Visible-Light-Promoted Selenylative Spirocyclization of Indolyl-ynones toward the Formation of 3-Selenospiroindolenine Anticancer Agents

Article abstract of DOI:10.1002/asia.202000298

A metal-free and efficient visible-light-induced spirocyclization of indolyl-ynones with diselenides at room temperature under air atmosphere to prepare 3-selenospiroindolenines in moderate to good yields has been developed. The resulting products were tested for in vitro anticancer activity by MTT assay, and compounds 3 c and 3 e showed potent cancer cell-growth inhibition activities.

Full text of DOI:10.1002/asia.202000298

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Visible Light-Promoted Selenylative Spirocyclization of Indolyl-
ynones toward the Formation of 3-Selenospiroindolenines
Anticancer Agents
Authors: Xiu-Jie Zhou, Hao-Yang Liu, Zu-Yu Mo, Xian-Li Ma, Yanyan
Chen, Hai-Tao Tang, Ying-Ming Pan, and Yan-Li Xu
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To be cited as: Chem. Asian J. 10.1002/asia.202000298
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Chemistry - An Asian Journal
10.1002/asia.202000298
COMMUNICATION
Visible Light-Promoted Selenylative Spirocyclization of Indolyl-
ynones toward the Formation of 3-Selenospiroindolenines
Anticancer Agents
[
a]
[a]
[b]
[a]
[a]
[b]
Xiu-Jie Zhou, Hao-Yang Liu, Zu-Yu Mo, Xian-Li Ma,* Yan-Yan Chen,* Hai-Tao Tang, Ying-
[
b]
[a]
Ming Pan, and Yan-Li Xu*
Dedication ((optional))
6
7
Abstract:
spirocyclisation of indolyl-ynones with diselenides at room
temperature under air atmosphere to prepare 3-
A
metal-free and efficient visible-light induced
Recently, the transition metal-catalyzed or TFA promoted
dearomative cascade cyclization with indolyl-ynones provides an
attractive strategy for the construction of spiroindoline
selenospiroindolenines in moderate to good yields has been
developed. The resulting products were tested for in vitro
anticancer activity by MTT assay, and the compounds 3c and 3e
showed potent cancer cell-growth inhibition activities.
compounds, in which
directly to provide 3-substituted
spiroindolenines. In 2018, Van der Eycken’s group reported an
intramolecular ipso-iodocyclization of indol ynones with NIS to 3-
8
iodospiroindolenines. In 2019, Unsworth’s group developed a
Pd-catalysted dearomatizing spirocyclization/cross-coupling
cascade for the conversion of indole ynones into functionalized
Organoselenium compounds have been extensively studied due
to their well-known biological activities, which mainly attributed
1
9
spirocycles containing tetrasubstituted alkenes. If the selenyl
to the fact that the selenium atom may serve as an electron
donor or a hydrogen bond acceptor in these applications,
altering the chemical characteristics of enzyme active sites.
groups and spiroindolenines core can be simultaneously
introduced into organic compounds, a series of new selenium-
containing spiroindolenines were formed and which provided an
opportunity to obtain the pharmaceutical lead compounds or
2
Considering the importance of organoselenium compounds in
medicinal chemistry, introducing selenium to heterocyclic
molecules are expected to find applications in drug discovery
drugs to adjust their bioactivity. However,
a method for
introducing selenyl group into the unique spiroindoline
a
3
programmes.
skeleton was rarely studied.
Spirocyclic compounds have attracted great attention in the
chemical world because of its original stereostructure and
Visible light is abundant and available in nature, appreciating
10
4
as a mild energy source to drive chemical transformations. In
particular, visible-light photoredox catalysis using O as the
challenging complexity of their synthesis. The spiroindolenines
2
are common structural scaffolds with diverse pharmacological
activities and found in various natural products (Fig 1),
oxidant is regarded as an ideal methodology for the oxidative
functionalization reactions owing to its economical, safe and
5
occupying a prominent position in drug discovery research.
1
1
environmentally friendly properties. In 2018, Baidya’s group
reported a radical dearomative cascade cyclization to
Figure 1. Spiroindolenine natural products.
[
a] X.-J. Zhou, H.-Y. Liu, Prof. X.-L. Ma, Dr. Y.-Y. Chen and Dr. Y.-L. Xu
Pharmacy School
Guilin Medical University
541004 People’s Republic of China
E-mail: mxl78@glmc.edu.cn
chenyy269614@163.com
yanli.xu@163.com
[
b] Z.-Y. Mo, Dr. H.-T. Tang and Prof. Y.-M. Pan
State Key Laboratory for the Chemistry and Molecular Engineering of
Medicinal Resources
Guangxi Normal University
5
41004 People’s Republic of China
Scheme 1. Synthesis of seleno-spirocyclic compounds via selenylative
dearomative cascade cyclization
Supporting information for this article is given via a link at the end of the
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Chemistry - An Asian Journal
10.1002/asia.202000298
COMMUNICATION
[
a]
scale (Table 1, entry 15). Thus, the best conditions for the
synthesis of 3a involved in THF in air at room temperature under
the irradiation of 50 W white LEDs or in sunshine.
