A simple entry to sugar derived bispiropyrrolidines through non-stabilized azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2013.05.027

1,3-Dipolar cycloaddition reaction of a carbohydrate-derived exocyclic olefin with in situ generated non-stabilized azomethine ylides, formed by the reaction of sarcosine (a secondary α-amino acid) with isatins, acenaphthenedione and cycloalkanones in refluxing toluene afforded bispiropyrrolidine derivatives in 78-92% yield, when DIPEA was used as a base. However, using Et₃N/DBU, the reaction of the olefin precursor with azomethine ylide (derived from the condensation of cyclopentanone and sarcosine) furnished the product in 51-53% yield. On the other hand, in the absence of a base the yield of the cycloaddition product was dramatically decreased to 10-22%.

Full text of DOI:10.1016/j.tetlet.2013.05.027

Tetrahedron Letters 54 (2013) 3801–3804
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple entry to sugar derived bispiropyrrolidines through
non-stabilized azomethine ylides
Piyali Deb Barman, Divya Goyal, Upendra Kumar Daravath, Ishita Sanyal, Sukhendu B. Mandal,
⇑
Asish Kumar Banerjee
Department of Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolar cycloaddition reaction of a carbohydrate-derived exocyclic olefin with in situ generated non-
Received 5 March 2013
Revised 6 May 2013
Accepted 9 May 2013
Available online 15 May 2013
stabilized azomethine ylides, formed by the reaction of sarcosine (a secondary a-amino acid) with isatins,
acenaphthenedione and cycloalkanones in refluxing toluene afforded bispiropyrrolidine derivatives in
78–92% yield, when DIPEA was used as a base. However, using Et3N/DBU, the reaction of the olefin pre-
cursor with azomethine ylide (derived from the condensation of cyclopentanone and sarcosine) furnished
the product in 51–53% yield. On the other hand, in the absence of a base the yield of the cycloaddition
product was dramatically decreased to 10–22%.
Keywords:
Heterocycles
Bispiropyrrolidines
Carbohydrates
Ó 2013 Elsevier Ltd. All rights reserved.
Azomethine ylides
Cycloaddition reactions
Recent research has witnessed a rising demand on the develop-
ment of unique and diversified structural motifs due to their pres-
ence in many bioactive natural and synthetic molecules1 that have
potential usefulness as drugs for the treatment of antitumor,2 HINI
influenza,3 HIV,4 cancer5 etc. Some bioactive naturally occurring
alkaloids, viz. rhynchophylline,6a formsamine,6b horsfiline,6c elaco-
mine,6d spirotryprostatin A & B6e,f contain monospiropyrrolidinyl-
oxindole moiety and are reported to have numerous biological
activities including antitumor activity against various cell lines,
inhibitory activity against microtubule assembly and mammalian
cell cycles, and modification of function of muscarinic serotonin
receptors. Synthesis of these scaffolds and several spirooxindole
analogues exhibiting inhibitory activities against poliovirus/rhino-
virus 3C-proteinase and aldose reductase have been realized by uti-
lizing the well known 1,3-dipolar azomethine ylide cycloaddition
reaction.7–9 Even sugar-based spiropyrrolidinyl-oxindoles have re-
cently been synthesized utilizing this key step.10 The presence of
bispiropyrrolidinyl-oxindole scaffolds in natural products, to the
best of our knowledge, is hitherto unknown in the literature. Nev-
ertheless, they have received a great deal of attention among syn-
thetic chemists due to their immense activity11 against diabetes,
bacteria, fungi, microbes and mycobacteria. A numerous reports12
for the synthesis of bispiropyrrolo-/pyrrolizino-/pyrrolothiazolo-
oxindoles by addition of azomethine ylides to a variety of non-su-
gar-based olefins have been documented. However, much synthetic
research work on sugar-based bispiro compounds has not been
initiated.
