Synthesis of new enantiomerically pure spirooxindolopyrrolizidines via a three-component asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides derived from isatin

Article abstract of DOI:10.1016/j.tetlet.2012.07.066

An efficient, one-pot, three-component procedure for the synthesis of a small library of new chiral spirooxindolopyrrolizidines with high regio-, diastereo-, and enantioselectivity, from the 1,3-dipolar cycloaddition of azomethine ylides and optically active cinnamoyl oxazolidinone is described. The process occurs at room temperature in aqueous ethanol as a green solvent and in the absence of any Lewis acids. The oxazolidinone chiral auxiliary is removed in a non-destructive manner. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of the cycloadducts, and on theoretical calculations.

Full text of DOI:10.1016/j.tetlet.2012.07.066

Tetrahedron Letters 53 (2012) 5148–5150
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new enantiomerically pure spirooxindolopyrrolizidines
via a three-component asymmetric 1,3-dipolar cycloaddition reaction
of azomethine ylides derived from isatin
Mohammad Javad Taghizadeh a,b, Hamid Arvinnezhad a, Saadi Samadi a, Khosrow Jadidi a,
,
⇑
Abdollah Javidan b, Behrouz Notash a
a Department of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran
b Department of Chemistry, Imam Hossein University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, one-pot, three-component procedure for the synthesis of a small library of new chiral spiro-
oxindolopyrrolizidines with high regio-, diastereo-, and enantioselectivity, from the 1,3-dipolar cycload-
dition of azomethine ylides and optically active cinnamoyl oxazolidinone is described. The process occurs
at room temperature in aqueous ethanol as a green solvent and in the absence of any Lewis acids. The
oxazolidinone chiral auxiliary is removed in a non-destructive manner. The reaction mechanism is dis-
cussed on the basis of the assignment of the absolute configuration of the cycloadducts, and on theoret-
ical calculations.
Received 5 June 2012
Revised 28 June 2012
Accepted 12 July 2012
Available online 20 July 2012
Keywords:
Chiral spirooxindolopyrrolizidines
Asymmetric 1,3-dipolar
Chiral auxiliaries
Ó 2012 Elsevier Ltd. All rights reserved.
Azomethine ylide
Three-component reaction
Chiral pyrrolizidines are bicyclic heterocyclic compounds which
form the central skeleton of a variety of alkaloids and constitute
classes of compounds with diverse biological activity.1 Also, chiral
spirooxindoles such as horsfiline,2 elacomine,3 alstonisine,4 and
spirotryprostatin5 are found extensively as very important building
blocks in numerous biologically relevant alkaloids and are of con-
siderable interest in medicinal chemistry. It is noteworthy that sys-
tematic investigation has shown that spirooxindolopyrrolizidine
ring systems, formed from joining spirooxindole and pyrrolizidine
rings at C-3 (spiro carbon), provide more opportunities for the
development of a wide spectrum of biologically active com-
pounds.6 Although various derivatives of this important class of
spiro compounds have been synthesized,7 only a few chiral spiro-
oxindolopyrrolizidines have been prepared. In addition, the re-
ported methods suffer from many limitations, such as multi-step
reactions, the use of toxic solvents under reflux, lack of generality
and diversity of the reaction, retention of the chiral auxiliary in the
products, and/or the formation of unwanted by-products after its
removal.8
of enantiomerically pure novel spirooxindolopyrrolizidines by
applying chirally modified dipolarophiles in an asymmetric
three-component 1,3-dipolar cycloaddition reaction with azome-
thine ylides derived from isatin.
Initially, the chiral auxiliary, oxazolidinone, was easily prepared
from the reaction of readily available (S)-phenylglycinol with
diethyl carbonate.10 This chiral auxiliary was deprotonated with
n-BuLi and reacted with cinnamoyl chloride to form chiral cinnam-
oyl oxazolidinone 1.11 The one-pot, three-component, 1,3-dipolar
cycloaddition was carried out under mild conditions at room tem-
perature in aqueous ethanol and in the absence of any catalyst or
Lewis acids12 (Scheme 1). Condensation of isatin derivative 2 and
(S)-proline (3), after decarboxylation, led to the non-stabilized azo-
methine ylide 4. The [3+2] cycloaddition of chiral dipolarophile 1
with azomethine ylide 4 resulted in the formation of new chiral
spirooxindolopyrrolizidine 5 which contains four contiguous stere-
ogenic centers. Despite the fact that sixteen different stereoiso-
mers could be prepared theoretically, only diastereoisomer 5 was
obtained in high yield and high optical purity using this strategy
(Scheme 1). Finally, in order to explore the scope and generality
of the present strategy, a small library of new chiral spirooxindolo-
pyrrolizidines 5a–i was synthesized and the results are summa-
rized in Table 1.
According to the above facts and in continuation of our previous
work on the synthesis of spirooxindoles,7o–p,9 we were interested
in establishing a new protocol for the synthesis of a small library
The structures of cycloadducts were assigned from their ele-
⇑
Corresponding author. Tel./fax: +98 021 22431661.
E-mail address: k-jadidi@sbu.ac.ir (K. Jadidi).
mental and spectroscopic analyses including IR, 1H NMR, 13C
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.066

