Facile approach to alkaloid-like 6/6/5/5-tetracyclic spiroheterocycles via 1,3-dipolar cycloaddition reaction of fused 1H-pyrrole-2,3-diones with nitrones

Article abstract of DOI:10.1016/j.tetlet.2020.151595

A facile synthetic approach towards 6/6/5/5-tetracyclic spiroheterocycles has been developed from the highly diastereoselective 1,3-dipolar cycloaddition reaction of [e]-fused 1H-pyrrole-2,3-diones with nitrones. The described novel heterocyclic systems are heteroanalogs of cytotoxic alkaloids, kibalaurifoline and gitingensine. The developed reaction represents the first example of involvement of 1H-pyrrole-2,3-diones fused at [e]-side in a 1,3-dipolar cycloaddition reaction.

Full text of DOI:10.1016/j.tetlet.2020.151595

Journal Pre-proofs
Facile approach to alkaloid-like 6/6/5/5-tetracyclic spiroheterocycles via 1,3-
dipolar cycloaddition reaction of fused 1H-pyrrole-2,3-diones with nitrones
Ekaterina E. Stepanova, Maksim V. Dmitriev, Andrey N. Maslivets
PII:
S0040-4039(20)30004-6
DOI:
https://doi.org/10.1016/j.tetlet.2020.151595
TETL 151595
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 November 2019
28 December 2019
6 January 2020
Please cite this article as: Stepanova, E.E., Dmitriev, M.V., Maslivets, A.N., Facile approach to alkaloid-like 6/6/5/5-
tetracyclic spiroheterocycles via 1,3-dipolar cycloaddition reaction of fused 1H-pyrrole-2,3-diones with nitrones,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151595
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Graphical Abstract
Facile approach to alkaloid-like 6/6/5/5-tetracyclic
spiroheterocycles via 1,3-dipolar cycloaddition
reaction of fused 1H-pyrrole-2,3-diones with nitrones
Ekaterina E. Stepanova, Maksim V. Dmitriev, Andrey N. Maslivets
O
O
N
toluene or
X
O
X
N
1
,4-dioxane, rt,
Ph
O
Ph
O
N
1-5 days
Ar2
O
N
+
Ar1
R
Ar2
R
O
O
Ar1
O
O
1
0
3 examples
0-00% yield
X = O, NH; R = H, Cl, Br, Me

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Facile approach to alkaloid-like 6/6/5/5-tetracyclic spiroheterocycles via 1,3-dipolar
cycloaddition reaction of fused 1H-pyrrole-2,3-diones with nitrones
Ekaterina E. Stepanova, Maksim V. Dmitriev and Andrey N. Maslivets
Department of Chemistry, Perm State University, ul. Bukireva 15, Perm 614990, Russian Federation
—
——
ARTICLE INFO
ABSTRACT


Corresponding author. Tel.: +7-902-792-5170; e-mail: caterina.stepanova@psu.ru
Corresponding author. E-mail: koh2@psu.ru
Article history:
Received
A facile synthetic approach towards 6/6/5/5-tetracyclic spiroheterocycles has been developed
from the highly diastereoselective 1,3-dipolar cycloaddition reaction of [e]-fused 1H-pyrrole-
2,3-diones with nitrones. The described novel heterocyclic systems are heteroanalogs of
cytotoxic alkaloids, kibalaurifoline and gitingensine. The developed reaction represents the first
example of involvement of 1H-pyrrole-2,3-diones fused at [e]-side in a 1,3-dipolar cycloaddition
reaction.
Received in revised form
Accepted
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
1
,3-Dipolar cycloaddition
Isoxazole
Nitrones
1
H-Pyrrole-2,3-diones
Due to new discoveries in molecular biology and medicine, modern drug discovery requires development of small molecules with
complex 3D structures (shape complexity) to reduce binding promiscuity and improve clinical success [1]. From these points of view,
polycyclic spiro-type frameworks (Figure 1) are promising motives for design of 3D complex scaffolds. Moreover, this type of
scaffolds is the core element of numerous biologically active natural products [2], for example, neuroprotective bilobalide [2a],
cytotoxic dankasterone A [2b], anticonvulsant (+)-erythravine [2c], antiviral pretazettine [2d], cytotoxic kibalaurifoline and gitingensine
[2e], etc. (Figure 1).
polycyclic spiro-type motive
O
O
O
O
OH
OH
O
O
O
O
O
bilobalide
dankasterone A
O
H
N
HO
O
O
O
H
N
O
O
OH
(+)-erythravine
pretazettine
O
O
O
O
O
N
H2N
kibalaurifoline
gitingensine
Figure 1. Selected examples of biologically active natural
products bearing a polycyclic spiro-type motive.

