10b): Preparation of the enol ether using β-
(m, 3 H, Ar), 7.05 (d, J = 15.9 Hz, 1 H, vinylic), 5.08 (q, J = 6.9 Hz, ketosulfone 22b (3.96 g, 6 mmol), dimethyl sulfate (2.86 mL,
1 H, CH), 1.54 (d, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, 30 mmol), and K2CO3 (8.28 g, 60 mmol) in THF (100 mL) at room
CDCl3): δ = 190.0, 148.0, 140.5, 137.5, 136.5, 136.1, 135.7, 134.7, temperature followed by electrocyclization and subsequent column
Eur. J. Org. Chem. 2014, 1266–1279
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1273

V. Saravanan, B. Muthu Ramalingam, A. K. Mohanakrishnan
FULL PAPER
chromatographic purification (silica gel; hexane/ethyl acetate, 8:2)
30 mmol), and K2CO3 (8.28 g, 60 mmol) in THF (100 mL) at room
temperature followed by electrocyclization and subsequent column
chromatographic purification (silica gel; hexane/ethyl acetate, 8:2)
gave carbazole 10e (2.17 g, 67%) as a colorless solid, m.p. 220–
222 °C. 1H NMR (300 MHz, CDCl3): δ = 8.26 (d, J = 8.4 Hz, 1
H, Ar), 8.13 (s, 1 H, Ar), 8.07 (d, J = 7.8 Hz, 1 H, Ar), 7.84 (s, 1
H, Ar), 7.66 (d, J = 7.5 Hz, 2 H, Ar), 7.47 (s, 1 H, Ar), 7.44–7.33
as described above gave carbazole 10b (2.23 g, 71%) as a colorless
1
solid, m.p. 192–194 °C. H NMR (300 MHz, CDCl3): δ = 8.33 (d,
J = 8.4 Hz, 1 H, Ar), 8.14 (d, J = 7.8 Hz, 1 H, Ar), 7.95 (s, 1 H,
Ar), 7.76–7.73 (m, 3 H, Ar), 7.52–7.40 (m, 3 H, Ar), 7.37–7.30 (m,
2 H, Ar), 6.77 (s, 1 H, Ar), 4.05 (s, 3 H, OCH3), 3.98 (s, 3 H,
OCH3), 3.91 (s, 3 H, OCH3), 2.10 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 153.5, 152.8, 148.4, 141.1, 139.4, 138.4, (m, 3 H, Ar), 7.30–7.24 (m, 2 H, Ar), 3.83 (s, 3 H, OCH3), 2.05 (s,
137.6, 137.2, 133.9, 131.0, 129.0, 127.1, 126.5, 125.0 (2 C), 124.5, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.7, 146.4,
122.8, 119.4, 115.1, 113.4, 111.3, 107.6, 60.3, 56.6, 56.5, 12.6 ppm.
HRMS (EI): calcd. for C28H24N2O7S [M]+ 532.1304; found
532.1295. For single-crystal X-ray analysis of 10b, all calculations
were performed with the SHELXL-97 program.[27] Crystal data of
10b: C28H24N2O7S, MW = 532.56 g/mol, Orthorhombic crystal
system, space group Pca21, Z = 4, a = 8.4543(3) Å, b =
13.6605(5) Å, c = 21.6359(9) Å, α = 90.000(0)°, β = 90.000(0)°, γ =
90.000(0)°, V = 2498.73(16) Å3, Dcalcd. = 1.416 Mg/m3. In total,
5152 independent reflections were collected, of which 4175 were
considered as observed [IϾ2σ(I)]. The structure was solved by di-
rect methods and refined by full-matrix least-squares procedures to
a final R-value of 3.40%.
137.5, 136.6, 136.2, 135.0 (2 C), 133.0, 132.6, 132.0, 128.1, 126.5,
125.5, 125.2, 123.7 (2 C), 123.6, 121.9, 119.2, 114.0, 110.2, 59.3,
11.7 ppm (only 23 carbon signals appeared). HRMS (EI): calcd.
for C26H18Cl2N2O5S [M]+ 540.0313; found 540.0310.
General Procedure for the Bromination of 3-Methylcarbazoles 10a–
10e: A mixture of 3-methylcarbazoles 10a–10e (3.5 mmol) and NBS
(0.93 g, 5.25 mmol) in dry CCl4 (100 mL) containing a catalytic
amount of AIBN (50 mg) was heated at reflux for 1 h. Then, the
mixture was cooled to room temperature, and further NBS (0.93 g,
5.25 mmol) and AIBN (50 mg) were added. The mixture was then
heated at reflux for a further 1 h. Then the reaction mixture was
cooled to room temperature, and the undissolved succinimide was
removed by filtration through an Na2SO4 pad, followed by washing
with hot CCl4 (20 mL). The solvent was removed from the filtrate
The CCDC-952296 (for 10b) contains the supplementary crystallo-
graphic data for 10b. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via in vacuo, and the crude product was triturated with MeOH (10 mL)
www.ccdc.cam.ac.uk/data_request/cif.
to give 3-(bromomethyl)carbazoles 23a–23e.
2-(4-Chloro-2-nitrophenyl)-4-methoxy-3-methyl-9-(phenylsulfonyl)-
9H-carbazole (10c): Preparation of the enol ether using β-ketosulf-
one 22c (3.81 g, 6 mmol), dimethyl sulfate (2.86 mL, 30 mmol), and
K2CO3 (8.28 g, 60 mmol) in THF (100 mL) at room temperature
followed by electrocyclization and subsequent column chromato-
graphic purification (silica gel; hexane/ethyl acetate, 8.5:1.5) gave
carbazole 10c (2.55 g, 84%) as a colorless solid, m.p. 202–204 °C.
3-(Bromomethyl)-4-methoxy-2-(2-nitrophenyl)-9-(phenylsulfonyl)-
9H-carbazole (23a): Benzylic bromination of 3-methylcarbazole
10a (1.65 g, 3.5 mmol) using NBS (1.86 g, 10.5 mmol) and AIBN
(50 mg) in dry CCl4 (100 mL) at reflux followed by work-up as
described above gave 3-(bromomethyl)carbazole 23a (1.71 g, 89%)
as a dull white solid, m.p. 210–212 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.28 (d, J = 8.4 Hz, 1 H, Ar), 8.06–8.02 (m, 2 H, Ar),
1H NMR (300 MHz, CDCl3): δ = 8.22 (d, J = 8.4 Hz, 1 H, Ar), 7.92 (s, 1 H, Ar), 7.71–7.66 (m, 3 H, Ar), 7.61–7.56 (m, 2 H, Ar),
8.02 (d, J = 7.8 Hz, 1 H, Ar), 7.92–7.91 (m, 1 H, Ar), 7.81 (s, 1 H,
Ar), 7.63 (d, J = 7.8 Hz, 2 H, Ar), 7.54–7.51 (m, 1 H, Ar), 7.38 (t,
J = 7.8 Hz, 1 H, Ar), 7.31–7.24 (m, 3 H, Ar), 7.18–7.13 (m, 2 H,
Ar), 3.76 (s, 3 H, OCH3), 1.99 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 153.6, 149.5, 138.4, 137.5, 137.1 (2 C), 134.6,
134.5, 134.0, 133.4, 132.8, 129.1, 127.4, 126.5, 125.0, 124.8, 124.6,
124.4, 122.9, 120.0, 115.0, 111.3, 60.3, 12.7 ppm. HRMS (ESI):
calcd. for C26H19ClN2O5S [M]+ 506.0703; found 506.0668.
