Synthesis of Thia-Analogues of Calothrixin B Involving FeCl3-Mediated Domino Reaction

Article abstract of DOI:10.1055/s-0036-1588072

The total synthesis of thiacalothrixins, an isostere of the biologically important carbazoloquinone alkaloid calothrixin B, was achieved from ethyl benzo[b]thiophene-2-carboxylate. Alternatively, the multi-step synthesis of thiaisocalothrixins could be achieved from 3-methylbenzo[b]thiophene. A preliminary in vitro cytotoxicity evaluation of the synthesized thia analogues of calothrixins displayed promising potential against cancer cell cultures.

Full text of DOI:10.1055/s-0036-1588072

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
A
letter
Synlett
B. M. Ramalingam et al.
Letter
Synthesis of Thia-Analogues of Calothrixin B Involving FeCl -Medi-
3
ated Domino Reaction
Bose Muthu Ramalingama
Nachiappan Dhatchana Moorthyb
Elangovan Vellaichamyb
Arasambattu K. Mohanakrishnan*a
R2
O
R1
N
Me
O
R1
O
7 steps
5 steps
R1
N
22–28%
30–37%
(overall yield)
S
OEt
S
S
S
(
overall yield)
O
O
thiacalothrixins B
thiaisocalothrixins B
R , R = H, Cl, F (9 examples)
a
R1 = H, Cl, F (3 examples)
GI50 0.20–4 µM
1
2
Department of Organic Chemistry, University of Madras,
Guindy Campus, Chennai-600 Tamil Nadu, India
mohanakrishnan@unom.ac.in
GI50 0.05–4 µM
mohan_67@hotmail.com
Department of Biochemistry, University of Madras,
b
Guindy Campus, Chennai-600 Tamil Nadu, India
Received: 05.08.2016
Accepted after revision: 27.08.2016
Published online: 12.09.2016
Me
Me
N
DOI: 10.1055/s-0036-1588072; Art ID: st-2016-d0514-l
N
X
X
Me
Abstract The total synthesis of thiacalothrixins, an isostere of the bio-
logically important carbazoloquinone alkaloid calothrixin B, was
achieved from ethyl benzo[b]thiophene-2-carboxylate. Alternatively,
the multi-step synthesis of thiaisocalothrixins could be achieved from
Me
ellipticine 1 (X = NH)
thiaellipticine 2 (X = S)
isoellipticine 3 (X = NH)
thiaisoellipticine 4 (X = S)
O
O
3-methylbenzo[b]thiophene. A preliminary in vitro cytotoxicity evalua-
O
tion of the synthesized thia analogues of calothrixins displayed promis-
ing potential against cancer cell cultures.
N
N
N
N
H
H
O
O
Key words carbazole alkaloids, calothrixin B, electrocyclization, Lewis
acid, quinones
calothrixin A 5
calothrixin B 6
Figure 1 Bioactive pyrido[4,3-b]carbazoles and calothrixins
The pyridocarbazole alkaloid ellipticine (1, Figure 1)
1
was first isolated from leaves of Ochrosia elliptica. Ellipti-
Our group also recently synthesized analogues of calo-
thrixin B. Even though more than 20 different synthetic
2
10
cine and its derivatives are well-known for their role as
DNA intercalator and topoisomerase II inhibitor. Recent re-
routes have been explored for calothrixins, only few reports
are available on the biological potency of these com-
pounds.
search confirms that 1 also interacts with a number of cell
2f
5–8
cycle regulators. Although several ellipticine derivatives
3
have been evaluated in clinical trials, their role in cancer
The development of more potent, as well as more selec-
tive, derivatives of calothrixin may well lead to a suitable
clinical candidate. In that respect, it is known that thiaisoel-
lipticine (4), a sulfur analogue of 1, is capable of restoring
2f
treatment remains peripheral. Calothrixin A (5) and B (6,
Figure 1) are two naturally occurring carbazole-1,4-qui-
none alkaloids isolated from Calothrix cyanobacteria by
4
11
Rickard et al. The pentacyclic indolo[3,2-j]phenanthridine-
mutant p53 function, just like the parent compound. Thi-
dione ring system consists of indole, quinone, and quinoline
moieties. The compounds proved to be nanomolar growth
inhibitors of HeLa cervical cancer cells and of P. falci-
aellipticine (2) is also known,12 but its bioactivity seems to
be unexplored. On the other hand, aroylbenzo[b]thio-
phenes13 as well as benzo[b]thiopheno quinolones are
known for their antimitotic and cytotoxic properties. We
were thus inspired to prepare and evaluate some thia ana-
logues of calothrixin B.