We, therefore, envisioned that hybridizing bispiropyrrolidinyl-
oxindole decoration with sugar derived precursors involving azo-
methine ylides could lead to the discovery of a unique class of car-
bohydrate-derived bispiro heterocycles of potential biological
significance. To this end, we now report an expeditious approach
to target a new kind of sugar-fused bispiropyrrolidinyl-oxin-
doles/-acenaphthylenone/-cycloalkane derivatives using a second-
ary
a-amino acid (sarcosine), 1,2-diketones (isatin and
acenaphthoquinone), cycloalkanones and the sugar-derived olefin
precursor.
O
O
R1
O
O
O
H
O
N
O
R2
O
Me
O
N
COOEt
R1
2a-d
O
H
O
O
Sarcosine (3)
N
toluene, reflux, 11-14 h
R2
O
4a-d
CO2Et
4a: R1 = H, R2 = H
2a: R1 = H, R2 = H
2b: R1 = F, R2 = H
1a
: R1 = F, R2 = H
4b
4c
2c
: R1 = OMe, R2 = H
: R1 = OMe, R2 = H
4d: R1 = H, R2 = Ph
: R1 = H, R2 = Ph
2d
⇑
Corresponding author. Tel.: +91 33 2429 2422; fax: +91 33 2473 5197.
E-mail address: ashisbanerjee@iicb.res.in (A.K. Banerjee).
Scheme 1. Synthesis of sugar-based bispiroheterocycles via azomethine ylides.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.027

3802
P. D. Barman et al. / Tetrahedron Letters 54 (2013) 3801–3804
In our initial attempt (Scheme 1), reaction of the sugar-derived
O
exocyclic olefin, the required dipolarophile 1a with the non-stabi-
lized azomethine ylide, generated in situ by the condensation of
isatin 2a with the amino acid sarcosine (3) in toluene at reflux tem-
perature for 12 h furnished the bispiropyrrolidinyl-oxindole deriv-
ative 4a in 83% yield. Similar reactions of the substituted isatins
2b–d afforded 4b–d in 78%, 85% and 81% yields, respectively. The
structure of 4a–d13,14 was elucidated from the 1H and 13C NMR
spectroscopic data. The formation of the pyrrolidine moiety in 4a
was confirmed by the appearance of three-proton singlet (NCH3)
at d 2.21 and two-proton singlet (NCH2) at d 3.43 in the 1H NMR
spectrum. The observed singlet at d 3.97 was assigned for the
CHCO2Et in the pyrrolidine moiety. The presence of the signals at
d 55.0 (CH), 56.2 (CH2), 57.4 (C) and 73.1 (C) in the 13C NMR spec-
trum also indicated the creation of the pyrrolidine ring during the
cycloaddition reaction. Finally, the structural confirmation of 4a
was obtained from a single crystal X-ray crystallographic study
(the ORTEP diagram is given in Fig. 1).15
We next turned our attention to generalize the methodology
employing non-aromatic cycloalkanones, instead of isatins, for
the generation of azomethine ylide (1,3-dipoles) by the reaction
with sarcosine, although a very few reports exist in the literature
on this method.16 Thus, at the outset, we chose cyclopentanone
(5a) and sarcosine (3) as the ylide generator and reacted with 1a
(Scheme 2) under the previously optimized reaction condition.
This although produced the desired product 6a,13 the yield was
too low (22% Table 1). A careful modification of the reaction condi-
tion was, therefore, needed.
O
H
O
O
O
O
H
n
R4
O
Me
N
COOR3
O
5a-d
O
n
R4
O
Sarcosine (3)
DIPEA, toluene
reflux
6a-e
O
3
4
CO2R3
6a
6b
6c
: R = Et, R = H, n = 1
: R = Et, R = H, n = 2
: R = Et, R = Et; n = 2
4
3
4
5a
: n = 1, R = H
4
3
4
1a: R3 = Et
5b
: n = 2, R = H
5c: n = 2, R4 = Et
5d: n = 3, R4 = H
6d: R3 = Et, R4 = H, n = 3
6e: R3 = Me, R4 = H, n = 2
1b: R3 = Me
Scheme 2. Synthesis of sugar-fused bispiroheterocycles using cycloalkanones.