7.49–7.36 (m, 3 H, Ar), 7.33–7.28 (m, 2 H, Ar), 4.68 (d, J =
10.2 Hz, 1 H, CH), 4.14 (d, J = 10.2 Hz, 1 H, CH), 4.05 (s, 3 H,
OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.0, 147.6, 138.1,
137.2, 137.0, 135.7, 132.9, 132.7, 131.3, 131.2, 128.0, 127.9, 126.3,
125.1, 123.7, 123.4, 123.0, 122.8, 121.6, 118.5, 113.6, 110.8, 60.0,
24.5 ppm. DEPT-135 (75 MHz, CDCl3): δ = 134.2, 132.6, (2CH),
129.4, 129.3, 127.7, 126.5, 124.7, 124.3, 123.0, 115.0, 112.2, 61.3,
25.9 ppm. HRMS (EI): calcd. for C26H19BrN2O5S [M]+ 550.0198;
found 550.0190.
2-(4-Fluoro-2-nitrophenyl)-4-methoxy-3-methyl-9-(phenylsulfonyl)-
9H-carbazole (10d): Preparation of the enol ether using β-ketosulf-
one 22d (3.7 g, 6 mmol), dimethyl sulfate (2.86 mL, 30 mmol), and
K2CO3 (8.28 g, 60 mmol) in THF (100 mL) at room temperature
followed by electrocyclization and subsequent column chromato-
graphic purification (silica gel; hexane/ethyl acetate, 8.5:1.5) gave
carbazole 10d (2.26 g, 77%) as a colorless solid, m.p. 190–192 °C.
3-(Bromomethyl)-2-(4,5-dimethoxy-2-nitrophenyl)-4-methoxy-9-
(phenylsulfonyl)-9H-carbazole (23b): Benzylic bromination of 3-
methylcarbazole 10b (1.86 g, 3.5 mmol) using NBS (1.86 g,
10.5 mmol) and AIBN (50 mg) in dry CCl4 (100 mL) at reflux fol-
lowed by work-up as described above gave 3-(bromomethyl)carb-
azole 23b (1.86 g, 87%) as a colorless solid, m.p. 256–258 °C. 1H
1H NMR (300 MHz, CDCl3): δ = 8.33 (d, J = 8.4 Hz, 1 H, Ar), NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 8.1 Hz, 1 H, Ar), 8.04
8.14 (d, J = 7.8 Hz, 1 H, Ar), 7.92 (s, 1 H, Ar), 7.79 (d, J = 7.8 Hz,
1 H, Ar), 7.75 (d, J = 7.5 Hz, 2 H, Ar), 7.53–7.40 (m, 5 H, Ar),
7.34 (t, J = 7.35 Hz, 2 H, Ar), 3.90 (s, 3 H, OCH3), 2.10 (s, 3 H,
(d, J = 7.8 Hz, 1 H, Ar), 7.90 (s, 1 H, Ar), 7.69–7.67 (m, 3 H, Ar),
7.49–7.33 (m, 3 H, Ar), 7.31–7.26 (m, 2 H, Ar), 6.99 (s, 1 H, Ar),
4.73 (d, J = 9.9 Hz, 1 H, CH), 4.11 (d, J = 9.9 Hz, 1 H, CH), 3.99
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.5 (d, J = 250 Hz), (s, 3 H, OCH3), 3.97 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3) ppm.
153.6, 149.6 (d, J = 8.37 Hz), 138.4, 137.5, 137.2 (2 C), 134.0, 133.7
(d, J = 7.69 Hz), 132.3 (d, J = 4.5 Hz), 129.1, 127.3, 126.5, 125.0
(d, J = 19.38 Hz), 124.6, 122.8, 120.2, 119.9, 115.1, 111.9 (d, J =
26.46 Hz), 111.6, 60.3, 12.7 ppm (only 23 carbon signals appeared).
HRMS (EI): calcd. for C26H19FN2O5S [M]+ 490.0999; found
490.0992.
13C NMR (75 MHz, CDCl3): δ = 154.5, 152.4, 148.7, 141.0, 139.6,
139.5, 138.4, 137.1, 134.2, 129.2, 128.7, 127.6, 126.5, 124.9, 124.7,
124.2, 122.9, 119.7, 115.0, 114.1, 112.0, 107.7, 61.3, 56.7, 56.5,
26.5 ppm. DEPT-135 (75 MHz, CDCl3): δ = 134.2, 129.2, 127.6,
126.5, 124.7, 123.0, 115.0, 114.1, 112.0, 107.6, 61.3, 56.7, 56.5,
26.5 ppm. HRMS (EI): calcd. for C28H23BrN2O7S [M]+ 610.0409;
found 610.0400.
2-(4,5-Dichloro-2-nitrophenyl)-4-methoxy-3-methyl-9-(phenylsulf-
onyl)-9H-carbazole (10e): Preparation of the enol ether using β-
ketosulfone 22e (4.0 g, 6 mmol), dimethyl sulfate (2.86 mL,
3-(Bromomethyl)-2-(4-chloro-2-nitrophenyl)-4-methoxy-9-(phenyl-
sulfonyl)-9H-carbazole (23c): Benzylic bromination of 3-methyl-
1274
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1266–1279

Total Synthesis of Calothrixin B and Its Analogs
carbazole 10c (1.77 g, 3.5 mmol) using NBS (1.86 g, 10.5 mmol)
and AIBN (50 mg) in dry CCl4 (100 mL) at reflux followed by
work-up as described above gave 3-(bromomethyl)carbazole 23c
(1.88 g, 92 %) as a colorless solid, m.p. 158–160 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.35 (d, J = 8.1 Hz, 1 H, Ar), 8.13–8.11
(m, 2 H, Ar), 7.96 (s, 1 H, Ar), 7.77–7.72 (m, 3 H, Ar), 7.63–7.45
(m, 4 H, Ar), 7.41–7.34 (m, 2 H, Ar), 4.75 (d, J = 9.9 Hz, 1 H,
CH), 4.19 (d, J = 9.9 Hz, 1 H, CH), 4.11 (s, 3 H, OCH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 154.4, 149.3, 139.4, 138.4, 137.3,
137.1, 135.2, 134.3, 133.7, 132.7, 132.4, 129.3, 127.9, 126.5, 125.0,
124.8, 124.5, 124.0, 123.1, 120.1, 115.0, 112.2, 61.4, 25.7 ppm.
DEPT-135 (75 MHz, CDCl3): δ = 134.3, 133.7, 132.7, 129.3, 127.9,
126.5, 124.8, 124.5, 123.1, 115.0, 112.2, 61.4, 25.7 ppm. HRMS
(EI): calcd. for C26H18BrClN2O5S [M]+ 583.9808; found 583.9800.
160.0, 148.4, 142.3, 139.6, 138.4, 137.1, 135.9, 134.4, 132.9, 131.6,
129.3, 128.7, 128.1, 126.5, 125.0, 124.3, 123.8, 123.0, 122.9, 119.7,
114.9, 112.6, 63.8 ppm. DEPT-135 (75 MHz, CDCl3): δ = 187.7,
133.5, 131.9, 130.6, 128.4, 127.8, 127.1, 125.5, 124.0, 123.3, 122.1,
113.9, 111.6, 62.8 ppm. HRMS (ESI): calcd. for C26H18N2O6S
[M]+ 486.0886; found 486.0889.