14
4,5
6
parum. They also inhibit bacterial RNA polymerase and
7
poison DNA topoisomerase I. Calothrixin A is also known
to induce the intracellular formation of reactive oxygen
8
species. The promising biological activity of calothrixins
Our synthetic plan for thiacalothrixin B (8) and thiaiso-
calothrixin (10) is depicted in Scheme 1. It was anticipated
that condensation of the 2-nitroarylvinyl-3-acetyl ben-
zo[b]thiophene 7 with DMF dimethyl acetal, followed by
prompted chemists to develop a plethora of synthetic
9
routes for these natural products.
10a
FeCl -mediated domino reaction of the resulting enam-
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
Synlett
B. M. Ramalingam et al.
Letter
ine, would lead to thiacalothrixin B (8). A similar sequence
of reactions would advance 2-acetyl benzo[b]thiophene 9
to thiaisocalothrixin B (10).
and trituration of the crude product with methanol fur-
nished the respective 2-(2′-nitroarylvinyl)-3-acetyl ben-
zo[b]thiophenes 17a–c as yellow solids. The initial attempts
to carry out Friedel–Crafts acylation of 17a using MeCOCl in
the presence of anhydrous AlCl in dry CH Cl at 0 °C failed
O
O
3
2
2
Me
N
to give the desired compound 7a, instead a complex mix-
ture was formed. Eventually, after several attempts, smooth
R1
R1
S
S
acylation of benzo[b]thiophenes 17a–c could be achieved
O2N
O
7
8
R2
17
employing FeCl as a mild Lewis acid catalyst to furnish
R2
3
3
-acetyl-2-nitroarylvinylbenzo[b]thiophenes
7a–c
R1
O
R1
(Scheme 2).
N
After having established a method for the synthesis of
the required precursors 7a–c of thiacalothrixins, the prepa-
ration of isomeric 2-acetyl-3-nitroarylvinyl-benzo[b]thio-
phenes 9a–i from 5-substituted 3-methylbenzo[b]thio-
NO2
Me
S
S
O
O
9
10
Scheme 1 Schematic pathway for thiacalothrixins 8 and 10
16
phenes 18a–c was initiated (Scheme 3). Friedel–Crafts ac-
ylation of 18a–c with MeCOCl in the presence of SnCl in
4
As per the objective, preparation of 3-acetyl-2-(2′-ni-
troaryl)vinylbenzo[b]thiophene (7) was initiated. Routine
Friedel–Crafts acylation of 2-methylbenzo[b]thiophene
dry CH Cl2 at 0 °C afforded 2-acetyl benzo[b]thiophenes
2
19a–c in good yields. In spite of the failure encountered
with isomeric 3-acetyl-2-methylbenzo[b]thiophene 12
(Scheme 2), to our delight, the allylic bromination of 2-ace-
tyl-3-methylbenzo[b]thiophene 19a–c using NBS and a cat-
15
(
11) using acetyl chloride in the presence of AlCl in dry
3
CH Cl afforded 3-acetyl-2-methylbenzo[b]thiophene (12).
2
2
Unfortunately, the expected benzylic bromination of com-
pound 12 using NBS and a catalytic amount of AIBN in CCl4
at reflux led to the formation of a complex mixture
alytic amount of AIBN in CCl at reflux led to the isolation of
4
3-bromomethyl-2-acetybenzo[b]thiophenes 20a–c as sta-
ble compounds in 89–91% yield. At this juncture, the exact
reason for the complexity observed during the allylic bro-
mination of 2-methyl-3-acetybenzo[b]thiophene (13) is not
clear (Scheme 2). In the next step, the reaction of bromo
(
Scheme 2). Failure to prepare the bromo compound 13
forced us to follow a slightly detoured route for compound
. Accordingly, a cautious LAH reduction of known ethyl
7
benzo[b]thiophene-2-carboxylate (14) followed by the re-
action of resulting benzo[b]thiophen-2-methanol16 with
PBr3 in CH Cl furnished 2-bromomethyl benzo[b]thio-
phene, which upon Arbuzov reaction led to the phospho-
nate ester 15. As expected, the Wittig–Horner reaction of
phosphonate ester 15 with 2-nitroarylaldehydes 16a–c us-
ing NaH as a base in dry THF at 0 °C followed by workup
compounds 20a–c with Ph P in dry THF upon reflux for 3
3
hours followed by Wittig reaction of the resulting phospho-
nium salts 21a–c with 2-nitroaryl aldehydes 16a–c using
K CO as a base in CH Cl at room temperature led to the for-
2
2
2
3
2
2
mation of 2-acetyl-3-nitroarylvinyl-benzo[b]thiophenes
1
9a–i (E isomer as major product by H NMR analysis) in
good yields (Scheme 3).