Table 1. Optimization of reaction conditions.
With the optimal reaction conditions identified, the scope and
generality of this reaction were firstly investigated using different
indolyl-ynones (Scheme 2). In general, the alkynes substituent
2
R , the process is compatible with aryl groups containing methyl,
methoxy, phenyl, halide, trifluoromethyl substituents, which
[
b]
Entry
Base
-
Solvent
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCE
THF
Yield (%)
55
75
65
70
0
80
40
75
85 (82)
30
77
60
reacted with diphenyldiselenide (2a) gave the desired products
1
2
3
4
5
6
7
8
9
3
b-3i in 50%-90% yields. However, 4-(2-bromophenyl)-1-(1H-
2
Na CO
3
NaHCO
3
indol-3-yl)but-3-yn-2-one (1j) treated with 2a affording a trace
amount of 3j (detected by LC-MS). In addition, 2-thienyl
substituent on the alkyne was also well-tolerated, giving 3k in 60%
yield. The alkyl-substituted alkynes were also found to be
suitable substrates for this transformation, giving the desired
products 3l-3o in 54%-78% yields. However, none of the desired
product 3p was detected and the materials were recovered
K
2
CO
3
2
Cs CO
3
NaOAc
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
10
3
CH CN
toluene
acetone
1
1
12
13
14
15
[
[
[
c]
d]
e]
NaOAc
NaOAc
NaOAc
THF
THF
THF
86 (82)
<5%
82 (78)
[
a]
[
a]
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), base (0.2 mmol), solvent
Scheme 2. Synthesis of 3-selenospiroindolenines 3 and 4.
o
(
1.0 mL), 50 W white LEDs, in air at room temperature (35-40 C, detected by
[b]
1
thermometer) for 3 h.
standard, data in parentheses are the yields of isolated product.
sunshine (reaction time: PM 12:00-14:00). Reaction in the dark condition for
2
Determined by H NMR with DMAP as the internal
[c]
2 h, in
[d]
[e]
4 h. The reaction was performed in 1 mmol scale.
selenylative spirocyclization of N-aryl alkynamides at room
1
2
temperature under oxygen atmosphere (Scheme 1a).
Unsworth’s group reported a visible-light-induced intramolecular
charge transfer in the radical spirocyclisation of indol ynones
with thiols leading the formation of 3-thiospiroindolenines under
the argon condition, in which an intramolecular EDA complex
1
3
was formed (Scheme 1b). As our continued interest in visible
1
4
15
light photoredox catalysis and the formation of C-Se bond,
herein, we present an efficient visible-light-promoted selenylative
spirocyclisation of indolyl-ynones to 3-selenospiroindolenines at
room temperature under air condition (Scheme 1c).
The reaction of 1-(1H-indol-3-yl)-4-phenylbut-3-yn-2-one (1a)
with diselenide (2a) was chosen as a model system for the
optimization studies and the results are summarized in Table 1.
Initially, the reaction was carried out in PhCl under the irradiation
of 50 W white LEDs, giving the desired product 3a in 55% yield
(
Table 1, entry 1). The single crystals of 3a was obtained by
gradual crystallization in methanol, and characterized as 2-
phenyl-3-(phenylselanyl)spiro[cyclopent[2]ene-1,3'-indol]-4-one
16
(
for details see SI). Then, the investigation of various bases
such as Na CO , NaHCO , K CO , Cs CO , NaOAc and KOAc
2
3
3
2
3
2
3
revealed that NaOAc was the optimal base for this reaction and
afforded 3a in 80% yield (Table 1, entries 6 vs 2-7). In addition,
a solvent screening study indicated that THF was the most
suitable solvent for the formation of 3a (Table 1, entries 6 vs 8-
12). Moreover, when the reaction was conducted in sunshine,
the product 3a was obtained in 86% yield (Table 1, entry 13).
When the reaction performed in the dark condition, a trace
amount of 3a was detected by GC-MS with most of materials
were recovered (Table 1, entry 14). These results indicating that
the light is essential for this transformation. Besides, the reaction
was scalable and practical since a satisfactory yield (82%) could
be obtained when the reaction was performed on a 1 mmol
[
a]
Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), NaOAc (0.6 mmol), THF
(
(
3.0 mL), under the irradiation of 50 W white LEDs in air at room temperature
35-40 C, detected by thermometer). Isolated yield.
o
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COMMUNICATION
Scheme 4. Proposed mechanism
when the substrate 1-(1H-indol-3-yl)-5,5- dimethylhex-3-yn-2-
one (1p) treated with 2a, revealing that the steric effects of the
substituent on the alkynes played an important role in this
transformation. Moreover, the substituents on the indole core
such as 2-methyl, 5-methoxy, 5-bromo, 4-chloro, would also be
used in this system and afforded the corresponding products 3q-
3t in 70%-84% yields. The reaction of N-methyl indolyl-ynone
(
1u) with 2a failed to give the desired product 3u. Besides, the
diaryldiselenides with electron-donating (OMe, Me) and electron-
withdrawing (F, Cl) substituents reacted smoothly to provide the
desired products 4a-4e in 65-84% yields. The substrate 1, 2-
di(thiophen-2-yl)diselane was also well-tolerated, giving 4f in 66%
yield. Unfortunately, the substrate 1,2-dimethyldiselane failed to
afford the desired product 4g.