2-(4,5-Dimethoxy-2-nitrophenyl)-4-methoxy-9-(phenylsulfonyl)-9H-
carbazole-3-carbaldehyde (24b): A solution of 3-(bromomethyl)-
carbazole 23b (1.53 g, 2.5 mmol) and bis(tetrabutylammonium) di-
chromate (2.63 g, 75 mmol) in dry CHCl3 (50 mL) was heated at
reflux for 10 h. Removal of the solvent in vacuo followed by purifi-
cation of the residue by flash column chromatography (silica gel;
hexane/ethyl acetate, 3:1) gave carbazole aldehyde 24b (1.19 g,
86%) as a colorless solid, m.p. 198–200 °C. 1H NMR (300 MHz,
CDCl3): δ = 10.34 (s, 1 H, CHO), 8.35 (d, J = 8.4 Hz, 1 H, Ar),
8.20 (d, J = 7.5 Hz, 1 H, Ar), 8.01 (s, 1 H, Ar), 7.80–7.78 (m, 3 H,
Ar), 7.60–7.45 (m, 3 H, Ar), 7.38 (t, J = 7.65 Hz, 2 H, Ar), 6.72 (s,
1 H, Ar), 4.11 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 3.95 (s, 3 H,
OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 188.9, 159.7, 152.9,
148.4, 142.4, 140.6, 140.5, 138.5, 137.2, 134.5, 130.5, 129.4, 128.0,
126.5, 125.0, 123.9, 123.1, 119.6, 115.0, 113.0, 112.5, 107.6, 63.8,
56.5 (2 C) ppm (only 25 carbon signals appeared). DEPT-135
(75 MHz, CDCl3): δ = 188.9, 134.5, 129.4, 128.1, 126.5, 125.0,
123.1, 115.0, 113.0, 112.5, 107.6, 63.8, 56.5 (2 CH) ppm. HRMS
(ESI): calcd. for C28H22N2O8S [M]+ 546.1097; found 546.1091. For
single-crystal X-ray analysis of 24b, all calculations were performed
with the SHELXL-97 program.[ 2 7 ] Crystal data of 24b:
C28H22N2O8S, MW = 546.55 g/mol, Orthorhombic crystal system,
space group Pca21, Z = 4, a = 8.3976(6) Å, b = 13.7584(9) Å, c =
21.7971(12) Å, α = 90.000(0)°, β = 90.000(0)°, γ = 90.000(0)°, V
= 2518.4(3) Å3, Dcalcd. = 1.441 Mg/m3. In total, 5538 independent
reflections were collected, of which 4047 were considered as ob-
served [IϾ2σ(I)]. The structure was solved by direct methods and
refined by full-matrix least-squares procedures to a final R-value
of 4.33%.
3-(Bromomethyl)-2-(4-fluoro-2-nitrophenyl)-4-methoxy-9-(phenyl-
sulfonyl)-9H-carbazole (23d): Benzylic bromination of 3-methyl-
carbazole 10d (1.72 g, 3.5 mmol) using NBS (1.86 g, 10.5 mmol)
and AIBN (50 mg) in dry CCl4 (100 mL) at reflux followed by
work-up as described above yielded 3-(bromomethyl)carbazole 23d
(1.69 g, 85 %) as a colorless solid, m.p. 178–180 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.35 (d, J = 8.4 Hz, 1 H, Ar), 8.12 (d, J =
7.8 Hz, 1 H, Ar), 7.97 (s, 1 H, Ar), 7.85 (dd, J = 8.1, J = 2.4 Hz,
1 H, Ar), 7.76 (d, J = 7.8 Hz, 2 H, Ar), 7.68–7.64 (m, 1 H, Ar),
7.57–7.34 (m, 6 H, Ar), 4.74 (d, J = 10.2 Hz, 1 H, CH), 4.19 (d, J
= 10.2 Hz, 1 H, CH), 4.11 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.8 (d, J = 252.59 Hz), 153.3, 148.3 (d, J
= 8.37 Hz), 138.3, 137.3, 136.5, 136.0, 133.2, 133.1 (d, J = 7.65 Hz),
129.0 (d, J = 3.92 Hz), 128.2, 126.8, 125.4, 124.1, 123.7, 123.0,
121.9, 119.0, 118.9 (d, J = 20.85 Hz), 113.7, 111.3, 111.0 (d, J =
26.54 Hz), 60.3, 24.7 ppm. DEPT-135 (75 MHz, CDCl3): δ = 133.2
(d, J = 7.65 Hz), 133.2, 133.1, 128.2, 126.8, 125.4, 123.7, 121.9,
118.9 (d, J = 21.03 Hz), 113.9, 111.3, 111.0 (d, J = 26.62 Hz), 60.3,
24.6 ppm. HRMS (EI): calcd. for C26H18BrFN2O5S [M]+ 568.0104;
found 568.0100.
3-(Bromomethyl)-2-(4,5-dichloro-2-nitrophenyl)-4-methoxy-9-(phen-
ylsulfonyl)-9H-carbazole (23e): Benzylic bromination of 3-methyl-
carbazole 10e (1.9 g, 3.5 mmol) using NBS (1.86 g, 10.5 mmol) and
AIBN (50 mg) in dry CCl4 (100 mL) at reflux followed by work-up
as described above 3-(bromomethyl)carbazole 23e (1.89 g, 87%) as
The CCDC-952297 contains the supplementary crystallographic
data for 24b. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1
a colorless solid, m.p. 204–206 °C. H NMR (300 MHz, CDCl3): δ
2-(4-Chloro-2-nitrophenyl)-4-methoxy-9-(phenylsulfonyl)-9H-carb-
azole-3-carbaldehyde (24c): A solution of 3-(bromomethyl)carb-
azole 23c (1.50 g, 2.5 mmol) and bis(tetrabutylammonium) di-
chromate (2.63 g, 3.75 mmol) in dry CHCl3 (50 mL) was heated
at reflux for 10 h. Removal of the solvent in vacuo followed by
purification of the residue by flash column chromatography (silica
gel; hexane/ethyl acetate, 4:1) gave carbazole aldehyde 24c (1.08 g,
81%) as a colorless solid, m.p. 226–228 °C. 1H NMR (300 MHz,
CDCl3): δ = 10.38 (s, 1 H, CHO), 8.36 (d, J = 8.1 Hz, 1 H, Ar),
8.20–8.17 (m, 2 H, Ar), 8.00 (s, 1 H, Ar), 7.80 (d, J = 7.5 Hz, 2 H,
Ar), 7.66 (d, J = 7.8 Hz, 1 H, Ar), 7.61–7.45 (m, 3 H, Ar), 7.39 (t,
J = 7.5 Hz, 2 H, Ar), 7.30 (d, J = 8.1 Hz, 1 H, Ar), 4.10 (s, 3 H,
OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 188.7, 160.3, 148.7,
142.5, 138.5, 138.1, 137.2, 134.6, 134.5, 133.1, 132.6, 129.4, 128.3,
126.5, 125.1, 124.5, 123.7, 123.1, 122.8, 119.9, 115.0, 112.8,
64.1 ppm (only 23 carbon signals appeared). DEPT-135 (75 MHz,
CDCl3): δ = 188.7, 134.6, 133.1, 132.6, 129.4, 128.3, 126.5, 125.1,
124.5, 123.1, 115.0, 112.8, 64.1 ppm. HRMS (EI): calcd. for
C26H17ClN2O6S [M]+ 520.0496; found 520.0490.
= 8.35 (d, J = 8.1 Hz, 1 H, Ar), 8.26 (s, 1 H, Ar), 8.12 (d, J =
7.5 Hz, 1 H, Ar), 7.96 (s, 1 H, Ar), 7.77–7.74 (m, 3 H, Ar), 7.58–
7.44 (m, 3 H, Ar), 7.41–7.34 (m, 2 H, Ar), 4.73 (d, J = 10.2 Hz, 1
H, CH), 4.21 (d, J = 10.2 Hz, 1 H, CH), 4.11 (s, 3 H, OCH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 154.4, 147.2, 139.5, 138.5, 137.6,
137.2, 136.3, 134.3, 134.1, 133.8, 133.6, 129.4, 129.3, 128.0, 126.5,
126.3, 124.8, 123.9, 123.1, 120.3, 115.0, 112.0, 61.4, 25.3 ppm.
DEPT-135 (75 MHz, CDCl3): δ = 134.3, 134.1, 129.3, 128.0, 126.5,
126.3, 124.8, 123.1, 115.0, 112.0, 61.6, 25.3 ppm. HRMS (EI):
calcd. for C26H17BrCl2N2O5S [M]+ 617.9419; found 617.9410.
