Total synthesis of calothrixin B via sequential Sonogashira coupling/copper-catalyzed oxidative cyclization

Article abstract of DOI:10.1039/c5ob01766a

A total synthesis of the antimalarial indolo[3,2-j]phenanthridine alkaloid calothrixin B is reported. The key intermediate, ketoester 11, was assembled using sequential Sonogashira coupling and intra/intermolecular fashioned copper-catalyzed oxidative cyclization reactions.

Full text of DOI:10.1039/c5ob01766a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: N. Ramkumar and
R. Nagarajan, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB01766A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C5OB01766A
Journal Name
ARTICLE
Total Synthesis of Calothrixin B via Sequential Sonogashira
Coupling/Copper-Catalyzed Oxidative Cyclization
Received 00th January 20xx,
Accepted 00th January 20xx
Nagarajan Ramkumar and Rajagopal Nagarajan*
A total synthesis of antimalarial indolo[3,2-j]phenanthridine alkaloid, Calothrixin B is reported. The key intermediate,
ketoester 11 was assembled using sequential Sonogashira coupling and intra/intermolecular fashioned copper-catalyzed
oxidative cyclization reactions.
DOI: 10.1039/x0xx00000x
www.rsc.org/
route for Calothrixin
B involving sequential Sonogashira
Introduction
coupling and copper-catalyzed oxidative cyclization reactions.
Calothrixin B
1
is a pentacyclic quinone that possesses a
or quinolino[4,3-b]carbazole
indolo[3,2-j]phenanthridine
Results and discussion
skeleton and is unique among other naturally occurring
alkaloids (Fig. 1). Since its first isolation from Calothrix
cyanobacteria in 19991, several research groups have reported
the synthesis and biological studies of Calothrixin B, principally
because of its potent biological activities, such as anti-malarial
and anti-cancer activities.2, 3 Various synthetic methods have
been reported for the production of Calothrixin B, including a
The retrosynthetic disconnection pathway for the synthesis of
Calothrixin B
1 is shown in Scheme 1. We envisaged that 1
could be derived from ketoester 11 through subsequent ester
hydrolysis, cyclodehydration and debenzylation. The key
intermediate 11 could be accessed from compounds
using intra/intermolecular copper-catalyzed
cyclization. In turn, the compounds
from the Sonogashira coupling of
8 and 10
oxidative
metallation
strategy,4
Pd-catalyzed
coupling,5
8
and 10 could be obtained
electrocyclization,6 hetero Diels-Alder reaction,7 Friedel-Crafts
acylation/alkylation8 and a radical reaction.9 In addition, two
biomimetic approaches for Calothrixin B synthesis have also
been reported.10
7
with
3
and
9
respectively.
i. Ester hydrolysis
ii. Cyclodehydration
iii. Debenzylation
O
N
EtO2C
N
O
N
N
Bn
N
H
O
O
11
1
N
O
H
Calothrixin B 1
Figure 1. Structure of Calothrixin B
N
Bn
Copper-catalyzed
oxidative cyclization
Sonogashira
coupling
NHR
CO2Et
HC
8
, R =
10, R = H
The Sonogashira coupling reaction is widely used in the
synthesis of 1,n-enyne system, which is an important unit in
biologically active natural compounds.11 Copper-catalyzed
oxidative cyclization of 1,n-enynes is an elegant tool for the
synthesis of 4-carbonyl quinoline system that is found in many
natural compounds.12 Herein, we report a novel total synthetic
I
N
NHR
Bn
CO2Et
7
HC
3
, R =
9, R = H
School of Chemistry, University of Hyderabd, Hyderabad-500046, India.
E-mail: rnsc@uohyd.ernet.in (Dr. R. Nagarajan); Fax: +91 40-23012460
Electronic Supplementary Information (ESI) available: Copies of 1H, 13C and Mass
spectra for all the compounds. See DOI: 10.1039/x0xx00000x
Scheme 1. Retrosynthetic approach to Calothrixin B (1)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C5OB01766A
ARTICLE
Journal Name
We embarked on the proposed synthetic route by conducting
a Sonogashira coupling reaction of 2-ethynyl-1H-indole and
(E)-ethyl 3-((2-iodophenyl)aminowhich )acrylate produced a
coupled product in the presence of Pd(PPh3)2Cl2 (5 mol%),
2
3
N
Bn
4
N
Bn
Pd(PPh3)2Cl2 (5 mol%)
CuI (10 mol%), DIPA
CuI (10 mol%) and diisopropylamine (DIPA) (2 equiv.) in THF
with 92% yield (Scheme 2). Our next step was to focus on
7
NHR
THF, rt, 2 h, 94%
I
copper-catalyzed oxidative cyclization reaction of enyne
4.