Table 1
Optimization of reaction condition between 1a and 5a
Entry
Base
Solvent
Time (h)
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
8
None
None
None
None
None
Et3N
Toluene
Methanol
o-Xylene
DMF
10
10
12
12
12
10
10
10
Reflux
Reflux
120
130
130
Reflux
Reflux
Reflux
22
10
20
14
12
51
53
92
DMSO
Toluene
Toluene
Toluene
DBU
DIPEA
a
Isolated yield.
We first decided to screen solvents of the reaction. Attempts
employing methanol, o-xylene, DMF, DMSO etc. under the conven-
tional solution-phase protocols were frustrating, yielding product
6a to the extent of 10–22% (entries 1–5). Thus, in a modified ap-
proach, the addition of Et3N into the reaction mixture to facilitate
the decarboxylation of sarcosine-iminium ion9b in forming an ylide
improved the yield up to 51% (entry 6). The coupling was then fur-
ther reinvestigated by replacing Et3N by DBU. This, however, failed
to show any substantial improvement in the outcome (Table 1, en-
try 7) and had to be discarded. Finally, we tested DIPEA as the base
to condense 1a with 5a, which led to maximization of the product
yield (92%) in 10 h under reflux condition in toluene (entry 8).17
The success of the above cycloaddition reaction with cyclo-
pentanone prompted us to test this newly developed reaction tool
in other higher homologues of cycloalkanones (Scheme 2). Thus,
cyclohexanones (5b,c) and cycloheptanone (5d) were reacted with
the dipolarophiles (1a,b) under the optimal set of reaction condi-
tions, producing the corresponding cycloadducts (6b–e)12 in high
yields (Table 2, entries 2–5). The structures of all the bispiropyrro-
lidinyl-cycloalkanes were confirmed by NMR analyses. They also
exhibited exact masses in their mass spectra.
Once these bispiropyrrolidines with cycloalkane rings were
constructed, we moved towards attempting the synthesis of anal-
ogous bispiropyrrolidine using sterically hindered ketone acenaph-
thoquinone 7, which also led to the cycloadduct 8 (Scheme 3) in
75% yield upon reaction with the azomethine ylide, generated from
7 and 3, the structure of which was deduced by spectral analyses.
From mechanistic considerations, the cycloaddition reaction,
we believe, proceeds with an initial iminium ion formation, which
subsequently decarboxylates (facilitated by DIPEA) to generate an
ylide (1,3-dipole) (Fig. 2). Once the ylide is formed, it behaves as a
nucleophile and attacks the dipolarophile 1a/1b to produce the
cycloadducts in high yields upon [3+2] cycloaddition reaction. It
is worthy to mention that the cycloadducts were essentially
Table 2
Synthesis of sugar-fused bispiroheterocycles using cycloalkanones 5a–da
Entry
Dipolarophile
Ketone
Time (h)
Product
Yieldb (%)
1
2
3
4
5
1a
1a
1a
1a
1b
5a
5b
5c
5d
5b
10
14
11
11
14
6a
6b
6c
6d
6e
92
88
85
82
78
a
All the reactions were performed in toluene under reflux condition using sar-
cosine and DIPEA as the base.
Figure 1. ORTEP diagram of 4a. The displacement ellipsoids are drawn at the
probability of 50%.
b
Isolated yield.

P. D. Barman et al. / Tetrahedron Letters 54 (2013) 3801–3804
3803
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O
O
O
O
O
H
O
O
O
Me
O
N
O
COOEt
7
O
H
O
Sarcosine (3)
DIPEA, toluene
reflux, 12h, 75%
O
CO2Et
1a
8
Scheme 3. Synthesis of bispiroheterocycles using acenaphthaquinone.