4-Methoxy-2-(2-nitrophenyl)-9-(phenylsulfonyl)-9H-carbazole-3-
carbaldehyde (24a): A solution of 3-(bromomethyl)carbazole 23a
(1.38 g, 2.5 mmol) and bis(tetrabutylammonium) dichromate
(2.63 g, 3.75 mmol) in dry CHCl3 (50 mL) was heated at reflux for
10 h. Removal of the solvent in vacuo followed by purification of
the residue by flash column chromatography (silica gel; hexane/
ethyl acetate, 8.5:1.5) gave carbazole aldehyde 24a (0.98 g, 82%) as
1
a colorless solid, m.p. 188–190 °C. H NMR (300 MHz, CDCl3): δ
= 10.27 (s, 1 H, CHO), 8.30 (d, J = 8.4 Hz, 1 H, Ar), 8.14–8.11 2-(4-Fluoro-2-nitrophenyl)-4-methoxy-9-(phenylsulfonyl)-9H-carb-
(m, 2 H, Ar), 7.95 (s, 1 H, Ar), 7.74 (d, J = 7.8 Hz, 2 H, Ar), 7.66– azole-3-carbaldehyde (24d): A solution of 3-(bromomethyl)carb-
7.61 (m, 1 H, Ar), 7.58–7.40 (m, 4 H, Ar), 7.38–7.29 (m, 3 H, Ar),
azole 23d (1.42 g, 2.5 mmol) and bis(tetrabutylammonium) di-
chromate (2.63 g, 3.75 mmol) in dry CHCl3 (50 mL) was heated
4.04 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 188.7,
Eur. J. Org. Chem. 2014, 1266–1279
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1275

V. Saravanan, B. Muthu Ramalingam, A. K. Mohanakrishnan
FULL PAPER
at reflux for 10 h. Removal of the solvent in vacuo followed by
purification of the residue by flash column chromatography (silica
gel; hexane/ethyl acetate, 4:1) gave carbazole aldehyde 24d (1.06 g,
84%) as a colorless solid, m.p. 184–186 °C. 1H NMR (300 MHz,
ter the reaction was complete (monitored by TLC), the mixture was
poured into ice-water (50 mL) containing HCl (33%, 5 mL). The
organic phase was separated, and the aqueous phase was then ex-
tracted with CH2Cl2 (2ϫ 10 mL). The combined organic extracts
CDCl3): δ = 10.38 (s, 1 H, CHO), 8.36 (d, J = 8.1 Hz, 1 H, Ar), were washed with water (2ϫ 30 mL) and dried (Na2SO4). Removal
8.19 (d, J = 7.5 Hz, 1 H, Ar), 8.01 (s, 1 H, Ar), 7.94–7.91 (m, 1 H, of the solvent followed by trituration of the crude product with
Ar), 7.80 (d, J = 7.8 Hz, 2 H, Ar), 7.61–7.45 (m, 3 H, Ar), 7.42– MeOH (10 mL) gave 26a–26e.
7.32 (m, 4 H, Ar), 4.11 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz,
4-Hydroxy-2-(2-nitrophenyl)-9-(phenylsulfonyl)-9H-carbazole-3-
CDCl3): δ = 188.7, 161.6 (d, J = 249.75 Hz), 160.2, 148.8 (d, J =
8.14 Hz), 142.4, 138.5, 138.3, 137.2, 134.5, 133.0 (d, J = 7.76 Hz),
132.2 (d, J = 3.75 Hz), 129.4, 128.2, 126.5, 125.1, 123.7, 123.1,
122.9, 120.3 (d, J = 21.1 Hz), 119.9, 115.0, 112.9, 112.1 (d, J =
26.61 Hz), 64.0 ppm. DEPT-135 (75 MHz, CDCl3): δ = 188.8,
134.5, 133.0 (d, J = 8.4 Hz), 129.4, 128.2, 126.5, 125.1, 123.1, 120.3
(d, J = 21.4 Hz), 115.0, 112.9, 112.1 (d, J = 26.69 Hz), 64.0 ppm.
HRMS (EI): calcd. for C26H17FN2O6S [M]+ 504.0791; found
504.0790.
carbaldehyde (26a): Cleavage of the methyl ether of carbazole 24a
(0.73 g, 1.5 mmol) using a 1 m solution of BBr3 (1.65 mL,
1.65 mmol) in dry CH2Cl2 (20 mL) at 0 °C for 5 min, followed by
work-up as described above gave 4-hydroxycarbazole 26a (0.66 g,
93%) as a pale yellow solid, m.p. 220–222 °C, ref.[17] m.p. 216–
220 °C. 1H NMR (300 MHz, CDCl3): δ = 12.76 (s, 1 H, OH), 9.64
(s, 1 H, CHO), 8.31 (t, J = 7.05 Hz, 2 H, Ar), 8.11 (d, J = 7.5 Hz,
1 H, Ar), 7.80–7.65 (m, 5 H, Ar), 7.52–7.38 (m, 6 H, Ar) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 195.0, 159.8, 149.6, 143.0, 140.8,
137.9, 137.2, 134.5, 133.0, 132.6, 132.5, 129.8, 129.4, 127.5, 126.5,
124.7, 124.5, 123.5, 115.0, 114.6, 114.5, 107.8 ppm (only 22 carbon
signals appeared).
2-(4,5-Dichloro-2-nitrophenyl)-4-methoxy-9-(phenylsulfonyl)-9H-
carbazole-3-carbaldehyde (24e): A solution of 3-(bromomethyl)-
carbazole 23e (1.55 g, 2.5 mmol) and bis(tetrabutylammonium) di-
chromate (2.62 g, 3.75 mmol) in dry CHCl3 (50 mL) was heated
at reflux for 10 h. Removal of the solvent in vacuo followed by
purification of the residue by flash column chromatography (silica
gel; hexane/ethyl acetate, 3:1) gave carbazole aldehyde 24e (1.13 g,
82%) as a colorless solid, m.p. 224–226 °C. 1H NMR (300 MHz,
CDCl3): δ = 10.41 (s, 1 H, CHO), 8.37 (d, J = 8.4 Hz, 1 H, Ar),
8.32 (s, 1 H, Ar), 8.19 (d, J = 7.5 Hz, 1 H, Ar), 8.00 (s, 1 H, Ar),
7.80 (d, J = 7.5 Hz, 2 H, Ar), 7.63–7.57 (m, 1 H, Ar), 7.52 (t, J =
7.35 Hz, 2 H, Ar), 7.46–7.37 (m, 3 H, Ar), 4.11 (s, 3 H, OCH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 188.6, 160.5, 146.7, 142.5,
138.5, 137.9, 137.2, 136.8, 136.0, 134.6, 132.9, 132.7, 129.4, 128.4,
126.5, 126.2, 125.2, 123.5, 123.1, 122.7, 120.1, 115.0, 112.7,
64.2 ppm. DEPT-135 (75 MHz, CDCl3): δ = 188.6, 134.6, 132.7,
129.4, 128.4, 126.5, 126.3, 125.2, 123.1, 115.0, 112.7, 64.2 ppm.
HRMS (EI): calcd. for C26H16Cl2N2O6S [M]+ 554.0106; found
554.0100.
2-(4,5-Dimethoxy-2-nitrophenyl)-4-hydroxy-9-(phenylsulfonyl)-9H-
carbazole-3-carbaldehyde (26b): Cleavage of methyl ether of carba-
zole 24b (0.82 g, 1.5 mmol) using a 1 m solution of BBr3 (1.65 mL,
1.65 mmol) in dry CH2Cl2 (20 mL) at 0 °C for 5 min, followed by
work-up as described above gave 4-hydroxycarbazole 26b (0.73 g,
92%) as a pale yellow solid, m.p. 194–196 °C, ref.[17] m.p. 188–
190 °C. 1H NMR (300 MHz, CDCl3): δ = 12.74 (s, 1 H, OH), 9.64
(s, 1 H, CHO), 8.32 (d, J = 8.4 Hz, 2 H, Ar), 7.80–7.76 (m, 4 H,
Ar), 7.53 (t, J = 7.5 Hz, 2 H, Ar), 7.47–7.37 (m, 3 H, Ar), 6.84 (s,
1 H, Ar), 4.07 (s, 3 H, OCH3), 3.99 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 195.1, 159.7, 152.6, 149.2, 143.1, 142.0,
141.5, 137.8, 137.1, 134.5, 129.4, 127.4, 127.1, 126.5, 125.0, 124.8,
123.4, 114.7, 114.6, 114.1, 107.7, 56.7, 56.6 ppm (only 23 carbon
signals appeared).