2
Tetrahedron
1
,3-Dipolar cycloaddition reactions have proved themselves to be a facile tool for simultaneous introduction of several stereogenic
centers through a single step to afford 3D complex structures [3]. As well, these reactions were successfully applied to the synthesis of
many interesting polycyclic spiro-type compounds [4].
1
H-Pyrrole-2,3-diones are polyelectrophilic compounds enabling synthesis of various heterocyclic systems with divergent skeletons
[5]. Syntheses of several 3D complex polycyclic spiro-type heterocycles were developed on their basis. For example, 1H-pyrrole-2,3-
diones fused at [e]-side (FPDs) 1 were employed as key structures in the syntheses of 6/6/5/6-tetracyclic spiro-system of Erythrina and
related alkaloids [6] (Scheme 1), and FPDs 2 were utilized in the syntheses of 6/6/5/6-tetracyclic systems of heterocyclic analogs of
1
3(14→8)abeo-steroids [7] (Scheme 1).
N
N
N
O
O
ref. [6]
MeOOC
O
O
Erythrina alkaloid core
1
MeOOC
R
O
X
O
O
X
O
O
N
N
O
ref. [7]
Ar
Ar
O
13(148)abeo-steroid
O
2
core
Scheme 1. Synthesis of 3D complex polycyclic spiro-type
heterocycles via reactions of FPDs 1, 2.
Recently, monocyclic 1H-pyrrole-2,3-diones 3 were found to undergo a highly diastereoselective 1,3-dipolar cycloaddition reaction
with nitrones 4 to afford pyrrolo[3,2-d]isoxazoles 5 bearing three stereogenic centers (Scheme 2) [8]. We hypothesized that FPDs 2
could provide an access to a peculiar 6/6/5/5-tetracyclic system 6, a heterocyclic analog of cytotoxic alkaloids, kibalaurifoline and
gitingensine (Figure 1), via a 1,3-dipolar cycloaddition reaction with nitrones 4 (Scheme 2).
Herein, we report the first research on a 1,3-dipolar cycloaddition reaction of FPDs 2 with nitrones 4 to achieve a 6/6/5/5-tetracyclic
system 6 (Scheme 1), a heterocyclic analog of biologically active alkaloids, kibalaurifoline and gitingensine (Figure 1).
Initially, to test the preparation of the target alkaloid-like 6/6/5/5-tetracyclic compounds 6, we examined the reaction of FPD 2a with
O
R'
R'
N
Ar
O
Ph
N
O
Ph
R
R
4
Ar
O
N
N
OAlk
ref. [8]
O
O
O
O
OAlk
3
5
O
N
O
O
X
N
O
O
Ar
X
Ph
Ph
N
O
4
Ar
O
N
This work
Ar
O
O
O Ar
alkaloid-like core
2
6
Scheme 2. 1,3-Dipolar cycloaddition reactions of 1H-pyrrole-
,3-diones 2, 3 with nitrones.
2
nitrone 4a in acetonitrile at room temperature in the dark (since nitrones 4 are known to decompose in the sunlight [9]) (Table 1, entry
). In 1 h, the UPLC-MS chromatogram (ESI+) of the obtained reaction mixture demonstrated only peaks of the starting compounds
1
+
and the peak with m/z 517, which corresponded to the [M + H] ion of the desired adduct 6aa. However, the conversion of the starting
compounds 4a and 2a was low, and the yield of compound 6aa was poor (Table 1, entry 1). Longer reaction time resulted in a slight
increase of the yield of compound 6aa (Table 1, entry 2).
Then, we tested the reaction at the elevated temperature (Table 1, entry 3) as it was reported for monocyclic 1H-pyrrole-2,3-diones 3
[8]. Disappointingly, the reaction mixture obtained in boiling acetonitrile contained numerous side-products in addition to the starting
compounds 2a and 4a and adduct 6aa (UPLC-MS monitoring), and the yield of the target compound 6aa kept poor.
Table 1. Optimization of the reaction conditionsa.
O
O
O
O
N
O
O
N
Ph
O
N
Ph
Ph
N
O
4a
Ph
O
conditions
Ph
O
O
O Ph
2a
6aa