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O
O
N
H
H
N
iminium ion
formation
O
O
CO2H
N
H
O
2a
3
N
H
3a
O
O
Hd
O
H
O
Ha
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O
O
H
[3+2] cycloaddition
Hc
O
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O
O
O
N
CH2
N
Me
O
COOEt
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13. General procedure for the synthesis of glycobispiro heterocycles 4a–d, 6a–e and 8:
A mixture of the carbohydrate-derived olefin 1a (0.25 mmol, 1.0 equiv), isatins
2a–d (0.275 mmol, 1.1 equiv), sarcosine 3 (0.275 mmol, 1.1 equiv), was heated
at reflux in toluene (10 mL) under N2 for 11–14 h. The reaction mixture was
cooled and the solvent was evaporated under reduced pressure to a residue,
which was purified by column chromatography on silica gel (100–200 mesh)
using EtOAc/petroleum ether (1:4) as eluent to furnish 4a–d. The compounds
6a–e and 8 were similarly synthesized using 1a/b (0.25 mmol, 1.0 equiv), 5a–
COOEt
O
N
H
1a
HN
3a
4a
azomethine ylide
Figure 2. Mechanistic pathway for the formation of bispiroheterocycles.
formed by the attack of the dipole from the face opposite to the
tangled isopropylidene moiety in order to avoid a higher steric
crowding. This leads to the projection of the ester moiety towards
b-face. Furthermore, it is also expected that, in order to wipe out
the possibility of dipolar repulsion between amide carbonyl and
ester carbonyl groups, the amide group of isatin should be placed
in the plane opposite to the ester moiety. This proposition was in-
deed reflected in the reaction of the olefin 1a with azomethine
ylide 3a affording the cycloadduct 4a. The structure of 4a was con-
firmed by single crystal X-ray analysis.
In conclusion, three-component 1,3-dipolar azomethine cyclo-
addition reactions to synthesize bispiropyrrolidines containing
oxindoles, cycloalkanes and cycloalkanone in excellent yields in
an optimized reaction condition have been successfully demon-
strated. This strategy provides opportunities for the preparation
of libraries of carbohydrate-based bispiropyrrolidine hybrid mole-
cules for biological screening.
d/7 (0.275 mmol, 1.1 equiv),
3 (0.275 mmol, 1.1 equiv) and diisopropyl
ethylamine (DIPEA) (0.25 mmol, 1.0 equiv) followed by purification by
chromatography.
Spectral data of 4a: Light yellow solid; mp 230 °C; ½a D25
ꢀ
ꢁ69.4 (c 0.6, CHCl3); 1
H
NMR (600 MHz, CDCl3): d 0.66 (t, 3H, J = 7.2 Hz), 1.41 (s, 3H), 1.45 (s, 3H), 1.47
(s, 3H), 1.57 (s, 3H), 2.21 (s, 3H), 3.43 (s, 2H), 3.62–3.65 (m, 2H), 3.97 (s, 1H),
3.98ꢁ4.01 (m, 2 H), 4.11ꢁ4.14 (m, 2H), 5.48 (d, 1H, J = 3.6 Hz), 6.05 (d, 1H,
J = 4.2 Hz), 6.79 (d, 1H, J = 7.8 Hz), 7.05 (dt, J = 0.6, 1H, 7.8 Hz), 7.23 (dt, 1H,
J = 1.2, 7.8 Hz), 7.32 (d, J = 7.2 Hz, 1H), 7.49 (br s, 1H); 13C NMR (150 MHz,
CDCl3): d 13.3 (CH3), 25.4 (CH3), 26.6 (CH3), 26.8 (CH3), 26.9 (CH3), 35.1 (CH3),
55.0 (CH), 56.2 (CH2), 57.4 (C), 60.6 (CH2), 68.0 (CH2), 73.1 (C), 74.5 (CH), 79.4
(CH), 83.2 (CH), 105.9 (CH), 109.2 (C), 109.8 (CH), 111.0 (C), 122.9 (CH), 126.4
(CH), 128.2 (C), 129.5 (CH), 141.5 (C), 169.5 (C), 78.9 (C). HRMS (ESI): m/z
[M+H]+ calcd for C26H35N2O8: 503.2388; found: 503.2408.