2-(4-Chloro-2-nitrophenyl)-4-hydroxy-9-(phenylsulfonyl)-9H-carb-
azole-3-carbaldehyde (26c): Cleavage of methyl ether of carbazole
24c (0.78 g, 1.5 mmol) using a 1 m solution of BBr3 (1.65 mL,
1.65 mmol) in dry CH2Cl2 (20 mL) at 0 °C for 5 min, followed by
work-up as described above gave 4-hydroxycarbazole 26c (0.73 g,
96%) as a pale yellow solid, m.p. 264–266 °C, ref.[17] m.p. 262–
264 °C. 1H NMR (300 MHz, CDCl3): δ = 12.75 (s, 1 H, OH), 9.64
(s, 1 H, CHO), 8.33–8.29 (m, 2 H, Ar), 8.11–8.10 (m, 1 H, Ar),
7.78 (d, J = 7.5 Hz, 2 H, Ar), 7.73–7.70 (m, 2 H, Ar), 7.56–7.37
(m, 6 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.5, 159.9,
149.9, 142.9, 139.4, 137.9, 137.2, 135.8, 134.5, 133.9, 132.6, 131.0,
129.5, 127.6, 126.4, 125.1, 124.7, 124.6, 123.6, 115.2, 114.6, 114.4,
107.8 ppm.
7-Methoxy-12-(phenylsulfonyl)-12H-indolo[3,2-j]phenanthridine
(25): Raney Ni (1 g) was carefully added to a solution of 4-meth-
oxycarbazole-3-carbaldehyde 24a (0.1 g, 0.20 mmol) in acetone
(20 mL), and the mixture was heated at reflux for 3 h. After the
starting material had been consumed, the reaction mixture was fil-
tered through Celite, which was then washed with acetone (2ϫ
10 mL). Removal of the solvent from the filtrate followed by col-
umn chromatographic purification of the residue (silica gel; hexane/
ethyl acetate, 8:2) gave quinocarbazole 25 (50 mg, 56%) as a color-
1
less solid, m.p. 202–204 °C. H NMR (300 MHz, [D6]DMSO): δ =
9.66 (s, 1 H, Ar), 9.30 (s, 1 H, Ar), 8.89–8.85 (m, 1 H, Ar), 8.36
(d, J = 8.4 Hz, 1 H, Ar), 8.32 (d, J = 7.8 Hz, 1 H, Ar), 8.19–8.16
(m, 1 H, Ar), 8.05 (d, J = 7.5 Hz, 2 H, Ar), 7.88 (t, J = 7.5 Hz, 2
H, Ar), 7.72 (t, J = 7.35 Hz, 1 H, Ar), 7.67–7.57 (m, 2 H, Ar), 7.52
(t, J = 7.35 Hz, 2 H, Ar), 4.19 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 153.8, 148.1, 144.3, 141.3, 138.8, 136.9,
135.7, 133.0, 130.5, 130.3, 130.0, 129.4, 128.3, 127.0, 125.8, 124.0,
123.7, 123.5, 118.7, 117.4, 115.0, 102.8, 63.8 ppm (only 23 carbon
signals appeared). 13C NMR (DEPT-135, 75 MHz, [D6]DMSO): δ
= 147.5, 135.2, 130.0, 129.8, 129.4, 128.9, 127.8, 126.5, 125.3, 123.4,
123.0, 114.5, 102.2, 63.3 ppm. HRMS (ESI): calcd. for
C26H18N2O3S [M]+ 438.1038; found 438.1046.
2-(4-Fluoro-2-nitrophenyl)-4-hydroxy-9-(phenylsulfonyl)-9H-carb-
azole-3-carbaldehyde (26d): Cleavage of methyl ether of carbazole
24d (0.76 g, 1.5 mmol) using a 1 m solution of BBr3 (1.65 mL,
1.65 mmol) in dry CH2Cl2 (20 mL) at 0 °C and stirred for 5 min,
followed by work-up as described above gave 4-hydroxycarbazole
26d (0.73 g, 96%) as a pale yellow solid, m.p. 228–230 °C, ref.[17]
1
m.p. 222–224 °C. H NMR (300 MHz, CDCl3): δ = 12.76 (s, 1 H,
OH), 9.63 (s, 1 H, CHO), 8.34–8.31 (m, 2 H, Ar), 7.85 (dd, J =
7.8, J = 2.1 Hz, 1 H, Ar), 7.78 (d, J = 7.8 Hz, 2 H, Ar), 7.74 (s, 1
H, Ar), 7.57–7.47 (m, 4 H, Ar), 7.45–7.38 (m, 3 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 194.6, 162.2 (d, J = 250.32 Hz), 159.9,
150.0 (d, J = 8.14 Hz), 143.0, 139.6, 137.9, 137.2, 134.5, 134.4 (d,
General Procedure for the Preparation of 4-Hydroxy-carbazole-3-
carbaldehydes 26a–26e:[17] BBr3 (1 m solution in CH2Cl2; 1.65 mL, J = 7.95 Hz), 129.4, 128.6 (d, J = 4.00 Hz), 127.6, 126.4, 125.0,
1.65 mmol) was added to a solution of 4-methoxycarbazole-3-car-
baldehydes 24a–24e (1.5 mmol) in dry CH2Cl2 (20 mL) at 0 °C. Af-
124.7, 123.6, 120.0 (d, J = 22.62 Hz), 115.2, 114.6, 114.5, 112.4 (d,
J = 28.27 Hz), 108.1 ppm.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1266–1279

Total Synthesis of Calothrixin B and Its Analogs
2-(4,5-Dichloro-2-nitrophenyl)-4-hydroxy-9-(phenylsulfonyl)-9H-
carbazole-3-carbaldehyde (26e): Cleavage of methyl ether of carb-
azole 24e (0.83 g, 1.5 mmol) using a 1 m solution of BBr3 (1.65 mL,
1.65 mmol) in dry CH2Cl2 (20 mL) at 0 °C for 5 min, followed by
work-up as described above gave 4-hydroxycarbazole 26e (0.74 g,
92%) as a pale yellow solid, m.p. 222–224 °C, ref.[17] m.p. 210–
212 °C. 1H NMR (300 MHz, CDCl3): δ = 12.74 (s, 1 H, OH), 9.66
(s, 1 H, CHO), 8.32 (d, J = 7.8 Hz, 2 H, Ar), 8.25 (s, 1 H, Ar),
7.79–7.74 (m, 3 H, Ar), 7.64 (s, 1 H, Ar), 7.55–7.53 (m, 2 H, Ar),
7.48–7.38 (m, 3 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
194.1, 160.0, 147.6, 142.9, 138.2, 137.9, 137.8, 137.2, 134.6, 134.4,
134.1, 132.3, 129.5, 127.7, 126.4, 125.1, 124.5, 123.6, 115.4, 114.6,
114.2, 107.8 ppm (only 22 carbon signals appeared).
113.9 ppm (only eight CH carbon signals appeared). HRMS (EI):
calcd. for C19H10N2O2 [M]+ 298.0742; found 298.0731.