3
Entry
Solvent
Temperature, °C
Time, h
Yield of
b
6
aa (%)
1
2
3
4
5
6
acetonitrile
acetonitrile
acetonitrile
25
25
82
1
18
28
23
60
64
95c
24
3
1,4-dioxane 25
1,4-dioxane 25
3
24
24
toluene
25
aA suspension of FPD 2a (31 µmol, 10.0 mg) and nitrone 4a (31 µmol, 6.2 mg) in the corresponding solvent (0.5 mL) were stirred in an oven-dried closed
micro reaction vial in the dark.
bUPLC yield (the chromatograms were recorded immediately after sample preparation).
cBefore the investigation by UPLC, the reaction mixture was diluted with chloroform (1 mL) to dissolve the formed precipitate of 6aa.
With these in mind, we tested the reaction of FPD 2a with nitrone 4a in other solvents at room temperature (Table 1, entries 4-6).
Surprisingly, the reaction carried out in 1,4-dioxane gave target adduct 6aa in a good yield (Table 1, entries 4, 5). Analyzing these, we
assumed that the investigated reaction could be a reversible process. Such an increase of the yield of compound 6aa could be caused by
the change in polarity of solvents, i.e. the non-polar solvent (1,4-dioxane) facilitated the cycloaddition reaction of zwitterionic nitrone
4
a to form non-ionic adduct 6aa, and controversially, the polar solvent (acetonitrile) facilitated adduct’s 6aa dissociation to give
zwitterionic nitrone 4a.
Interestingly, the conduction of the reaction of FPD 2a with nitrone 4a in toluene resulted in an almost quantitative formation of the
target adduct 6aa (Table 1, entry 6). The possible explanation of this could consist of two major factors. The first factor was the low
polarity of toluene facilitating the cycloaddition reaction. And the second one was the low solubility of compound 6aa in toluene, i.e.
the formed compound 6aa precipitated and did not undergo the dissociation. Filtration of the formed precipitate gave pure compound
6
aa in an excellent yield (90%).
Adduct 6aa was isolated and characterized by NMR, IR and mass spectra, elemental analysis and single crystal X-ray analysis
(CCDC 1974540). The NMR spectra demonstrated the same characteristic signals as the NMR spectra of pyrrolo[3,2-d]isoxazoles 5 [8].
Considering these, we established the structure of adduct 6aa to be the desired 6/6/5/5-tetracyclic alkaloid-like compound (Table 1).
As a result, we found optimal conditions for preparation and isolation of the target compounds 6 (Table 1, entry 6). It should be
mentioned that the end of reaction could be easily monitored by the reaction mixture color, i.e. the starting FPDs 2 are dark violet
compounds, and the compounds 6 are pale yellow or colorless ones (Figure 2). So, when the dark violet color of the reaction mixture
a
b
Figure 2. Reaction of FPD 2a with nitrone 4a progress
monitoring. a – Reaction time of 0 h; b – 24 h.
disappeared, the reaction was ended, and the product could be isolated by simple filtration directly from the reaction mixture.
Also, it should be mentioned that compound 6aa was found to dissociate when it was stored in solutions (observed by the appearance
of the dark violet color of the solution). This proved our assumption on the reversibility of the studied reaction. Therefore, all the
spectra acquisitions of the solutions of this compound should be made immediately after the dissolution.
Next, we explored the reagent scope of the reaction by involvement of nitrones 4a-f in the reaction with FPD 2a (Table 2). We
observed that reaction time depended on the electron effect of the substituent in aryl of nitrones 4a-d. Reaction with electron-donating
groups (phenyl and 4-methoxyphenyl) bearing nitrones 4a,c was completed in 1 d; reaction with electron-withdrawing group (4-
bromophenyl) bearing nitrone 4b required 5 d for completion, and reaction with strong electron-withdrawing group (4-nitrophenyl)
bearing nitrone 4d resulted only in trace amounts of the target adduct 6ad through 7 d. Unfortunately, alkyl substituted nitrones 4e,f
reacted with FPD 2a unselectively, yielding difficult mixtures of various products. Such trend in selectivity of cycloaddition reactions
with alkyl substituted nitrones 4e,f was observed earlier [10], and can be explained by poorer resonance stabilization of the reaction’s
transition state by alkyl substituents.
Table 2. Exploration of the reagent scope (variation of nitrones)a.
O
O
O
N
R2
a-f
O
N
O
N
O
O
N
R1
R1
O
4
R2
O
toluene, rt,
time
Ph
O
O
O Ph
2a
6aa-af