CO2Et
8, 94%, R = HC
10, 96%, R = H
Most surprisingly, on carrying out this reaction using
CuCl2.2H2O (10 mol%), Phen (20 mol%) and 1,4-
NHR
CO2Et
o
diazabicyclo[2.2.2]octane (DABCO) (2 equiv.) in DMF at 100 C
3 R = HC
9 R = H
under oxygen atmosphere (using balloon), we isolated
benzo[f]indolo[1,2-b][2,7]naphthyridine-7,14-dione
6 in 78%
Scheme 3. Sonogashira coupling reaction of 1-benzyl-2-ethynyl-1H-indole (7)
yield instead of the expected ketoester 5. From this result, we
concluded that ketoester
lactamized to a compound
5
was formed in situ and readily
With the coupled products
8 and 10 in hand, we were able to
6
due to the presence of free indole
obtain the key intermediate 11 in two ways; intramolecular
and intermolecular copper-catalyzed oxidative cyclization
reactions (Scheme 4). Firstly, we carried out intramolecular
NH in the enyne
previously reported in literature.13 Data from spectroscopic
analysis of the compound matched literature report in all
4. The isolated compound 6 has been
6
copper-catalyzed oxidative cyclization of enyne
8. After several
aspects (see Supporting information).
screening conditions, we found that the conversion of
8
to 11
proceeded smoothly in the presence of CuCl2.2H2O (10 mol%),
Phen (20 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (2
o
equiv.) in DMF at 100 C under oxygen atmosphere with 82%
yield in 3 h. This reaction proceeded through a sequence of
intramolecular carbocupration of the alkyne
isomerization, elimination and further oxidation gave the
desired product 11 12e
Next, we carried out intermolecular
8 followed by
N
H
N
H
2
Pd(PPh3)2Cl2(5 mol%)
.
CuI (10 mol%), DIPA
copper-catalyzed oxidative cyclization reaction of 10 with ethyl
acrylate 12. The conversion of 10 to 11 was effected using 20
mol% CuCl and 1,4-diazabicyclo[2.2.2]octane (DABCO) (2
equiv.) in NMP at 100 oC under oxygen atmosphere for 6 h.
CO2Et
THF, rt, 2 h, 92%
I
N
H
4
CO2Et
N
H
3
EtO2C
N
CuCl2.2H2O (10 mol%)
Intramolecular fashion:
1,10-phen (20 mol%)
N
lactamization
DABCO, DMF, 100 o
O2, 3 h, 78%
C
H
O
CuCl2.2H2O (10 mol%)
1,10-Phen (20 mol%)
N
EtO2C
5
N
Bn
DABCO, DMF, 100 oC
O2, 3 h, 82%
formed in situ
not isolated
CO2Et
N
Bn
N
H
O
11
8
O
N
O
N
N
Bn
6
CuCl (20 mol%)
DABCO
N
EtO2C
CO2Et
NMP, 100 o
O2, 6 h, 78%
C
NH2
Scheme 2. Synthesis of benzo[f]indolo[1,2-b][2,7]naphthyridine-7,14-dione (6)
N
Bn
O
10
Intermolecular fashion:
12
11
In order to achieve the desired outcome, we protected the
free NH in indole with benzyl group After this
modification, 1-benzyl-2-ethynyl-1H-indole was subjected to
Sonogashira coupling reactions with (E)-ethyl 3-((2-
iodophenyl)amino)acrylate and 2-iodoaniline by employing
a
7.
Scheme 4. Copper-catalyzed oxidative cyclization
7
At this juncture, having the key intermediate 11 in hand, we
performed further functional group manipulations, consisting
of ester hydrolysis, cyclodehydration and debenzylation
(Scheme 5). The ketoester 11 was hydrolyzed using
NaOH/EtOH to generate ketoacid 13, which was in turn
3
9
Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%) and diisopropylamine
(DIPA) (2 equiv.) in THF at room temperature. These reactions
afforded
3).