In order to explore the possible reaction pathway, control
experiments were carried out as shown in Scheme 3. Firstly, the
reaction of 1a and 2a under the standard condition without the
addition of NaOAc, 3a was obtained in 60% yield (Scheme 3,
eqn 1a). This photoreaction cannot be fully inhibited and the
desired product (3a) was obtained in 40% yield even though 5
equiv. of TEMPO was added (Scheme 3, eqn 1b). In addition,
On the basis of these experimental results, two possible
pathways are proposed and depicted in Scheme 4. The
irradiation of diphenyl diselenide (2a) produced phenylselenyl
the reaction of 1a and 2a with
2 equiv. of ethene-1,1-
diyldibenzene was added, providing 3a in 70% yield with a trace
amount of 5 and 6 (5 and 6 were detected by LC-MS) (Scheme
1
7
13
free radicals A. In path a, the addition of indolyl-ynone 1a
with the phenylselenyl radicals A afforded an alkenyl radical B,
followed by cyclising with the indole at its 3-position to form a
spirocyclic radical intermediate C. Oxidation of C to D in the air
atmosphere, which underwent dehydrogenation in the base
3
, eqn 2). When the reaction was conducted in the nitrogen
atmosphere, the reaction was inhibited seriously, only gave 3a in
0% yield, and most of the remaining substrate was
3
decomposed and no major product was observed (Scheme 3,
eqn 3). Moreover, the reaction of 1a and PhSeCl under the
standard condition offered 3a was obtained in 75% yield,
18
condition to afford the desired product 3a. In path b, Oxidation
+
+
of phenylselenyl radicals A to PhSe in the air atmosphere,
indicating that PhSe is a possible intermediate for the formation
which reacted with the alkyne group of indolyl-ynone 1a leaded
the formation of selenium ion E. Then, the cyclization of E at 3-
position of indole to give the desired product 3a.
of 3a (Scheme 3, eqn 4).
Scheme 3. Control experiments.
To explore the biological activities of these series of 3-
selenospiroindolenines, the in vitro antitumor activities of
compounds 3 and 4 were evaluated via the MTT assays of the
MGC-803, HpeG-2, T-24, and HeLa tumor cell lines. 5-
Fluorouracil (5-FU) was used as the positive control. Most of the
compounds exhibited significant antitumor activity against the
five tumor cell lines and even demonstrated better cytotoxic
activities than the commercial anticancer drug 5-FU. The half
maximal inhibitory concentration (IC50) values of compounds
with good antitumor activity are listed in Table S1. Notably,
Compound 3c exhibited potent inhibitory activities against Hela
cell lines and MGC-803 cell lines, with IC50 values of 5.2 μM, 6.7
μM, respectively. Compound 3e was found to be powerful
cytotoxic agent against T-24 cell lines with IC50 values of 8.0 μM
(
Fig 2).
Figure 2. IC50 (μM) values for compounds 3b, 3c, and 3e.
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Chemistry - An Asian Journal
10.1002/asia.202000298
COMMUNICATION
In summary, we have developed a simple and efficient visible-
light-promoted metal-free spirocyclisation of indolyl-ynones with
diselenides, providing a series of new selenium-containing
spiroindolenines. This reaction performed in the air condition,
easy operation, no transition metal catalyst or photocatalyst
required. Furtheremore, the synthesized compounds 3c and 3e
exhibited potent anticancer activities in vitro and further
applications of this reaction are currently underway in our
laboratory.
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support.
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950-3961; d) J. Chen, S. Su, D. Hu, F. Cui, Y. Xu, Y. Chen, X. Ma, Y.
Keywords:
visible-light
initiation;
photocatalyst-free;
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for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
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COMMUNICATION
a
a
Xiu-Jie Zhou, Hao-Yang Liu, Zu-Yu
b
a
a
Mo, Xian-Li Ma,* Yan-Yan Chen,* Hai-
Tao Tang, Ying-Ming Pan and Yan-Li
b
b
a
Xu *
Page No. – Page No.
Visible Light-Promoted Selenylative
Spirocyclization of Indolyl-ynones
Text for Table of Contents
toward
the
Formation
of
3-
Selenospiroindolenines
Agents
Anticancer
A visible-light induced spirocyclisation of indolyl-ynones with diselenides was developed
with provieding selenospiroindolenines as products. Furthermore, the obtained products
showed potent cancer cell-growth inhibition activities.
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