M. J. Taghizadeh et al. / Tetrahedron Letters 53 (2012) 5148–5150
5149
O
N
X
EtOH / H2O (80:20), rt, 5 h
- CO2
X
O
+
CO2H
S
O
N
H
N
N
R
R
3
2
4
O
H
S
H2
H
R
R
H3
N
H
O
R
R
O
H
1
N
N
H
H
O
X
X
S O
O
R
R
OH
N
H2O2, LiOH, 0 ºC, 2 h
1
SO
N
N
O
O
[3+2]
R
R
(82-91%) ee >99%
(88-98%) ee >99%
5
6
Scheme 1. Asymmetric synthesis of new chiral spirooxindolopyrrolizidines 5 and 6.
Table 1
New chiral spirooxindolopyrrolizidines 5 and 6
Entry
R
X
Product
5a
Yieldb (%)
6
Yieldb (%)
½
a 2D5
ꢀ
½ ꢀ
a 2D5
c
c
1
2
3
4
5
6
7
8
9
H
H
H
Me
Me
Me
Et
Et
Et
H
Br
NO2
H
Br
NO2
H
Br
a
b
c
d
e
f
g
h
i
95
93
98
89
90
95
86
88
85
+260.5
+273.5
+256.7
+264.9
+253.4
+248.8
+261.7
+267.5
+294.4
98
90
98
95
87
93
88
91
88
+241.3
+342.1
+263.7
+283.2
+282.8
+301.4
+243.6
+264.1
+343.8
NO2
a
b
c
The reaction was carried out in the ratio of 1:2:3 = 1:1:1.
Isolated yield based on substituted isatin.
(c 1, CH2Cl2).
NMR, and mass spectral data. The observation of two characteristic
triplets and one doublet in the 1H NMR spectra of compounds 5
and 6 confirmed unambiguously the formation of a new pyrrolizi-
dine ring. The absolute configuration of chiral spirooxindolopyrro-
lizidine 5e was determined by single-crystal X-ray analysis as 5R
(spiro carbon C7), 6S (C21), 7R (C14), 8R (C13) (Fig. 1).13
Interestingly, the chiral auxiliary was removed easily with
hydrogen peroxide in the presence of lithium hydroxide and
cleanly produced products 6a–i in excellent to quantitative yields
(Scheme 1).14 However, in contrast to this method, reductive cleav-
age of this auxiliary with lithium borohydride yielded only 25% of
the corresponding product.8b
The stereochemistry and the structures of products 6 were also
determined by 2D NMR spectroscopic techniques. For example, the
1H NMR spectrum of 6a exhibited a triplet signal at d 3.67, a mul-
tiplet at d3.96, and a doublet at d 4.44 assigned to the H-2, H-3, and
H-1 protons, respectively. Also, the DEPT 135° spectrum showed
signals corresponding to three (CH) carbons that were directly
bonded to H-2, H-3, and H-1 at d 37.6, 55.4, and 67.1, respectively.
In the HMQC spectrum of cycloadduct exo-6a, the positions of the
three protons (H-2, H-3, and H-1) that were directly bonded to
these carbon atoms (CH) were assigned. Accordingly, the exact
chemical shifts of these protons (dH-2 = 3.67, dH-3 = 3.96, dH-
1 = 4.44) were assigned by means of the (H–H)-COSY spectrum.
The stereochemistry of exo-6a was assigned from the ROESY spec-
trum. The absence of correlation between H-3 and H-2 in the
Figure 1. The ORTEP diagram of one of the four crystallographic independent
molecules in the asymmetric unit of 5e is shown. Thermal ellipsoids are at 30%
probability level.
ROESY spectrum showed that the H-2 hydrogen had a trans spatial
relationship to H-3. However, an intense interaction between H-1
and H-3 showed that these two hydrogens were cis to each other.
This was also confirmed from the NOE pattern between these two
hydrogens. Therefore, the correct stereochemistry is shown in
Scheme 1.
Since the stereochemistry of the cycloadduct was clarified by
single-crystal X-ray analysis and 2D NMR spectroscopic tech-
niques, the transition state and the reaction pathway were investi-
gated by the AM1 semi-empirical method. The calculations were
performed on chiral cinnamoyl oxazolidinone 1 and the transition
state of the reaction. Several intermediate structures of dipolaro-
phile 1 were investigated computationally. It was found that the
most stable conformation of chiral cinnamoyl oxazolidinone 1
was that possessing two carbonyl groups trans-disposed (Z-con-
former, Fig. 2). This conformer was more stable energetically by
3.2 kcal/mol than the U-conformer, in which the two carbonyl
groups are cis to each other.