4
Tc etrahedron
Entry
R1
ArR2
Ph
Time, db
Yield of 6 (%)
6
6
6
6
6
6
aa
ab
ac
ad
ae
af
Ph
Ph
Ph
Ph
Ph
Me
1
90
C
C
C
6
6
6
H
4
H
4
H
4
Br-4
5
92
OMe-4
1
91
NO
2
-4
7d
7e
7e
tracesd
–e
Me
Ph
–e
aA suspension of FPD 2a (783 µmol, 250.0 mg) and nitrone 4 (783 µmol) in toluene (5 mL) were stirred in an oven-dried closed micro reaction vial in the
dark.
bReaction time was monitored by the disappearance of the dark violet color of FPD 2a.
cIsolated yield.
dThe dark violet color of FPD 2a did not disappear, and the reaction was monitored by UPLC-MS.
eThe reaction was monitored by UPLC-MS.
Then the reagent scope in relation to various FPDs 2 was investigated (Table 3). Reaction of aroyl bearing FPDs 2b-i (X = O) with
nitrones 4a,c proceeded smoothly under developed above conditions, and no dependence of reaction time on the substituents in
compounds 2b-i was found.
To involve FPD 2j (X = NH, Table 3) in reaction with nitrone 4a, a mixture of toluene and 1,4-dioxane (1 : 1 v/v) had to be been
used as the solvent, since compound 2j is insoluble in toluene [11]. So, the reaction of FPD 2j with nitrone 4a afforded the desired
adduct 6ja in excellent yield.
Surprisingly, reaction of ethoxycarbonyl bearing FPD 2k with nitrone 4a proceeded much more rapidly (reaction time was about 5
min) and did not result in the target adduct 6ka (Table 3). The UPLC-MS chromatograms of the reaction mixture and the filtrated
+
product demonstrated a peak with m/z 503 (ESI+), which corresponded to the [M(2k) + M(4a) - CO + C
2
H
5
OH + H] ion, and m/z 501
(
ESI-),
which
corresponded
to
the
-
2 5
[M(2k) + M(4a) - CO + C H OH - H] ion. NMR spectra of the isolated compound proved addition of one molecule of ethanol and loss
of one carbonyl group. However, it is obvious that reaction of FPD 2k with nitrone 4a proceeded via another pathway with the
participation of ethoxycarbonyl group. Unfortunately, we did not succeed to establish the structure of the formed compound yet.
Table 3. Exploration of the reagent scope (variation of FPDs)a.
O
O
O
X
N
O
N
Ar
X
N
Entry
Ar
R
R´
X
Ti
me,
db
Yiel
d of
6с
Ph
Ph
N
O
4
a,c
Ar
O
R
R
solvent, rt,
time
R'
(%)
O
O
O
a-k
O
R'
87d
6
6
6
6
6
6
6
6
6
6
6
ba
ca
cc
da
ea
fa
Ph
Ph
H
C
C
C
6
H
H
H
4
4
4
Cl-4
O
O
O
O
O
O
O
O
O
NH
O
3
1
1
3
1
1
2
1
1
5
0f
2
6ba-ka
H
6
6
Me-4
Me-4
84d
91d
92d
85d
85d
88d
90d
91d
87e
–d
C
6
H
4
OMe-4
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
H
Ph
C
6
H
4
F-4
Me
Br
H
Ph
Ph
ga
ha
ia
C
C
6
6
H
4
4
OMe-4
OEt-4
H
H
ja
H
Ph
ka
H
OEt
aA suspension of FPD 2 (783 µmol) and nitrone 4 (783 µmol) in solvent (5 mL) were stirred in an oven-dried closed micro reaction vial in the dark.
bReaction time was monitored by the disappearance of dark violet color of FPDs 2.
сIsolated yield.
dThe reaction was carried out in toluene.
eThe
reaction
was
carried
out
in
the
mixture
of
toluene
and
1,4-dioxane
(
1 : 1 v/v).
fReaction time was 5 min.
We assume that the formation of 6/6/5/5-tetracyclic compounds 6aa-ja proceeded via a 1,3-dipolar cycloaddition reaction of nitrones
to the C=С double bond of FPDs 2 (Scheme 3). The products 6 were formed highly diastereoselectively, and no stereoisomers 6´ were
4
observed neither by UPLC-MS nor by NMR. The possible reason of such diastereoselectivity could be that endo transition state (endo-
TS) was more energetically favorable than exo transition state (exo-TS) (Scheme 3), due to less steric hindrance between phenyl
substituent of nitrone 4 and FPD 2 in endo-TS (Scheme 3), and in addition, due to the presence in endo-TS of favorable secondary