7,13-Dioxo-12,13-dihydro-7H-indolo[3,2-j]phenanthridine 5-Oxide
(Calothrixin A; 1): Red solid (29 mg, 31 %), m.p. Ͼ280 °C. IR
(KBr): ν = 3441, 1659 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ
˜
= 13.19 (s, 1 H, NH), 9.66 (d, J = 9.0 Hz, 1 H, Ar), 8.86 (s, 1 H,
Ar), 8.59 (d, J = 8.7 Hz, 1 H, Ar), 8.10 (d, J = 7.5 Hz, 1 H, Ar),
7.98–7.95 (m, 2 H, Ar), 7.59 (d, J = 8.1 Hz, 1 H, Ar), 7.44 (t, J =
7.35 Hz, 1 H, Ar), 7.36 (t, J = 7.5 Hz, 1 H, Ar) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 178.2, 177.7, 143.1, 138.6, 138.1, 131.9,
131.8, 131.7, 129.8, 128.1, 127.0, 126.8, 124.4, 123.4, 122.0, 121.8,
119.1, 115.1, 114.0 ppm. DEPT-135 (75 MHz, [D6]DMSO): δ =
131.9, 131.7 (2 C), 128.0, 126.9, 124.4, 121.9, 119.0, 113.9 ppm.
HRMS (EI): calcd. for C19H10N2O3 [M]+ 314.0691; found
314.0672.
4-Hydroxy-2-(2-nitrophenyl)-9H-carbazole-3-carbaldehyde (27):[8]
NaOH (50% aq.; 2 g NaOH; 4 mL) was added to a solution of
carbaldehyde 26a (0.5 g, 1.06 mmol) in DMSO (10 mL), and the
mixture was stirred at room temperature for 3 h. After the reaction
was complete (monitored by TLC), the mixture was poured onto
crushed ice (20 g) containing HCl (33%, 2 mL). The resulting solid
was filtered and dried (CaCl2). The crude product was then washed
with methanol to give 27 (0.33 g, 95%) as a brown solid, m.p. 266–
Synthesis of Calothrixin B (2) and Calothrixin A (1) by Oxidation
Using Fremy’s Salt: Pd/C (10%; 0.2 g) was added to a solution of
4-hydroxycarbazole-3-carbaldehyde 27 (0.1 g, 0.30 mmol) in EtOH
(20 mL), and the mixture was stirred at room temperature for 6 h
under a hydrogen atmosphere (balloon). Then, work-up as de-
scribed above gave the quinocarbazoles. Frémy’s salt (0.24 g,
0.90 mmol) and H2O (4 mL) were added to a solution of the quino-
carbazoles (85 mg) in THF (20 mL) at 0 °C, and the mixture was
stirred for 1 h. Then, the mixture was poured onto crushed ice
(50 g). The resulting red solid was filtered and dried (CaCl2). The
1H NMR spectrum of the crude product confirmed the presence
of calothrixin A (1) and calothrixin B (2) in a 1:1 ratio.
1
268 °C. H NMR (300 MHz, [D6]DMSO): δ = 13.31 (s, 1 H, NH),
12.10 (s, 1 H, OH), 9.51 (s, 1 H, CHO), 8.26–8.16 (m, 2 H, Ar),
7.85–7.61 (m, 4 H, Ar), 7.49 (t, J = 6.9 Hz, 1 H, Ar), 7.34 (t, J =
6.45 Hz, 1 H, Ar), 6.94 (s, 1 H, Ar) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 194.0, 160.3, 149.2, 144.6, 139.3, 139.2, 132.9, 132.8,
132.2, 129.8, 125.8, 124.1, 122.2, 121.7, 120.8, 111.7, 110.7, 109.7,
105.1 ppm. DEPT-90 (75 MHz, [D6]DMSO): δ = 194.0, 132.9,
132.8, 129.8, 125.8, 124.1, 122.1, 120.8, 111.7, 105.1 ppm.
General Procedure for the Formation of Quinocarbazoles 32a–32e:
Fe powder (0.22 g, 4.0 mmol), CaCl2 (0.14 g, 1.27 mmol), and H2O
(5 mL) were added to a solution of 4-hydroxycarbazole-3-carbal-
dehydes 26a–26e (0.4 mmol) in EtOH (150 mL), and the reaction
mixture was heated at reflux for 5 h. After the starting material
had been consumed, the solvent was removed in vacuo, and the
organic portion was dissolved in DMSO (20 mL). Then, the
DMSO solution was carefully filtered through Celite. The filtrate
was then poured onto crushed ice (100 g) containing HCl (33%,
5 mL). The resulting solid was filtered and dried (CaCl2). The
crude product was then washed with THF (10 mL) to give quino-
carbazoles 33a–33e.
Reductive Cyclization of 2-Nitrophenylcarbazole-3-carbaldehyde
Using Hibino’s Procedure:[8] Pd/C (10%; 0.2 g) was added to a solu-
tion of 4-hydroxycarbazole-3-carbaldehyde 27 (0.1 g, 0.30 mmol) in
EtOH (20 mL), and the mixture was stirred at room temperature
for 6 h under a hydrogen atmosphere (balloon). After the starting
material had been consumed, the solvent was removed in vacuo to
give an orange residue. This residue was then extracted with THF
(3ϫ 20 mL), and the combined THF extracts were filtered through
Celite. Evaporation of the filtrate gave a mixture of quinocarb-
azoles 30 and 31. HRMS (EI): calcd. (for 30) for C19H13N2O2 [M
+ H]+ 301.0977; found 301.0981; calcd. (for 31) for C19H13N2O [M +
H]+ 285.1028; found 285.1028. (see Supporting Information for
spectra.)
12-(Phenylsulfonyl)-12H-indolo[3,2-j]phenanthridin-7-ol (32a): Re-
ductive cyclization of carbazole-3-carbaldehyde 26a (0.19 g,
0.4 mmol) using Fe powder (0.22 g, 4.0 mmol), CaCl2 (0.14 g,
1.27 mmol), and H2O (5 mL) in EtOH (150 mL) at reflux as de-
scribed above gave quinocarbazole 32a (0.14 g, 81%) as an orange
solid, m.p. Ͼ300 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.53
(s, 1 H, Ar), 8.70 (d, J = 6.6 Hz, 1 H, Ar), 8.57 (s, 1 H, OH), 8.44
(d, J = 6.9 Hz, 1 H, Ar), 8.26 (d, J = 8.1 Hz, 1 H, Ar), 8.00–7.97
(m, 3 H, Ar), 7.83–7.75 (m, 2 H, Ar), 7.63 (t, J = 6.9 Hz, 1 H, Ar),
7.54–7.43 (m, 5 H, Ar) ppm. 13C NMR {75 MHz, CDCl3 (0.4 mL)/
[D]TFA (0.1 mL)}: δ = 154.4, 146.6, 144.3, 138.4, 136.7, 135.1,
134.0, 131.9, 131.4, 130.6, 129.6, 129.2, 126.4, 125.6, 125.0, 124.0,
123.8, 122.9, 121.0, 115.7, 114.3, 111.0, 100.1 ppm. HRMS (EI):
calcd. for C25H16N2O3S [M]+ 424.0882; found 424.0880.
Ceric ammonium nitrate (0.82 g, 1.49 mmol) was added to a sus-
pension of crude quinocarbazoles 30 and 31 (85 mg) in a mixture
of CH3CN (20 mL) and H2O (4 mL) at 0 °C, and the mixture was
stirred for 1 h. Then, the mixture was poured onto crushed ice
(50 g). The resulting red solid was filtered and dried (CaCl2). The
crude product was purified by flash column chromatography (silica
gel; hexane/ethyl acetate, 8:2) to give calothrixin B (2). Further elu-
tion of the column (silica gel; CH2Cl2/Et3N, 99:1) gave calothrixin
A (1).