5150
M. J. Taghizadeh et al. / Tetrahedron Letters 53 (2012) 5148–5150
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.07.066.
O
O
H
O
O
N
H
N S
S
References and notes
H
O
H
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Z-conformer of 1
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Figure 2. S-cis conformations of 1.
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Cα Si Face
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S
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O
S
H
Br
O
H
O
exo
Br
N
Me
N
N
Me
N
R
O
R
O
H
H
TS
5e
Figure 3. Proposed models for endo/exo cycloaddition.
Hence, the AM1 calculated energies showed that there was a
remarkable energy difference (about 2.5 kcal/mol) between the
exo and endo transition states. Consequently, the high level of ste-
reoselectivity results from the exo transition state in which the
azomethine ylide approaches from the re-face of the dipolarophile
as shown in Figure 3, which is in good agreement with the exper-
imentally observed X-ray crystal structure of molecule 5e, and
with the 2D NMR spectroscopic data of products 6.
In conclusion, we have prepared a small library of new chiral
spirooxindolopyrrolizidines through a one-pot, three-component
reaction between readily available isatin derivatives, (S)-proline,
and chiral cinnamoyl oxazolidinone 1 under mild reaction condi-
tions in the presence of environmentally friendly aqueous ethanol
as the solvent. The products were obtained in high to excellent
yields and with high optical purity. Removal of the chiral auxiliary
was achieved easily without racemization and/or by-product for-
mation, except oxazolidinone. The structures of the products were
elucidated using IR, mass, one and two dimensional NMR tech-
niques, and X-ray single crystal diffraction. The reaction mecha-
nism is briefly discussed on the basis of the assignment of the
absolute configuration of the cycloadduct, and theoretical
calculations.
10. Guerlavais, V.; Carroll, P. J.; Joullié, M. M Tetrahedron: Asymmetry 2002, 13, 675.
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12. (a) Ruano, J. L. G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981; (b) Nàjera,
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P. Bioorg. Med. Chem. Lett. 2007, 17, 1321.
13. X-ray data for 5e: C31H28BrN3O4, M = 586.46, triclinic system, space group P1,
a = 10.1837(4), b = 15.3844(6), c = 17.7233(7) Å,
a
= 86.429(3), b = 81.529(3),
= 77.831(3)°; V = 2683.31(19) Å3, Z = 4, Z’ = 4, Dcalcd = 1.452 g cmꢁ3
(Mo–
) = 1.575 mmꢁ1
crystal dimensions of 0.28 ꢂ 0.25 ꢂ 0.15 mm. X-ray
c
K
, l
a
,
diffraction measurements were made on a STOE IPDS-II diffractometer with
graphite monochromated Mo–K radiation. The structure was solved using
a
Acknowledgements
SHELXS. The data reduction and structure refinement were carried out with
SHELXL using the X-STEP32 crystallographic software package.15 The non-
hydrogen atoms were refined anisotropically by full matrix least-squares on F2
values to final R1 = 0.1010, wR2 = 0.2554, and S = 1.034 with 1409 parameters
using 23418 independent reflections (h range = 2.07–29.19°). All hydrogen
atoms were added in idealized positions. The crystallographic information file
has been deposited with the Cambridge Crystallographic Data Centre, CCDC
880899.
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
Supplementary data
14. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141.
15. X-STEP32 Version 1.07b, Crystallographic Package; Stoe & Cie GmbH: Darmstadt,
Germany, 2000.
Supplementary data (general procedures and IR, mass, 1H and
13C NMR data of all compounds) associated with this article can