8 and 10 in 94% and 96% yield respectively (Scheme
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 6
View Article Online
DOI: 10.1039/C5OB01766A
Journal Name
ARTICLE
converted into a known N-benzyl calothrixin 14 by treatment THF (5 mL) at room temperature. After stirring for 15 min, 2-
with concd H2SO4 at 140 oC. The N-benzylated calothrixin 14 iodoaniline
(210 mg, 1 mmol) in THF (5 mL) was added. The
9
was readily deprotected by treatment with 10% Pd/C and resulting mixture was stirred for 12 h at room temperature
HCOONH4 in MeOH at reflux to finally obtain the target and the solvent was removed under a reduced pressure. The
compound 1 in 71% yield. Spectroscopic data of 1 and 14 are residue was dissolved in ethyl acetate (75 mL) and repeatedly
fully consistent with those previously reported in literatures.1, 7 washed with 1 M NaOH solution and water. The organic layer
was separated, dried over anhydrous Na2SO4 and the solvent
was removed to give the crude product which was purified by
silica gel column chromatography using petroleum ether.
Rf = 0.60 (petroleum ether: EtOAc, 95:5); colourless oil (240
N
mg, 80%); IR (neat): 3380, 1730 cm-1; 1H NMR (CDCl3, 400
MHz): δ 10.16 (s, br, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.2
Hz, 1H), 7.25-7.20 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.75 (t, J =
7.2 Hz, 1H), 4.97 (d, J = 8.4 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H),
1.35 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 169.7,
141.8, 141.6, 139.9, 129.4, 123.6, 113.6, 89.7, 87.3, 59.6, 14.5;
HRMS (ESI): [M+H]+ calcd for C11H12INO2 317.9991, found
317.9987.
N
HO2C
EtO2C
NaOH, EtOH
reflux, 1 h, 98%
N
Bn
N
Bn
O
O
13
11
O
N
10% Pd/C
HCO2NH4
concd H2SO4
1
Calothrixin B
5 steps
41.5% overall
yield
140 oC, 2 h, 78%
MeOH, reflux
3 h, 71%
N
Preparation of 1-benzyl-2-ethynyl-1H-indole (7)
Bn
O
To a solution of 1-benzyl-2-ethynyl-1H-indole
2 (150 mg, 1
14
mmol) in DMF (10 mL), K2CO3 (293 mg, 2 mmol) was added
and stirred for 30 min at room temperature. Benzyl bromide
(0.25 mL, 2 mmol) was added and the mixture was stirred for
12 h under nitrogen atmosphere at room temperature. After
completion of reaction (TLC), the reaction mixture was poured
into water (100 mL) and extracted with ethyl acetate (75 mL).
The organic layer was washed with brine, dried over
anhydrous Na2SO4 and the solvent was removed to give the
crude product which was purified by silica gel column
chromatography using petroleum ether.
Scheme 5. Reactions to complete synthesis of Calothrixin B (1)
Conclusions
In summary, the total synthesis of Calothrixin B
1 has been
accomplished using a novel route comprising of sequential
Sonogashira coupling and copper-catalyzed oxidative
cyclization reactions with an overall yield of 40.6% to 41.8%
over 5 steps. This synthetic strategy provides a promising
platform to synthesize novel indolonaphthyridine ring systems
with ease.
Rf = 0.64 (petroleum ether:EtOAc, 95:5); light yellow solid (235
mg, 96%); mp 112-114 oC; IR (KBr): 3320, 3095, 2260, 1445,
890 cm-1 ; 1H NMR (CDCl3, 400 MHz): δ 7.64 (d, J = 7.6 Hz, 1H),
7.33-7.14 (m, 8H), 6.94 (s, 1H), 5.49 (s, 2H), 3.48 (s, 1H); 13C
NMR (CDCl3, 100 MHz): δ 137.5, 136.6, 128.6 (2C), 127.4,
127.2, 126.7 (2C), 123.5, 121.2, 120.8, 120.4, 110.2, 109.0,
83.6, 75.6, 47.9; HRMS (ESI): [M+H]+ calcd for C17H13N
232.1126, found 232.1119.
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), N,N-dimethylformamide
(DMF), methanol, ethyl acetate and dichloromethane were
dried by using standard distillation methods. Commercially
available reagents and solvents were used without further
purification and were purchased. Melting points were
determined using open capillary tubes and are uncorrected.