Acknowledgements
The authors gratefully acknowledge the Council of Scientific
and Industrial Research for providing Senior Research Fellowships
(to P.D.B. and I.S.).
6a: Sticky light yellow liquid; ½a D25
ꢀ
ꢁ90.4 (c 0.56, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.26 (t, 3H, J = 7.2 Hz), 1.33 (s, 3H), 1.37 (s, 3H), 1.42 (s, 3H), 1.49 (s,
3H), 1.53ꢁ1.69 (m, 6H), 1.93ꢁ1.97 (m, 2H), 2.28 (s, 3H), 2.85 (d, 1H, J = 9.6 Hz),
3.05 (br s, 2H), 3.87 (d, 1H, J = 7.8 Hz), 3.97 (dd, 1H, J = 5.1, 8.4 Hz), 4.06ꢁ4.23
(m, 4H), 5.23 (d, 1H, J = 3.6 Hz), 5.61 (d, 1H, J = 3.6 Hz); 13C NMR (75 MHz,
CDCl3): d 14.1 (CH3), 24.5 (CH2), 25.1 (CH2), 25.3 (CH3), 26.3 (CH3), 26.6 (CH3),
26.7 (CH3), 29.3 (CH2), 34.4 (CH2), 35.0 (CH3), 55.2 (CH), 56.3 (CH2), 56.9 (C),
60.6 (CH2), 67.8 (CH2), 74.0 (CH), 74.3 (C), 80.4 (CH), 82.9 (CH), 104.6 (CH),
109.4 (C), 110.7 (C), 172.0 (C). HRMS (ESI): m/z [M+Na]+ calcd for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
027.
C23H37NNaO7: 462.2462; found: 462.2480. 8: sticky brown liquid; ½ ꢀ
a 2D5
ꢁ153.8 (c 0.18, CHCl3); 1H NMR (300 MHz, CDCl3): d 0.88 (t, 3H, J = 3.6 Hz),
1.47 (s, 3H), 1.51 (s, 3H), 1.54 (s, 3H), 1.62 (s, 3H), 2.14 (s, 3H), 3.27ꢁ3.33 (m,
2H), 3.55 (s, 2H), 4.02ꢁ4.19 (m, 5H), 5.65 (d, 1H, J = 3.9 Hz), 6.12 (d, 1H,
J = 3.9 Hz), 7.68 (apparent d, 1H, J = 3.9 Hz), 7.75 (t, 2H, J = 7.5 Hz), 7.83ꢁ7.90
(m, 2H), 7.95 (d, 1H, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3): d 12.5 (CH3), 25.4
(CH3), 26.6 (CH3), 26.8 (CH3), 26.9 (CH3), 35.4 (CH3), 55.1 (CH), 57.3 (C), 57.4
(CH2), 60.1 (CH2), 68.1 (CH2), 74.5 (CH), 79.7 (CH), 83.3 (CH), 106.1 (CH), 109.8
References and notes
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2878–2890. and references cited therein; (b) Batanero, B.; Barba, F. Tetrahedron

3804
P. D. Barman et al. / Tetrahedron Letters 54 (2013) 3801–3804
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; or
(C), 111.0 (C), 118.9 (C), 121.1 (CH), 122.1 (CH), 128.5 (2 ꢂ CH), 130.2 (C), 131.0
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discernible. HRMS (ESI): m/z [M+Na]+ calcd for C30H35NNaO8: 560.2255; found:
560.2258.
14. Characterization data of 4b–d and 6b–e and copies of 1H and 13C NMR of all
new compounds are given in the Supplementary data.
15. Crystallographic data of 4a reported in this manuscript have been deposited
with Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-926342. Copies of the data can be obtained free of charge via
www.ccdc.cam.ac.uk/deposit (or from the Cambridge Crystallographic Data