7H-Indolo[3,2-j]phenanthridine-7,13(12H)-dione (Calothrixin B; 2):
Red-orange solid (27 mg, 30%), m.p. Ͼ300 °C. IR (KBr): ν = 3441,
˜
1659 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 13.12 (s, 1 H,
NH), 9.57 (s, 1 H, Ar), 9.53 (d, J = 8.4 Hz, 1 H, Ar), 8.13 (d, J =
2,3-Dimethoxy-12-(phenylsulfonyl)-12H-indolo[3,2-j]phenanthridin-
7-ol (32b): Reductive cyclization of carbazole-3-carbaldehyde 26b
8.1 Hz, 2 H, Ar), 7.92 (t, J = 7.05 Hz, 1 H, Ar), 7.85 (t, J = 7.8 Hz, (0.21 g, 0.4 mmol) using Fe powder (0.22 g, 4.0 mmol), CaCl2
1 H, Ar), 7.58 (d, J = 6.9 Hz, 1 H, Ar), 7.44 (t, J = 7.35 Hz, 1 H,
(0.14 g, 1.27 mmol), and H2O (5 mL) in EtOH (150 mL) at reflux
Ar), 7.35 (t, J = 7.35 Hz, 1 H, Ar) ppm. 13C NMR (75 MHz, [D6]- for 5 h as described above gave quinocarbazole 32b (0.17 g, 88%)
1
DMSO): δ = 180.8, 180.3, 151.2, 147.5, 138.4, 138.0, 132.6, 131.6,
as a red-orange solid, m.p. 258–260 °C. H NMR (300 MHz, [D6]-
130.2, 129.8, 127.1, 124.8, 124.3, 123.3, 122.5, 122.3, 115.5, DMSO): δ = 9.48 (s, 1 H, Ar), 8.45 (s, 1 H, OH), 8.37 (d, J =
113.9 ppm (only 18 carbon signals appeared). DEPT-90 (75 MHz,
[D6]DMSO): δ = 147.5, 131.6, 130.2, 129.8, 127.2, 124.3, 122.3,
7.2 Hz, 1 H, Ar), 8.23 (d, J = 7.8 Hz, 1 H, Ar), 7.96 (d, J = 7.8 Hz,
2 H, Ar), 7.85 (s, 1 H, Ar), 6.30 (t, J = 7.2 Hz, 1 H, Ar), 7.53–7.42
Eur. J. Org. Chem. 2014, 1266–1279
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1277

V. Saravanan, B. Muthu Ramalingam, A. K. Mohanakrishnan
FULL PAPER
(m, 6 H, Ar), 4.11 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3) ppm.
7H-Indolo[3,2-j]phenanthridine-7,13(12H)-dione (Calothrixin B;
13C NMR {75 MHz, CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 153.4, 2):[17] NaOH (25% aq.; 1 g NaOH in 4 mL) was added to a solution
153.0, 151.5, 145.8, 140.8, 138.0, 136.6, 135.1, 133.3, 129.6, 128.7,
127.6, 126.3, 125.4, 123.7, 122.9, 119.9, 114.5, 114.0, 110.7, 102.7,
101.2, 98.5, 56.4 (2 C) ppm. HRMS (ESI): calcd. for C27H21N2O5S
[M + H]+ 485.1171; found 485.1171.
of quinocarbazole 32a (85 mg, 0.2 mmol) in DMSO (10 mL) under
an O2 atmosphere (balloon). The reaction mixture was then stirred
at room temperature for 24 h. Work-up as described above gave
calothrixin B (2; 46 mg, 77%) as a red-orange solid, m.p. Ͼ300 °C.
2,3-Dimethoxy-7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione
(33b): NaOH (25% aq.; 1 g NaOH in 4 mL) was added to a solu-
tion of quinocarbazole 32b (0.10 g, 0.2 mmol) in DMSO (10 mL)
under an O2 atmosphere (balloon). The reaction mixture was then
stirred at room temperature for 36 h. Work-up as described above
3-Chloro-12-(phenylsulfonyl)-12H-indolo[3,2-j]phenanthridin-7-ol
(32c): Reductive cyclization of carbazole-3-carbaldehyde 26c
(0.20 g, 0.4 mmol) using Fe powder (0.22 g, 4.0 mmol), CaCl2
(0.14 g, 1.27 mmol), and H2O (5 mL) in EtOH (150 mL) at reflux
for 5 h, followed by work-up as described above gave quinocarb-
azole 32c (0.14 g, 74%) as a red-orange solid, m.p. Ͼ300 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 9.73 (s, 1 H, Ar), 8.80 (d, J =
8.7 Hz, 1 H, Ar), 8.43 (d, J = 7.8 Hz, 1 H, Ar), 8.29 (d, J = 8.1 Hz,
1 H, Ar), 8.09 (s, 1 H, Ar), 8.01 (d, J = 7.8 Hz, 2 H, Ar), 7.83–
7.80 (m, 1 H, Ar), 7.66–7.48 (m, 6 H, Ar) ppm. 13C NMR
{75 MHz, CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 154.9, 146.8,
145.5, 138.4, 138.2, 136.6, 135.2, 133.4, 131.9, 131.1, 129.6, 129.4,
126.4, 125.7, 125.2, 124.0, 123.2, 122.8, 120.5, 115.7, 114.2, 110.8,
99.7 ppm. HRMS (EI): calcd. for C25H15ClN2O3S [M]+ 458.0492;
found 458.0490.
gave 33b (64 mg, 87%) as a red solid, m.p. Ͼ300 °C. IR (KBr): ν
˜
= 3441, 1651, 1242 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ =
13.04 (s, 1 H, NH), 9.38 (s, 1 H, Ar), 9.00 (s, 1 H, Ar), 8.18 (d, J
= 7.5 Hz, 1 H, Ar), 7.63 (d, J = 8.4 Hz, 1 H, Ar), 7.51 (s, 1 H, Ar),
7.46 (d, J = 7.5 Hz, 1 H, Ar), 7.39 (t, J = 7.2 Hz, 1 H, Ar), 4.03
(s, 3 H, OCH3), 4.01 (s, 3 H, OCH3), ppm. 13C NMR {75 MHz,
CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 177.7, 177.1, 159.7, 155.9,
140.9, 138.9, 137.7, 137.1, 135.6, 130.1, 126.5, 125.9, 123.8, 123.5,
123.4, 118.0, 113.4, 105.1, 99.7, 57.2, 56.7 ppm. DEPT-135
{75 MHz, CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 137.7, 130.1,
126.5, 123.4, 113.5, 105.0, 99.7, 57.2, 56.7 ppm. HRMS (EI): calcd.
for C21H14N2O4 [M]+ 358.0954; found 358.0950.
3-Fluoro-12-(phenylsulfonyl)-12H-indolo[3,2-j]phenanthridin-7-ol
(32d): Reductive cyclization of carbazole-3-carbaldehyde 26d
(0.20 g, 0.4 mmol) using Fe powder (0.22 g, 4.0 mmol), CaCl2
(0.14 g, 1.27 mmol), and H2O (5 mL) in EtOH (150 mL) at reflux
for 5 h as described above gave quinocarbazole 32d (0.14 g, 77%)
as an orange solid, m.p. Ͼ300 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 9.70 (s, 1 H, Ar), 8.86–8.81 (m, 1 H, Ar), 8.76 (s, 1
H, OH), 8.42 (d, J = 7.2 Hz, 1 H, Ar), 8.29 (d, J = 8.1 Hz, 1 H,
Ar), 8.01 (d, J = 7.5 Hz, 2 H, Ar), 7.81 (dd, J = 9.9, J = 2.4 Hz, 1
H, Ar), 7.71–7.47 (m, 7 H, Ar) ppm. 13C NMR {75 MHz, CDCl3
(0.4 mL)/[D]TFA (0.1 mL)}: δ = 165.5, 154.6, 146.9, 145.5, 138.2,
136.6, 135.2, 133.8, 132.7 (d, J = 11.3 Hz), 129.6, 129.2, 126.6 (d,
J = 9.8 Hz), 126.4, 125.7, 123.9, 122.8, 121.6 (d, J = 1.5 Hz), 119.7
(d, J = 23.37 Hz), 115.4, 114.2, 110.8, 106.8 (d, J = 25.6 Hz),
99.6 ppm. HRMS (EI): calcd. for C25H15FN2O3S [M]+ 442.0787;
found 442.0800.