Preparation of (E)-ethyl 3-((2-iodophenyl)amino)acrylate (3)
General procedure for Sonogashira coupling reaction:
A mixture of (E)-ethyl 3-((2-iodophenyl)amino)acrylate
3 (150
mg, 1 mmol) or 2-iodoaniline 9 (150 mg, 1 mmol), Pd(PPh3)2Cl2
(0.05 mmol) and CuI (0.1 mmol) were dissolved in THF (5 mL).
Then DIPA (2 mmol) was added when the solution became
clear. After stirring the mixture for 15 min at room
temperature, corresponding indole 2 or 7 (1 mmol) was added.
The reaction mixture was further allowed to stir for 2 h at
room temperature. After completion of the reaction (TLC), the
solvent was evaporated. The crude mixture was purified by
silica gel column chromatography using petroleum ether/ethyl
actate.
(E)-Ethyl 3-((2-((1H-indol-2-yl)ethynyl)phenyl)amino)acrylate (4)
Rf = 0.44 (petroleum ether:EtOAc, 95:5); white solid (144 mg,
o
92%); mp 128-130 C; IR (KBr): 3380, 3345, 2985, 1750, 1585,
1335, 725 cm-1; 1H NMR (CDCl3, 400 MHz): δ 11.04 (d, J = 12.4
Hz, 1H), 10.57 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6
Hz, 1H), 7.46-7.41 (m, 1H), 7.33-7.23 (m, 3H), 7.16-7.12 (m,
2H), 6.99 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 0.8 Hz, 1H), 5.03 (d, J =
Bis-dichloro(acetonitrile)palladium(II) (24 mg, 0.1 mmol), p-
benzoquinone (98 mg, 1 mmol), lithium chloride (390 mg, 10
mmol) and ethyl acrylate 12 (100 mg, 1 mmol) were mixed in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C5OB01766A
ARTICLE
Journal Name
8.0 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 6.8 Hz, 3H); 13
C
Ethyl
(11)
4-(1-benzyl-1H-indole-2-carbonyl)quinoline-3-carboxylate
NMR (CDCl3, 100 MHz): δ 170.8, 141.8, 141.3, 136.7, 130.9,
129.5, 127.8, 123.3, 121.7, 121.0, 120.1, 118.8, 110.9, 110.8,
110.6, 107.5, 90.5, 88.3, 87.8, 59.9, 14.5; HRMS (ESI): [M+H]+
calcd for C21H18N2O2 331.1446, found 331.1441.
Rf = 0.42 (petroleum ether:EtOAc, 80:20); yellow solid (84 mg,
o
82%); mp 148-150 C; IR (KBr): 3120, 2850, 1765, 1650; 1430,
1245 cm-1; 1H NMR (CDCl3, 400 MHz): δ 9.55 (s, 1H), 8.22 (d, J =
8.4 Hz, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.55
(d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.39-7.22 (m, 9H),
(E)-Ethyl
3-((2-((1-benzyl-1H-indol-2-
yl)ethynyl)phenyl)amino)acrylate (8)
Rf = 0.48 (petroleum ether:EtOAc, 95:5); yellow solid (186 mg, 6.27 (d, J = 15.6 Hz, 1H), 5.95 (d, J = 16.0 Hz, 1H), 4.32 (m, 2H),
94%); mp 146-148 oC; IR (neat): 3350, 2985, 2310, 1755, 1430, 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 186.3,
1
1235, 760 cm-1; H NMR (CDCl3, 400 MHz): δ 10.70 (d, J = 8.0 164.6, 150.2, 149.7, 149.2, 138.8, 137.9, 131.8, 129.6, 128.7
Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 1.2, 7.6 Hz, 1H), (2C), 128.2, 127.9, 127.5, 126.9 (2C), 125.6, 125.0, 124.4,
7.35-7.20 (m, 10H), 7.14 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 121.8, 120.9, 119.9, 116.5, 111.1, 61.8, 49.2, 13.9; HRMS (ESI):
1H), 6.96 (t, J = 7.6 Hz, 1H), 5.62 (s, 2H), 4.97 (d, J = 8.4 Hz, 1H), [M+Na]+ calcd for C28H22N2O3 457.1528, found 457.1520.