X
N
O
O
O
Ar
O
2
5
O
N
Ar
Ph
4
endo-TS
exo-TS
Ph
O
N
O
N
Ph
O
Ar
Ar
O
X
O
X
O
O
N
N
Ar
Ar
O
O
O
O
O
O
X
N
X
O
Ph
Ph
N
N
Ar
O
N
Ar
O
O
O
O
O Ar
Ar
6
6'
Scheme 3. Pathways of 1,3-dipolar cycloaddition reaction of
FPDs 2 and nitrones 4 (in red is drawn positive charge
delocalization; in blue, negative).
electrostatic interorbital interactions between a partially positively charged fragment of nitrone 4 and a partially negatively charged 1,3-
dicarbonyl fragment of FPD 2.
In conclusion, we have developed a facile synthetic approach to 6/6/5/5-tetracyclic spiroheterocycles 6 via a highly
diastereoselective 1,3-dipolar cycloaddition reaction of FPDs 2 with nitrones 4. The obtained tetracyclic compounds 6 were found to be
unstable during their storage in solutions because of the reversibility of the 1,3-dipolar cycloaddition reaction. Reaction time of the
cycloaddition was found to be dependent on the electron effect of the substituents in aryl of nitrones 4 and independent on substituents
in aroyl bearing FPDs 2. FPD 2k, bearing ethoxycarbonyl group, was found to undergo another pathway of interaction with nitrones 4,
possibly, involving transformations of ethoxycarbonyl group. The described reaction is the first example of involvement of FPDs 2 in a
1
,3-dipolar cycloaddition reaction. The synthesized compounds 6 bear a pharmaceutically interesting 3D complex structure, which can
be considered as heterocyclic analogs of cytotoxic alkaloids, kibalaurifoline and gitingensine.
Acknowledgments
This work was supported by the Russian Science Foundation, project # 19-13-00290.
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Tetrahedron
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Supplementary Material
Supplementary data associated with this article can be found, in the online version, at.
Access to heterocyclic analogs of cytotoxic alkaloids, kibalaurifoline and gitingensine.
First example of involvement of fused at [e]-side 1H-pyrrole-2,3-diones in a 1,3-dipolar cycloaddition
reaction.
Highly diastereoselective.
Simultaneous formation of three stereogenic centers.
Graphical Abstract
Facile approach to alkaloid-like 6/6/5/5-tetracyclic
spiroheterocycles via 1,3-dipolar cycloaddition
reaction of fused 1H-pyrrole-2,3-diones with nitrones
Ekaterina E. Stepanova, Maksim V. Dmitriev, Andrey N. Maslivets
O
O
N
toluene or
,4-dioxane, rt,
1-5 days
X
O
X
N
1
Ph
O
Ph
O
N
Ar2
O
N
+
Ar1
R
Ar2
R
O
O
Ar1
O
O
1
0
3 examples
0-00% yield
X = O, NH; R = H, Cl, Br, Me