O
O
MeCOCl
AlCl3/CH2Cl2
Me
Me
NBS/CCl4
X
Me
0
°C, 83%
Me
AIBN, reflux
CH2Br
S
S
S
11
12
13
i) LAH/THF
OHC
R1
ii) PBr3/CH2Cl2
O
OEt
OEt
CO2Et
P
O2N 16a–c
S
iii) (OEt)3P/Δ
S
NaH/THF, 0 °C
82–87%
67% (over 3 steps)
14
15
O
1
6, 17, 7 R1
FeCl3
MeCOCl
Me
a
b
c
H
Cl
F
S
R1
CH2Cl2, 0 °C
5–80%
S
R1
O2N
7
O2N
17a–c
7a–c
Scheme 2 Synthesis of 3-acetyl- 2-nitroarylvinyl-benzo[b]thiophenes 7a–c
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
Synlett
B. M. Ramalingam et al.
Letter
R1
Me
R1
Br
Me
R1
Me
MeCOCl
SnCl4
Me
O
NBS/AIBN
S
CH2Cl2, 0 °C
0–85%
4
CCl , reflux, 2 h
S
S
O
8
89–91%
1
8a–c
19a–c
20a–c
R2
O2N
OHC
O2N 16a–c
R2
R1
R1
PPh3Br
Me
Ph3P/THF
reflux, 3 h
Me
S
K2CO3/CH2Cl2, 8 h
78–83%
O
S
21a–c
9a–i
O
1
8–21 R1
R1
H
R2
9
a
b
c
d
e
f
a
b
c
H
Cl
F
H
Cl
F
H
H
Cl
Cl
Cl
F
H
Cl
F
g
h
i
H
Cl
F
F
F
Scheme 3 Synthesis of 2-acetyl-3-nitroarylvinyl-benzo[b]thiophenes 10a–i
Having prepared the required 3/2-acetylbenzo[b]thio-
phene derivatives 7a–c and 10a–i, their transformation into
thiacalothrixin analogues was initiated (Scheme 4) follow-
ing our synthetic protocol outlined for the calothrixin B de-
vinylenes 7a–c with DMF·DMA in the presence of 50 mol%
glycocyamine as a catalyst at 100 °C for 2–3 hours followed
by aqueous workup furnished enamines 22a–c. The crude
enamines 22a–c upon reaction with four equivalents of
10a
rivatives.
As expected, reaction of 3-acetyl-2-nitroaryl-
FeCl in DMF at reflux for 3 hours followed by workup and
3
O
O
NMe2
N
DMF⋅DMA
FeCl3 (4 equiv)
7a–c
glycocyamine
50 mol%)
R1
DMF, reflux
h, 61–68%
S
S
(
3
O
R1
100 °C, 2–3 h
2
2a–c
O2N
23a–c
7
, 22, 23 R1
a
b
c
H
Cl
F
R2
R2
O2N
R1
O
R1
DMF⋅DMA
FeCl3 (4 equiv)
DMF, reflux
10a–i
N
NMe2
glycocyamine
(
50 mol %)
S
3
h, 62–70%
S
O
1
00 °C, 2-3 h
2
4a–i
O
2
5a–i
R2
H
1
0, 24, 25 R1
a
b
c
d
e
f
H
H
H
Cl
Cl
Cl
F
Cl
F
H
Cl
F
g
h
i
H
Cl
F
F
F
Scheme 4 Synthesis of thiacalothrixins B 10a–c and thiaisocalothrixins B 25a–i
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
Synlett
B. M. Ramalingam et al.
Letter
column chromatographic purification afforded thiacalo-
thrixins B 23a–c in 61–68% yield.18 Under identical condi-
tions, reaction of isomeric 2-acetyl-3-nitroarylvinylenes
the E-ring 25c. In general, introduction of halogens to the
A- and /or E-ring of thiaisocalothrixins 25b–i does not lead
to enhancement of the cytotoxic activity, although in some
cases, particularly with mono/difluoro substitution, the ac-
tivity is maintained as that of its parent analogue 25a.
In summary, we have reported a concise total synthesis
of thia analogues of carbazoloquinone alkaloid, calothrixin
9a–i with DMF·DMA in the presence of 50 mol% glycocyam-
ine at 100 °C followed by FeCl -mediated domino reaction
3
of resulting enamines 24a–i in DMF at reflux for 3 hours led
to the formation of thiaisocalothrixins B 25a–i in 62–70%
yield (Scheme 4).
B involving a FeCl -mediated domino reaction protocol. The
3
The synthesized thia analogues of calothrixins B are
thoroughly characterized by their spectral data. Relatively,
the solubility of most of the thiacalothrixins as well as thia-
isocalothrixins are found to be better than that of parent
calothrixins 5 and 6.