4.22 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
Procedure for intermolecular copper-catalyzed oxidative
cyclization reaction:
100 MHz): δ 169.7, 141.7, 141.2, 137.8, 132.5, 129.8, 128.7,
128.6 (2C), 127.8, 127.3, 126.9 (2C), 123.2, 121.7, 121.5, 121.1,
120.2, 112.0, 110.8, 110.1, 109.3, 90.8, 89.4, 88.0, 59.4, 48.2,
14.5; HRMS (ESI): [M+Na]+ calcd for C28H24N2O2 443.1736,
found 443.1730.
To a solution of 2-((1-benzyl-1H-indol-2-yl)ethynyl)aniline 10
(100 mg, 1 mmol) and ethyl acrylate 12 (50 µL, 1.5 mmol) in
NMP (2 mL), CuCl (0.2 mmol) and DABCO (2 mmol) were
added. The reaction mixture was then stirred for 6 h at 100 ºC
under O2 atmosphere. The resulting mixture was quenched
with water and extracted with EtOAc (2 × 30 mL). The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4 and concentrated. The crude product was
purified by silica gel column chromatography using petroleum
ether/ethyl acetate (80:20) afforded 11 as yellow solid (105
mg, 78%).
2-((1-Benzyl-1H-indol-2-yl)ethynyl)aniline (10)
Rf = 0.36 (petroleum ether:EtOAc, 90:10); yellow solid (212 mg,
o
96%); mp 108-110 C; IR (KBr): 3440, 3360, 3080, 2956, 1467,
1332, 1280, 764 cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.65 (d, J =
9.5 Hz, 1H), 7.33-7.28 (m, 3H), 7.26-7.21 (m, 3H), 7.16 (t, J =
7.0 Hz, 4H), 7.13 (s, 1H), 6.93-6.68 (m, 2H), 5.54 (s, 2H), 4.03 (s,
br, 2H); 13C NMR (CDCl3, 500 MHz): δ 147.9, 137.7, 136.9,
132.1, 130.1, 128.7 (2C), 127.5, 127.4, 126.4 (2C), 123.2, 121.9,
121.0, 120.3, 117.9, 114.3, 109.9, 107.9, 107.1, 92.0, 86.1,
47.8; HRMS (ESI): [M+H]+ calcd for C23H18N2 323.1548, found
323.1540.
Synthesis
carboxylic acid (13)
To solution
carbonyl)quinoline-3-carboxylate 11 (75 mg,
of
4-(1-benzyl-1H-indole-2-carbonyl)quinoline-3-
a
of
ethyl
4-(1-benzyl-1H-indole-2-
mmol) in
1
General procedure for intramolecular copper-catalyzed oxidative
ethanol (3 mL), NaOH ( 21 mg, 3 mmol) was added and
refluxed for 1 h. After completion of the reaction (TLC),
crushed ice was added to the mixture and neutralized with
10% dil HCl to pH 7. The solid formed was filtered off, washed
with water and dried. The crude product was used in the next
step without further purification.
cyclization reaction:
To a solution of appropriate enyne
4 or 8 (100 mg, 1 mmol) in
DMF (2 mL) was added CuCl2.2H2O (0.1 mmol), DABCO (2
mmol) and 1,10-Phen (0.2 mmol). The reaction mixture was
then stirred for 3 h at 100 oC under O2 atmosphere. The
resulting mixture was quenched with water and extracted with
EtOAc (2 × 30 mL). The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4 and
concentrated. The crude product was purified by silica gel
column chromatography using petroleum ether/ethyl acetate.