3-Chloro-7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione
(33c):
NaOH (25% aq.; 1 g NaOH in 4 mL) was added to a solution of
quinocarbazole 32c (90 mg, 0.2 mmol) in DMSO (10 mL) under an
O2 atmosphere (balloon). The reaction mixture was then stirred at
room temperature for 14 h. Work-up as described above gave 33c
(53 mg, 81%) as a red-orange solid, m.p. Ͼ300 °C. IR (KBr): ν =
˜
1
3441, 1651 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 13.15 (s, 1
H, NH), 9.61 (s, 1 H, Ar), 9.55 (d, J = 9.3 Hz, 1 H, Ar), 8.20 (s, 1
H, Ar), 8.14 (d, J = 7.5 Hz, 1 H, Ar), 7.91 (d, J = 9.3 Hz, 1 H,
Ar), 7.60 (d, J = 8.1 Hz, 1 H, Ar), 7.46 (t, J = 7.05 Hz, 1 H, Ar),
7.37 (t, J = 6.9 Hz, 1 H, Ar) ppm. 13C NMR {75 MHz, CDCl3
(0.4 mL)/[D]TFA (0.1 mL)}: δ = 176.6, 175.8, 146.0, 143.9, 141.1,
140.1, 139.2, 136.9, 135.3, 130.7, 130.3, 128.0, 126.9, 124.3, 124.0,
123.8, 121.0, 118.0, 113.7 ppm. DEPT-90 {75 MHz, CDCl3
(0.4 mL)/[D]TFA (0.1 mL)}: δ = 143.7, 135.1, 130.5, 130.1, 126.7,
123.5, 120.7, 113.5 ppm. HRMS (EI): calcd. for C19H9ClN2O2
[M]+ 332.0353; found 332.0313.
2,3-Dichloro-12-(phenylsulfonyl)-12H-indolo[3,2-j]phenanthridin-7-
ol (32e): Reductive cyclization of carbazole-3-carbaldehyde 26e
(0.22 g, 0.4 mmol) using Fe powder (0.22 g, 4.0 mmol), CaCl2
(0.14 g, 1.27 mmol), and H2O (5 mL) in EtOH (150 mL) at reflux
for 5 h as described above gave quinocarbazole 32e (0.14 g, 72%)
as a red-orange solid, m.p. Ͼ300 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 9.71 (s, 1 H, Ar), 8.87 (s, 1 H, Ar), 8.76 (s, 1 H, OH),
8.37 (d, J = 7.5 Hz, 1 H, Ar), 8.26 (d, J = 8.4 Hz, 1 H, Ar), 8.21
(s, 1 H, Ar), 8.04 (d, J = 7.8 Hz, 2 H, Ar), 7.60 (q, J = 8.1 Hz, 2
H, Ar), 7.48 (t, J = 7.65 Hz, 4 H, Ar) ppm. 13C NMR {75 MHz,
CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 155.1, 146.7, 145.7, 138.1,
137.1, 136.5, 136.1, 135.3, 132.1, 130.1, 129.7, 129.4, 126.4, 125.8,
125.1, 124.1, 124.0, 122.7, 122.2, 116.1, 114.1, 110.8, 99.9 ppm.
HRMS (EI): calcd. for C25H14Cl2N2O3S [M]+ 492.0102; found
492.0100.
3-Fluoro-7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione
(33d):
NaOH (25% aq.; 1 g NaOH in 4 mL) was added to a solution of
quinocarbazole 32d (0.88 g, 0.2 mmol) in DMSO (10 mL) under an
O2 atmosphere (balloon). The reaction mixture was then stirred
at room temperature for 10 h. Work-up following the procedure
described above gave 33d (42 mg, 72%) as a red-orange solid, m.p.
Ͼ300 °C. IR (KBr): ν = 3294, 1643 cm–1. 1H NMR (300 MHz, [D ]-
˜
6
DMSO): δ = 13.05 (s, 1 H, NH), 9.50 (s, 2 H, Ar), 8.05 (d, J =
6.9 Hz, 1 H, Ar), 7.79 (t, J = 10.8 Hz, 2 H, Ar), 7.52 (d, J = 6.9 Hz,
1 H, Ar), 7.39 (t, J = 7.65 Hz, 1 H, Ar), 7.31 (d, J = 6.9 Hz, 1 H,
Ar) ppm. 13C NMR {75 MHz, CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}:
δ = 176.4, 175.9, 167.4 (d, J = 270 Hz), 143.9, 142.6 (d, J =
13.42 Hz), 140.1, 139.1, 136.8, 132.6 (d, J = 10.10 Hz), 130.5, 127.5
(d, J = 2.02 Hz), 126.8, 124.7 (d, J = 24.88 Hz), 123.8, 123.5, 123.0,
117.9, 113.6, 106.5 (d, J = 25.41 Hz) ppm. DEPT-135 {75 MHz,
CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 143.9, 132.6 (d, J =
10.56 Hz), 130.5, 126.8, 124.7, 123.5, 113.6, 106.7 (d, J = 25.6 Hz)
ppm. HRMS (ESI): calcd. for C19H10FN2O2 [M + H]+ 317.0726;
found 317.0721.
General Procedure for the Synthesis of Calothrixin B (2) and 33b–
33e:[17] NaOH (25% aq.; 1 g NaOH in 4 mL) was added to a solu-
tion of quinocarbazoles 32a–32e (0.2 mmol) in DMSO (10 mL) un-
der an O2 atmosphere (balloon), and the mixture was stirred at
room temperature. After the reaction was complete (monitored by
TLC), the mixture was poured into ice-water (20 mL) containing
HCl (33%, 5 mL). The resulting solid was filtered, washed with
water (30 mL), and dried (CaCl2). Recrystallization of the crude
product from THF (10 mL) gave calothrixin B (2) and 33b–33e.
2,3-Dichloro-7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione (33e):
NaOH (25% aq.; 1 g NaOH in 4 mL) was added to a solution of
quinocarbazole 32e (0.1 g, 0.2 mmol) in DMSO (10 mL) under an
1278
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1266–1279

Total Synthesis of Calothrixin B and Its Analogs
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O2 atmosphere (balloon). The reaction mixture was then stirred
at room temperature for 10 h. Work-up following the procedure
described above gave 33e (62 mg, 84%) as a red-orange solid, m.p.
Ͼ300 °C. IR (KBr): ν = 3294, 1643 cm–1. 1H NMR (300 MHz, [D ]-
˜
6
DMSO): δ = 13.17 (s, 1 H, NH), 9.71 (s, 1 H, Ar), 9.60 (s, 1 H,
Ar), 8.42 (s, 1 H, Ar), 8.11 (d, J = 6.9 Hz, 1 H, Ar), 7.59 (d, J =
7.2 Hz, 1 H, Ar), 7.45 (t, J = 6.6 Hz, 1 H, Ar), 7.38 (d, J = 6.6 Hz,
1 H, Ar) ppm. 13C NMR {75 MHz, CDCl3 (0.4 mL)/[D]TFA
(0.1 mL)}: δ = 176.1, 175.7, 144.6, 143.7, 140.8, 139.1 (2 C), 136.6,
130.6, 129.3, 128.5, 126.9, 124.3, 123.9, 123.5, 122.3, 117.9,
113.6 ppm (only 18 carbon signals appeared). DEPT-135 {75 MHz,
CDCl3 (0.4 mL)/[D]TFA (0.1 mL)}: δ = 143.7, 130.6, 129.3, 126.9,
123.5, 122.3, 113.6 ppm. HRMS (EI): calcd. for C19H8Cl2N2O2
[M]+ 365.9963; found 365.9960.
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The authors thank the Council of Scientific and Industrial Re-
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(UGC), New Delhi for financial support. V. S. thanks the Univer-
sity Grants Commission (UGC) for a fellowship, and B. M. R.
thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for a JRF fellowship. The authors thank the Depart-
ment of Science and Technology Funds for the Improvement of
Science and Technology (DST-FIST) for the NMR facility. The
authors also thank SAIF, IIT Madras, for the HRMS data.
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Received: October 8, 2013
Published Online: December 12, 2013
Eur. J. Org. Chem. 2014, 1266–1279
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