The synthesized thiacalothrixins 23a–c and 25a–i were
evaluated for their antiproliferative activities against six
different cancer cell cultures. The in vitro GI50 (growth inhi-
bition) values of thiacalothrixins against individual cell
lines are presented along with parent calothrixin B (6, syn-
thetic) as a reference compound (Table 1). In the case of thi-
acalothrixins B 23a–c, replacing the nitrogen atom of calo-
thrixin B (6) with sulfur resulted in the reduction of the
cytotoxic profile in the cell lines tested. However, thiaiso-
calothrixins B 25a–i displayed enhanced cytotoxicity (al-
most >fivefold) in comparison to calothrixin B (6) as well as
thiacalothrixins B 23a–c.
synthesized thiacalothrixins 23a–c as well as thiaisocalo-
thrixins 25a–i are explored for their preliminary in vitro
cytotoxcity against six different cancer cell cultures. Among
the thia analogues of isocalothrixins B 25a–i, the parent
thiaisocalothrixin 25a, its 11-chloro, as well as 11-fluoro
derivatives 25d and 25g are found to be more potent than
naturally occurring calothrixin B (6).
Acknowledgment
Financial assistance from CSIR (02(0214)/14-EMR-II), New Delhi is ac-
knowledged. B.M.R thanks CSIR, New Delhi for fellowship. The au-
thors thank DST-FIST for high-resolution NMR facility. The authors
also thank SAIF, IIT Madras for HRMS data.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588072.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
Table 1 In vitro Cytotoxicity Data for Thia Analogues of Calothrixins B
Compd
GI50 (μM)a
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To a solution of enamine 22a (300 mg, 0.8 mmol) in dry DMF
(20 mL), FeCl3 (520 mg, 3.2 mmol) was added. The reaction
mixture was refluxed for 3 h under N atmosphere. It was then
2
poured over crushed ice (50 g) containing concd HCl (1 mL). The
crude product was filtered and dried. It was then purified by
flash column chromatography on silica gel (230–420 mesh, n-
hexane–CH Cl = 9:1 to 1:1) to afford thiacalothrixin B (23a) as
2
014, 70, 5928. (r) Kaliyaperumal, S. A.; Banerjee, S.; Kumar, S.
U. K. Org. Biomol. Chem. 2014, 12, 6105. (s) Dethe, D. M.;
Murhade, G. M. Eur. J. Org. Chem. 2014, 6953. (t) Ramkumar, N.;
Nagarajan, R. RSC Adv. 2015, 5, 87838.
2
2
a red-orange solid (160 mg, 65%); mp 260–262 °C. IR (film):
–1 1
1651, 1519, 1258, 1092 cm
. H NMR (300 MHz, CDCl ): δ =
3
(
10) (a) Ramalingam, B. M.; Saravanan, V.; Mohanakrishnan, A. K.
Org. Lett. 2013, 15, 3726. (b) Saravanan, V.; Ramalingam, B. M.;
Mohanakrishnan, A. K. Eur. J. Org. Chem. 2014, 1266.
9.81 (s, 1 H), 9.60 (d, J = 8.7 Hz, 1 H), 8.87 (d, J = 7.8 Hz, 1 H), 8.22
(d, J = 8.1 Hz, 1 H), 7.98 (d, J = 7.5 Hz, 1 H), 7.90 (t, J = 7.5 Hz, 1
H), 7.81 (t, J = 7.8 Hz, 1 H), 7.66–7.57 (m, 2 H) ppm. C NMR (75
13
(
11) (a) Fujiwara, A. N.; Acton, E. M.; Goodman, L. J. J. Heterocycl.
Chem. 1968, 5, 853. (b) Elmes, B. C.; Swan, J. M. Aust. J. Chem.
MHz, CDCl ): δ = 182.9, 180.3, 152.1, 148.7, 148.2, 142.4, 135.8,
3
133.6, 132.9, 132.1, 130.7, 130.4, 128.8, 127.7, 127.5, 127.3,
124.7, 123.0, 122.7 ppm. DEPT 135: δ = 148.2, 132.1, 130.7,
130.4, 128.8, 127.7, 127.5, 127.3, 123.0 ppm. HRMS (EI): m/z
1969, 22, 1963. (c) Kano, S.; Mochizuki, N.; Hibino, S.; Shibuya,
S. J. Org. Chem. 1982, 47, 3566.
+
(12) Shi, L. M.; Myers, T. G.; Fan, Y.; OʼConnor, P. M.; Paul, K. D.;
cacld for C19H NO S [M ]: 315.0354; found: 315.0354.
9
2
Friend, S. H.; Weinstein, S. H. Mol. Parmacol. 1998, 53, 241.
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Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E