Benzo[f]indolo[1,2-b][2,7]naphthyridine-7,14-dione (6)13
Note: This compound 13 exists as ‘rotamers’
Rf = 0.38 (DCM:MeOH, 90:10); yellow solid (84 mg, 98%); mp
218-220 oC; IR (neat): 3110, 2930, 1740, 1690, 1455, 1375, 890
cm-1; 1H NMR (CDCl3, 400 MHz): δ 10.05 (s, br, 2H), 9.70 (s,
1H), 9.69 (s, 1H), 8.22 (t, J = 7.6 Hz, 2H), 7.72-7.65 (m, 2H), 7.60
(t, J = 7.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.48-7.25 (m, 18H),
Rf = 0.57 (petroleum ether:EtOAc, 80:20); yellow solid (70 mg, 7.19 (t, J = 7.2 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.17 (d, J = 16.0
o
o
78%); mp 244-246 C (lit.13 mp 249 C); IR (KBr): 1690, 1660, Hz, 2H), 5.97 (d, J = 16.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
1573, 1415, 1384, 1245, 780 cm-1; 1H NMR (CDCl3, 500 MHz): δ 187.0, 186.0, 167.2, 167.0, 150.6, 150.1 (2C), 149.8, 148.2,
9.95 (s, 1H), 9.74 (dd, J = 1.0, 8.5 Hz, 1H), 8.60 (dd, J = 1.0, 8.5 140.6, 138.8, 138.1, 137.8 (2C), 134.7, 132.4, 129.7, 128.69
Hz, 1H), 8.26 (dd, J = 1.0, 8.5 Hz, 1H), 7.94 (td, J = 1.5, 8.5 Hz, (4C), 128.62 (2C), 128.3, 128.28, 128.23, 127.4, 127.3, 127.0,
1H), 7.85 (td, J = 1.0, 8.5 Hz, 1H), 7.77 (dt, J = 1.0, 7.5 Hz, 1H), 126.9 (6C), 126.2, 125.8, 125.1, 125.0, 124.8, 123.4, 121.8,
7.72 (d, J = 0.5 Hz, 1H), 7.63 (td, J = 1.0, 8.5 Hz, 1H), 7.41 (td, J 121.3, 120.9 (2C), 120.8, 116.4, 116.0, 111.1 (2C), 49.2, 48.6;
= 1.0, 8.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ 177.7, 158.3, HRMS (ESI): [M+H]+ calcd for C26H18N2O3 407.1395, found
151.7, 149.5, 136.7, 134.0, 133.8, 132.4, 130.7, 130.5, 130.3, 407.1387.
Synthesis of 12-benzyl-7H-indolo[3,2-j]phenanthridine-7,13(12H)-
128.7, 127.8, 125.7, 123.9, 123.3, 122.7, 117.9, 117.1; HRMS
(ESI): [M+H]+ calcd for C19H10N2O2 299.0820, found 299.0820.
dione (14)
4-(1-Benzyl-1H-indole-2-carbonyl)quinoline-3-carboxylic acid
13 (70 mg) was added to concd H2SO4 (2 mL) and heated to
140 oC for 2 h. After completion of the reaction (TLC), the
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 6
View Article Online
DOI: 10.1039/C5OB01766A
Journal Name
ARTICLE
Yamabuki, Y. Hieda, J. Nobuhiro and S. Hibino, Heterocycles
2010, 82, 397.
(a) N. T. Doan, R. W. Rickards, J. M. Rothschild and G. D.
Smith, J. Appl. Phycol., 2000, 12, 409; (b) N. T. Doan, P. R.
Stewart and G. D. Smith, Microbiol. Lett., 2001, 196, 135; (c)
reaction mixture was poured into ice cold water (50 mL) and
extracted with ethyl acetate (70 mL). The organic layer was
separated, washed with 10% aq NaOH and dried over
anhydrous Na2SO4. The solvent was removed to give the crude
residue which was purified by silica gel column
chromatography using petroleum ether/ethyl acetate.
3
X. Chen, G. D. Smith and P. Waring, J. Appl. Phycol., 2003, 15
,
269; (d) P. H. Bernardo, C. L. L. Chai, G. A. Heath, P. J. Mahon
and G. D. Smith, J. Med. Chem., 2004, 47, 4958; (e) P. H.
Bernardo, C. L. L. Chai, M. L. Guen, G. D. Smith and P.
Waring, Bioorg. Med. Chem. Lett., 2007, 17, 82; (f) Q. A.
Khan, J. Lu and S. M. Hecht, J. Nat. Prod., 2009, 72, 38; (g) N.
Hatae, R. Satoh, H. Chiba, T. Osaki, T. Nishiyama, M. Ishikura,
T. Abe, S. Hibino, T. Choshi, C. Okada and E. Yoyota, Med.
Chem. Res., 2014, 23, 4956.
(a) T. R. Kelly, Y. Zhao, M. Cavero, and M. Torneiro, Org.
Lett., 2000, 2, 3735; (b) N. Ramkumar and R. Nagarajan, J.
Org. Chem., 2014, 79, 736; (c) D. Mal, J. Roy and K. Biradha,
Org. Biomol. Chem., 2014, 12, 8196.
(a) P. H. Bernardo, W. Fitriyanto and C. L. L. Chai,. Synlett
2007, 1935; (b) T. Abe, T. Ikeda, R. Yanada and M. Ishikura,
Org. Lett., 2011, 13, 3356; (c) T. Abe, T. Ikeda, T. Choshi, S.
Hibino, N. Hatae, E. Toyata, R. Yanada and M. Ishikura, Eur. J.
Org. Chem., 2012, 5018; (d) S. M. Bhosale, R. L. Gawade, V.
Rf = 0.30 (petroleum ether:EtOAc, 80:20); red solid (84 mg,
78%); mp 258-260 oC (lit7. mp 264 oC); IR (KBr): 3050, 1650,
1
1530, 1430, 1248 cm-1; H NMR (CDCl3, 400 MHz): δ 9.80 (s,
1H), 9.55 (d, J = 8.8 Hz, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.19 (d, J =
8.0 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.46-
7.42 (m, 3H), 7.35-7.29 (m, 3H), 7.23 (d, J = 7.2 Hz, 2H), 6.01 (s,
2H); 13C NMR (CDCl3, 100 MHz): δ 182.0, 181.0, 152.1, 147.8,
140.1, 136.2, 135.1, 133.2, 131.3, 130.3, 130.1, 128.9 (2C),
128.0, 127.8, 127.7, 126.6 (2C), 125.1, 124.4, 123.9, 123.3,
123.1, 117.7, 111.5, 48.5; HRMS (ESI): [M+H]+ calcd for
C26H16N2O2 389.1290, found 389.1282.
4
5
Synthesis of 7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione (1)
(Calothrixin B)
G. Puranik and R. S. Kusurkar, Tetrahedron Lett., 2012, 53
,
To a solution of 12-benzyl-7H-indolo[3,2-j]phenanthridine-
7,13(12H)-dione 14 (50 mg, 0.13 mmol) in MeOH (5 mL), 10%
Pd/C (14 mg, 0.13 mmol) and ammonium formate (162 mg, 2.5
mmol) were added and refluxed for 3 h under nitrogen
atmosphere. After completion of the reaction using TLC, the
reaction mixture was filtered through celite pad and washed
with ethyl acetate (50 mL). The solvent was evaporated to give
crude oil which was purified by silica gel column
chromatography gave the titled product.
2894; (e) N. Ramkumar and R. Nagarajan, J. Org. Chem.,
2013, 78, 2802; (f) S. A. Kaliyaperumal, S. Banerjee and U. K.,
S. Kumar, Org. Biomol. Chem., 2014, 12, 6105; (g) S. M.
Bhosale, M. A. Momin, S. Kunjir, P. R. Rajamohanan and R. S.
Kusurkar, Tetrahedron Lett., 2014, 55, 155.
(a) S. Tohyama, T. Choshi, K. Matsumoto, A. Yamabuki, K.
Ikegata, J. Nobuhiro and S. Hibino, Tetrahedron Lett., 2005,
46, 5263; (b) B. M. Ramalingam, V. Saravanan and A. K.
Mohanakrishnan, Org. Lett., 2013, 15, 3726; (c) V.
Saravanan, B. M. Ramalingam and A. K. Mohanakrishnan,
Eur. J. Org. Chem., 2014, 1266.
(a) D. Sissouma, S. C. Collet and A. Y. Guingant, Synlett 2004,
2612; (b) D. Sissouma, L. Maingot, S. Collet and A. Guingant,
J. Org. Chem., 2006, 71, 8384; (c) L. Maingot, F. Thuaud, D.
Sissouma, S. Collet, A. Guingant and M. Evain, Synlett 2008,
263.
6
7
Rf = 0.30 (petroleum ether:EtOAc, 80:20); red solid (27 mg,
o
o
71%); mp 296-298 C (lit.1 mp ≥ 300 C); IR (neat): 3420, 1650
cm-1; 1H NMR (DMSO-d6, 400 MHz): δ 13.11 (s, br, 1H), 9.56 (s,
1H), 9.52 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.91 (t, J =
8.0 Hz, 1H), 7.84 (t, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.42
(t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H); 13C NMR (DMSO-d6,
100 MHz): δ 181.2, 180.7, 151.6, 147.9, 138.8, 138.4, 132.9,
132.0, 130.6, 130.28, 130.21, 127.6, 125.2, 124.7, 123.7, 123.0,
122.7, 115.9, 114.3; HRMS (ESI): [M+H]+ calcd for C19H10N2O2
299.0820, found 299.0822.
8
9
(a) P. H. Bernardo, C. L. L. Chai and J. A. Elix, Tetrahedron
Lett., 2002, 43, 2939; (b) P. H. Bernardo and C. L. L. Chai, J.
Org. Chem., 2003, 68, 8906.
(a) M.-L. Bennasar, T. Roca and F. Ferrando, Org. Lett., 2006,
8, 561; (b) S. Xu, T. Nguyen, I. Pomilio, M. C. Vitale and S.E.
Velu, Tetrahedron 2014, 70, 5928.
10 (a) A. Yamabuki, H. Fujinawa, T. Choshi, S. Tohyama, K.
Matsumoto, K. Ohmura, J. Nobuhiro and S. Hibino,
Tetrahedron Lett., 2006, 47, 5859; (b) K. Matsumoto, T.
Choshi, M. Hourai, Y. Zamami, K. Sasaki, T. Abe, M. Ishikura,
N. Hatae, T. Iwamura, S. Tohyama and J. Nobuhiro, Bioorg.
Med. Chem. Lett., 2012, 22, 4762; (c) C. S. P. McErlean, J.
Acknowledgements
We gratefully acknowledge DST for financial support (Project
No SR/S1/OC-70/2008). NR thanks CSIR, New Delhi for senior
research fellowship and contingency grant.
Sperry, A. J. Blake and C. J. Moody, Tetrahedron 2007, 63
,
10963; (d) J. Sperry, C. S. P. McErlean, A. M. Z. Slawin and C.
J. Moody, Tetrahedron Lett., 2007, 48, 231.
11 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron
Let., 1975, 16, 4467; (b) K. Sonogashira, J. Organomet.
Chem., 2002, 653, 46; (c) J. M. Pedersen, W. R. Bowman, M.
R. J. Elsegood, A. J. Fletcher and P. J. Lovell, J. Org. Chem.,
2005, 70, 10615; (d) C. Thongsornkleeb and R. L. Danhaiser,
J. Org. Chem., 2005, 70, 2364; (e) R. Chinchilla and C. Nájera,
Chem. Rev., 2007, 107, 874.
12 (a) N. T. Patil, H. Wu and Y. Yamamoto, J. Org. Chem., 2005,
70, 4531; (b) Z.-Q. Wang, W.-W. Zhang, L.-B. Gong, R.-Y.
Tang, X.-H. Yang, Y. Liu and J.-H. Li, Angew. Chem., Int. Ed.,
2011, 50, 8968; (c) C. Fehr, I. Farris and H. Sommer, Org.
Notes and reference
1
2
R. W. Rickards, J. M. Rothschild, A. C. Willis, N. M. de Chazal,
J. Kirk, K. Kirk, K. J. Saliba and G. D. Smith, Tetrahedron 1999,
55, 13513.
(a) A. W. Schmidt, K. R. Reddy and H.-J. Knölker, Chem. Rev.,
2012, 112, 3193; (b) H.-J. Knölker and K. R. Reddy, in The
Alkaloids, ed. G. A. Cordell, Elsevier Science, 2008, vol. 65, p
1–430; (c) H.-J. Knölker and K. R. Reddy, Chem. Rev., 2002,
102, 4303; (d) C. M. Miller and F. O. McCarthy, RSC Adv.,
Lett., 2006, 8, 1839; (d) K. K. Toh, S. Sanjaya, S. Sahnoun, S. Y.
Choung and S. Chiba, Org. Lett., 2012, 14, 2290; (e) X.-F. Xia,
2012, 2, 8883; (e) T. Choshi and S. Hibino, Heterocycles 2009,
77, 85; (f) S. Tohyama, T. Choshi, K. Matsumoto, A.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C5OB01766A
ARTICLE
L.-L. Zhang, .X.-R. Song, X.-Y. Liu and Y.-M. Liang, Org. Lett.,
Journal Name
2012, 10, 2480; (f) S. E. Allen, R. R. Walvoord, R. Padilla-
Salinas and M. C. Kozlowski, Chem. Rev., 2013, 114, 6234.
13 D. H. Dethe and G. M. Murhade, Eur. J. Org. Chem., 2014,
6953.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins