An easy access to novel sugar-based spirooxindole-pyrrolidines or -pyrrolizidines through [3+2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1055/s-0030-1260111

An efficient one-pot synthesis of a library of novel sugar-based spirooxindole-pyrrolidines or -pyrrolizidines has been accomplished by [3+2] cycloaddition. This method utilizes an azo-methine ylide derived from isatin and sarcosine or l-proline with an α

Full text of DOI:10.1055/s-0030-1260111

PAPER
2495
An Easy Access to Novel Sugar-Based Spirooxindole-pyrrolidines or
-pyrrolizidines through [3+2] Cycloaddition of Azomethine Ylides
S
ugar-Based Spiro
r
oxindole
a
-
pyrrolidin
s
es or -pyr
a
rolizidines ppan Hemamalini,a Subbiah Nagarajan,a Pawar Ravinder,b Venkatesan Subramanian,b
Thangamuthu Mohan Das*a
a
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai – 600 025, India
Fax +91(44)22352494; E-mail: tmdas_72@yahoo.com
Chemical Laboratory, Central Leather Research Institute (CSIR), Adyar, Chennai, 600 020, India
b
Received 27 December 2010; revised 25 May 2011
dole-pyrrolidines and spirooxindole-pyrrolizidines. To
the best of our knowledge, there are no reports on the
synthesis of sugar-based spirooxindole-pyrrolidines and
-pyrrolizidines from b-C-glycosidic ketones.
Abstract: An efficient one-pot synthesis of a library of novel sugar-
based spirooxindole-pyrrolidines or -pyrrolizidines has been ac-
complished by [3+2] cycloaddition. This method utilizes an azo-
methine ylide derived from isatin and sarcosine or L-proline with an
a,b-unsaturated b-C-glycosidic ketone as the dipolarophile. All
these sugar-based heterocyclics were characterized by NMR (1H
and 13C), HPLC, and elemental analysis
HO
MeO
Me
N
Key words: 4,6-O-butylidene-D-glucopyranose, a,b-unsaturated
b-C-glycosidic ketones, cycloaddition, azomethine ylide, mono-
spiroheterocyclics
Me
N
NH
HN
N
O
O
N
H
O
O
H
elacomine (1)
horsfiline (2)
coerulescine (3)
Intermolecular cycloaddition reactions of azomethine
ylides with a,b-unsaturated ketones and acetylenic dipo-
larophiles lead to a number of novel compounds. These
compounds are very useful for the construction of diverse
chemical libraries of drug-like molecules.1 Spiro-oxin-
doles (Figure 1) exist in nature and most of them exhibit
significant biological activity.2 A number of natural prod-
ucts having the skeleton of functionalized pyrrolidines
and oxindoles3 possesses well-defined biological proper-
ties, such as glucosidase inhibitory activity an potent anti-
viral, antibacterial, antidiabetic, and anticancer activity,
and they also act as a potent non-peptide inhibitor of the
p53-MDM2 interaction.4 Elacomine (1) is a naturally oc-
curring hemiterpene spiro-oxindole alkaloid isolated from
the roots of Elaeagnus commutate.5 The unsubstituted
spiro-oxindole core of (–)-horsfiline (2) is an interesting
target and has been reported by many synthetic groups.6
Coerulescine (3) was isolated in 1998 and its total synthe-
sis is often reported together with that of horsfiline.2b,6d,f,7
Some spirooxindole-pyrrolidine derivatives are potential
antileukemic and anticonvulsant agents and possess anti-
viral and local anesthetic activities.8 The spirotryprost-
atins A (4) and B (5) were isolated from the fermentation
broth of Aspergillus fumigatus and have been shown to in-
hibit completely the G2/M progression of mammalian
tsFT210 cells at concentrations in excess of 12.5 mg/
mL.8a,b
N
O
N
H
H
O
O
H
N
N
O
O
N
H
N
MeO
H
spirotryprostatin B (5)
spirotryprostatin A (4)
Figure 1 Representative spirooxindole-pyrrolidine natural products
4,6-O-Butylidene-D-glucopyranose (6) (see Supporting
Information) was synthesized from D-glucose by
adopting the literature procedure.10 Methyl ketones, viz.
1-(4,6-O-butylidene-b-D-glucopyranosyl)propan-2-one
(7a), 1-(2,3-di-O-acetyl-4,6-O-butylidene-b-D-glucopy-
ranosyl)propan-2-one (7b), and 1-(2,3,4,6-tetra-O-acetyl-
b-D-glucopyranosyl)propan-2-one (7c), were synthesized
by following the literature procedures.9a–c,11 E-Isomeric
a,b-unsaturated b-C-glycosidic ketones 9a–j were synthe-
sized in good yield by aldol condensation of b-C-glyco-
sidic methyl ketones 7a–c with different aromatic
aldehydes [4-(allyloxy)benzaldehyde (8a), 4-bromobenz-
aldehyde (8b), 4-fluorobenzaldehyde (8c), quinoline-2-
carbaldehyde (8d), benzaldehyde (8e), piperonal (8f), 5-
bromopyridine-3-carbaldehyde (8g), 2-nitrobenzalde-
hyde (8h)] at ambient temperature in the presence of py-
rrolidine as organocatalyst (30 mol%) (Scheme 1).9b,c
In continuation of our effort on synthetic carbohydrate
chemistry,9 we report an expeditious and facile one-pot
protocol for the synthesis of novel sugar-based spirooxin-
Among the different a,b-unsaturated b-C-glycosidic ke-
tones 9a–j, the 4-fluoro-substituted compound 9c crystal-
lized in methanol. ORTEP view of compound 9c is shown
in Figure 2. In molecule 9c, strong hydrogen bonding in-
teractions [O(5)–H(5A)⋅⋅⋅O(6) and O(4)–H(4A)⋅⋅⋅O(3)]
manifest in the formation of chain of molecules with over-
SYNTHESIS 2011, No. 15, pp 2495–2504
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260111; Art ID: N56510SS
© Georg Thieme Verlag Stuttgart · New York

2496
A. Hemamalini et al.
PAPER
H
H
O
O
O
O
8a–h, pyrrolidine
O
O
R
HO
HO
CH2Cl2, r.t.
70–90%
OH
OH
O
O
7a
9a–h
H
H
O
O
O
O
8a, pyrrolidine
O
O
O
AcO
CH2Cl2, r.t., 14 h
98%
AcO
OAc
OAc
O
O
O
7b
OAc
9i
OAc
Br
O
O
8b, pyrrolidine
AcO
AcO
AcO
AcO
CH2Cl2, r.t., 12 h
96%
OAc
OAc
O
7c
9j
Scheme 1 Synthesis of a,b-unsaturated b-C-glycosidic ketones 9a–j
lap of phenyl moieties. Existence of b-anomeric and the
E-isomeric form of 9c are identified from the correspond-
ing torsion angles [H(9)–C(9)–C(10)–H(10) = 177.32°
and H(13)–C(13)–C(14)–H(14) = 179.25°].
The [3+2] cycloaddition was optimized with compound
9a as a model substrate (Table 1). When the reaction was
carried out in refluxing toluene, the cycloadduct was not
formed presumably due to the poor solubility of the start-
ing material (entry 1). Changing the solvent to acetonitrile
afforded the desired product in 54% yield (entry 2). Uti-
lizing a solvent mixture of acetonitrile and toluene (1:1)
Figure 2 ORTEP view of compound 9c
improved the yield of the desired product 12a to 79% (en- One-pot reaction of various a,b-unsaturated b-C-glyco-
try 5).
sidic ketones 9a–g,i with the azomethine ylide derived
from isatin (1H-indole-2,3-dione) and sarcosine (N-meth-
Table 1 Optimization of Cycloaddition Reaction Conditions for the Synthesis of Sugar-Based Monospiroheterocyclicsa
H
H
N
O
O
Me
H
O
O
N
O
HO
O
isatin, sarcosine (10)
O
Ha
OH
O
O
solvent, reflux
HO
Hb
OH
12a
O
9a
O
Entry
Solvent
toluene
MeCN
MeOH
EtOH
Time (h)
Yieldb (%)
1
2
3
4
5
24
18
7
–
54
46
25
79
16
7
toluene–MeCN (1:1)
a Reactions were carried out under N2 on a 1-mmol scale.
b Yield of isolated product after column chromatography.
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

PAPER
Sugar-Based Spirooxindole-pyrrolidines or -pyrrolizidines
2497
Table 2 [3+2]-Cycloaddition Reaction of Sugar-Derived Dipolarophiles 9a–g,i with Isatin and Sarcosine (10)a
Entry
1
Substrate
R1
R2
H
Time (h)
7
Product
Yield (%)
79
Mp (°C)
9a
12a
104–106
134–136
O
Br
F
2
9b
H
10
12b
85
3
4
5
6
7
8
9c
9d
9i
H
7
15
4
12c
12d
12e
12f
83
77
77
80
69
84
126–128
138–140
153–155
128–130
150–154
130–132
N
H
Ac
H
O
9e
9f
13
12
8
O
H
12g
12h
O
Br
9g
H
N
a Based on chiral HPLC and 1H NMR analysis; >92% de.
ylglycine, 10) resulted in the formation of novel sugar- geometries of the sugar-derived dipolarophile, azo-
based monospirooxindole-pyrrolidines 12a–h in 69–85% methine ylide, and favored complex structures are shown
yield (Scheme 2 and Table 2). Similarly, sugar-based in Figure 3. Complex A is favored due to the H-bonding
monospirooxindole-pyrrolizidines 13a–f were synthe- interaction between the C=O of azomethine ylide and hy-
sized from the corresponding a,b-unsaturated b-C-glyco- droxy group (C3 position) of the sugar-derived dipolaro-
sidic ketones 9b,c,e,f,h,j and the azomethine ylide derived phile (Figure 3). Further, the calculated H-bond
from isatin and L-proline (11) in 44–84% yield (Scheme 3 stabilization energy (SE) value for the favored complex A
and Table 4). The reactions were found to be highly regio- is 6.13 kcal/mol. It is interesting to mention that the fa-
selective and proceeded via endo-transition state. Control vored complex B formed between H-bonding interaction
of the relative stereochemistry at the spiro core was ob- of C=O and NH groups of azomethine ylide with free hy-
served, presumably, due to the involvement of anti-ylide droxy groups at C2 and C3 positions of sugar-derived di-
in the transition state, which adds to the double bond of polarophile respectively (Figure 3). The calculated H-
a,b-unsaturated b-C-glycosidic ketones 9a–j, to give the bond SE value for the favored complex B formation is
corresponding expected cycloaddition products. Forma- 14.14 kcal/mol. Therefore, computer studies explicitly
tion of syn-ylide was ruled out due to the possible repul- demonstrate that the formation of complex B is energeti-
sion between the carbonyl groups of oxindole and the cally more feasible when compared to that of complex A.
sugar-derived dipolarophiles (Figure 3). The optimized Furthermore, the optimized geometries of favored com-
H
H
H
N
O
O
O
R1
isatin
sarcosine (10)
O
O
N
Me
O
O
R2O
toluene–MeCN (1:1)
reflux
R2O
OR2
Ha
OR2
O
R1
O
Hb
69–85%
9a–g,i
12a–h
Scheme 2 Synthesis of sugar-derived spirooxindole-pyrrolidines 12a–h
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

2498
A. Hemamalini et al.
PAPER
plex A and B reveal that these two can both undergo In order to confirm the purity and regioselectivity of the
[3+2]-cycloaddition reactions. The distance of active core products, HPLC was used with a chiral column [amylose
of azomethine ylide and dipolarophile are significantly tris 3,5-dimethylphenylcarbamate coated on 5 mm silica
smaller in the case of the complex B when compared with gel (AD-H)] (for more experimental details see the Sup-
complex A. Therefore, it is worthwhile mentioning that, porting Information). The HPLC profile of compound,
the [3+2]-cycloaddition reaction is more feasible by form- 12f obtained from compound 9e and anti-ylide formed
ing the favored complex B. Hence, the existence of H- from isatin and sarcosine (10) showed only one peak and
bonding interactions among various sites also plays a vital it is due to the regioselective nature of the reaction (see
role in the reaction mechanism (for more detail on the Supporting Information). In the case of the cycloaddition
computational studies, see the Supporting Information).
of dipolarophile 9j with the anti-ylide derived from isatin
Figure 3 Regioselective formation of sugar-based spirooxindole-pyrrolidines and the possible mode of approach of azomethine ylide
H
H
H
N
O
O
R
O
O
isatin, L-proline (11)
O
O
N
O
HO
toluene–MeCN (1:1)
reflux
HO
OH
Ha
OH
O
O
Hc
44–84%
R
Hb
9b,c,e,f,h
13a–e
H
N
OAc
OAc
O
R
O
O
N
isatin, L-proline (11)
AcO
AcO
AcO
AcO
toluene–MeCN (1:1)
Ha
OAc
OAc
reflux
80%
O
O
Hc
R Hb
9j
13f
Scheme 3 Synthesis of sugar-based spirooxindole-pyrrolizidines 13a–f
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

PAPER
Sugar-Based Spirooxindole-pyrrolidines or -pyrrolizidines
2499
the methyl proton attached to the pyrrolidine moiety. The
benzylic proton of the pyrrolidine ring appeared as a quar-
tet in the region of d = 4.48–4.54 ppm (Hb) with a coupling
constant of 8.1 Hz. The peaks observed between d = 3.31–
3.50 ppm corresponds to the NCH2 proton of the pyrroli-
dine ring. The pyrrolidine proton adjacent to the carbonyl
group of glycosyl part (Ha) appeared as a doublet at d =
3.75 ppm with a coupling constant of 8.7 Hz, which im-
plies a trans-stereochemistry. Signals corresponding to
the sugar skeleton appeared between d = 3.0–5.0 ppm, and
the acetyl protons appeared as two singlets at d = 1.82 and
1.98 ppm. The NH proton of oxindole moiety appeared as
a singlet at d = 7.59 ppm. The off-resonance proton decou-
pled 13C NMR spectrum of compound, 12e exhibited
peaks at d = 34.75 and 44.52 ppm, due to the pyrrolidine
NCH3 and NCH2 carbons. The spiro carbon in the hetero-
cyclic derivatives resonates at around d = 75.3 ppm. The
oxindole carbonyl carbon and the carbonyl carbon in gly-
cosyl part appeared at d = 179.30 and 204.41 ppm, respec-
tively. The stereochemistry of cycloadduct 12a was
identified from 2D NOESY experiment. The configura-
tion at pyrrolidine carbon adjacent to the carbonyl group
of glycosyl part was assigned based on the strong interac-
tion of Ha with aromatic hydrogen (Ar-H), which shows
the selectivity of the cycloadduct (endo-isomer). Howev-
er, if the other stereoisomer is formed under the given re-
action condition, one would not expect a NOESY
correlation peak for Ha with Ar-H. In addition, Hb has
strong interaction with aromatic proton and not with Ha
and it shows the trans-stereoselectivity. Thus NOESY ex-
periment clearly demonstrates the relative stereochemis-
try of the cycloadduct formation (Figure 5).
Table 3 Spectroscopic Data for Compounds 12a–h
Product 1H NMR d, J (Hz)
ano-H (3JH1H2
)
Ha (3JHaHb
)
Hb
Cspiro
12a
12b
12c
12d
12e
12f
3.8 (9.9)
3.72 (5.7)
3.84 (9.3)
4.36–4.43
4.35–4.44
4.31–4.35
4.48–4.54
3.35–3.55
4.09–4.16
3.34–3.53
75.9
75.8
76.2
75.3
74.9
74.2
74.8
3.94–4.05 (–a)
4.65 (8.4)
3.69–3.77 (–b)
3.75 (8.7)
4.29 (8.7)
4.38 (–b)
4.35 (5.1)
3.91 (9.2)
12g
12h
3.60–3.71 (–a)
3.60–3.66 (–a)
4.29 (8.7)
a Anomeric peaks merged with sugar proton peaks.
b Ha peaks merged with sugar proton peaks.
and L-proline (11), this leads to the formation of the cor-
responding sugar-based spirooxindole-pyrrolizidines 13f
as an inseparable mixture (see Supporting Information).
Structures of the sugar-based monospiroheterocyclics
were confirmed through spectral and elemental analysis.
Formation of b-anomeric products in 12a–f/13a–h were
1
confirmed by using H NMR studies (12f: Ano-H, d =
3.91 ppm, J = 9.2 Hz; 13d: Ano-H, d = 3.73–3.78 ppm,
J = 10.2 Hz) (Tables 3 and 5).
The structure and the regiochemistry of the cycloadducts
were confirmed by 2D NMR (Figure 4). The H NMR
spectrum of 12e exhibited a singlet at d = 2.16 ppm due to
1
Table 4 [3+2]-Cycloaddition Reaction of Sugar-Derived Dipolarophiles 9b,c,e,f,h,j with isatin and L-proline (11)a
Entry
Substrate
R
Time (h)
Product
Yield (%)
Mp (°C)
132–134
1
9b
13
13a
70
Br
F
2
9c
10
13b
44
150–153
3
4
9e
9f
7
8
13c
13d
53
79
140–144
156–158
O
O
5
6
9h
9j
13
9
13e
13f
84
80
116–120
130–132
O2N
Br
a Based on chiral HPLC and 1H NMR analysis; >55% de.
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

2500
A. Hemamalini et al.
PAPER
Table 5 Spectroscopic Data for Compounds 13a–f
Product
1H NMR d, J (Hz)
ano-H (3JH1H2
)
Ha (3JHaHb
)
Hb
Hc
Cspiro
74.8
75.5
75.6
75.7
75.5
75.3
13a
13b
13c
13d
13e
13f
3.47–3.57 (–a)
3.43–3.56 (–a)
3.75–3.67 (–a)
3.73–3.78 (10.2)
3.44–3.83 (–a)
3.94–4.07 (–a)
4.41–4.46 (5.4, 15.6)
4.39–4.44 (4.2, 13.8)
4.29–4.35 (5.1, 12.0)
4.14–4.21 (9.9, 10.2, 11.9)
4.34–4.38 (–b)
3.94–4.08
3.95–4.00
3.97–4.05
3.83–3.90
4.00–4.09
3.94–4.07
4.22–4.26
4.22–4.27
4.07–4.15
3.90–3.98
4.34–4.38
4.10–4.21
4.64–4.55 (–b)
a Anomeric peaks merged with sugar proton peaks.
b Ha peaks merged with sugar proton peaks.
1H NMR spectrum of the compound 13a exhibited a quar- In conclusion, we have developed an efficient one-pot
tet at d = 4.41–4.46 ppm, which is due to Ha proton. The protocol for the regioselective synthesis of sugar-based
methine proton (Hc) attached to the nitrogen appeared as spirooxindole-pyrrolidines through 1,3-dipolar cycload-
multiplet in the region of d = 4.22–4.26 ppm. The signal dition methodology. However, under identical reaction
corresponding to a benzylic proton (Hb) appeared as a conditions using the ylide derived from isatin and L-pro-
multiplet at d = 3.94–4.08 ppm. The 13C NMR spectrum line resulted in an inseparable mixtures of sugar-based
of compound 13a exhibited a signal at around d = 74.8 spirooxindole-pyrrolizidines. Based on the present study,
ppm, which corresponds to the spiro carbon of pyrrolidine change in the nature of ylide affects the stereochemical
moiety.
outcome of the products. In contrast to the ylides used in
Figure 4 1H-1H COSY spectrum of compound 12e
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

PAPER
Sugar-Based Spirooxindole-pyrrolidines or -pyrrolizidines
2501
4.51 (d, J = 5.1 Hz, 2 H), 4.41–4.34 (m, 1 H), 4.31–4.12 (m, 1 H),
3.84 (t, J = 9.0 Hz, 1 H), 3.71–3.60 (m, 3 H), 3.37–3.25 (m, 3 H),
3.12–2.74 (m, 4 H), 2.16 (s, 3 H), 1.59–1.47 (m, 2 H), 1.43–1.17 (m,
2 H), 0.88 (t, J = 7.65 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.7, 180.1, 157.5, 140.8, 134.2,
133.5, 129.5, 128.9, 126.5, 123.2, 117.7, 114.8, 110.4, 102.3, 80.2,
75.8, 74.8, 74.7, 73.5, 70.5, 68.9, 61.0, 60.7, 36.1, 34.9, 31.2, 17.5,
13.9.
H
H
N
O
O
O
N
Me
m, 3.31–3.50
O
HO
OH
Ha
O
Hb
H
H
q, 4.48–4.54
(J = 8.1 Hz)
d, 3.75
(J = 8.7 Hz)
Anal. Calcd for C33H40N2O8 (592.3): C, 66.87; H, 6.80; N, 4.73.
Found: C, 67.05; H, 6.96; N, 5.02.
O
12a
4¢-(4-Bromophenyl)-3¢-[2-(4,6-O-butylidene-b-D-glucopyrano-
syl)-1-oxoethyl]-1¢-methylspiro[indole-3,2¢-pyrrolidin]-2(1H)-
one (12b)
Figure 5 2D NOESY correlation of compound 12a
White solid; yield: 0.52 g (85%); mp 134–136 °C; Rf = 0.84
(MeOH–CHCl3, 0.2:9.8).
[a]D28 –0.8 (c 0.66, CHCl3).
the present study, sugar moieties exist in b-anomeric
form. Biological screening of sugar-based spirooxindole
derivatives is in progress.
1H NMR (300 MHz, CDCl3): d = 8.24 (s, 1 H), 7.46–7.41 (m, 2 H),
7.33 (t, J = 7.95 Hz, 2 H), 7.23–7.17 (m, 1 H), 7.13–7.01 (m, 2 H),
4.43–4.36 (m, 1 H), 4.30–4.15 (m, 1 H), 3.80 (t, J = 9.9 Hz, 1 H),
3.72 (d, J = 5.7 Hz, 1 H), 3.65–3.61 (m, 1 H), 3.53–3.42 (m, 3 H),
3.35 (t, J = 8.4 Hz, 2 H), 3.00–2.92 (m, 5 H), 2.18 (s, 3 H), 1.60–
1.50 (m, 2 H), 1.43–1.34 (m, 2 H), 0.92–0.89 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 205.0, 179.9, 141.2, 140.8, 131.6,
129.8, 126.7, 126.2, 126.3, 123.3, 120.8, 120.6, 110.4, 102.4, 80.3,
75.9, 75.4, 73.2, 70.3, 69.0, 68.0, 67.0, 60.7, 60.4, 43.5, 36.2, 34.9,
31.6, 22.7, 17.5, 13.9.
D-Glucose, 4-(allyloxy)benzaldehyde, 4-bromobenzaldehyde, 4-
fluorobenzaldehyde, quinoline-2-carbaldehyde, benzaldehyde, pip-
eronal, 5-bromopyridine-3-carbaldehyde, and 2-nitrobenzaldehyde,
isatin, sarcosine, and L-proline were obtained from Sigma-Aldrich
Chemicals Pvt. Ltd, USA and were of high purity. Butyraldehyde,
and the organic catalyst (pyrrolidine) were obtained from SRL, In-
dia. Other reagents such as HCl, NaHCO3, and solvents (AR Grade)
were obtained from Sd-fine, India, in high purity and were used
without any further purification. Ac2O was purchased from Fischer
Chemicals Pvt. Ltd, India. All reactions sensitive to air or moisture
were conducted under an N2 atmosphere. All anhydrous solvents
were purified according to standard methods. Column chromatog-
raphy was performed on silica gel (100–200 mesh). NMR spectra
were recorded on a Bruker DRX 300 MHz instrument in either
CDCl3 or DMSO-d6. Chemical shifts are referenced to internal
TMS. Single crystal XRD data was collected using Bruker axs kap-
pa apex2 CCD Diffractometer, at r.t. Elemental analysis was per-
formed by using Perkin-Elmer 2400 series CHNS/O analyzer.
Anal. Calcd for C30H35BrN2O7 (615.5): C, 58.54; H, 5.73; N, 4.55.
Found: C, 58.89; H, 5.36; N, 4.61.
3¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-4¢-(4-
fluorophenyl)-1¢-methylspiro[indole-3,2¢-pyrrolidin]-2(1H)-one
(12c)
White solid; yield: 0.46 g (83%); mp 126–128 °C; Rf = 0.9 (MeOH–
CHCl3, 0.2:9.8).
[a]D28 –18.41 (c 0.9, CHCl3).
1H NMR (300 MHz, CDCl3): d = 9.16 (d, J = 9.3 Hz, 1 H), 7.47–
7.35 (m, 2 H), 7.25–7.20 (m, 1 H), 7.17–7.11 (m, 1 H), 7.09–6.96
(m, 3 H), 6.90–6.86 (dd, J = 4.2, 7.5 Hz, 1 H), 4.44–4.35 (m, 1 H),
4.31–4.19 (m, 1 H), 4.05–3.94 (m, 2 H), 3.84 (d, J = 9.3 Hz, 1 H),
3.68–3.62 (m, 1 H), 3.49–3.27 (m, 4 H), 3.04–2.89 (m, 5 H), 2.22
(s, 3 H), 1.59–1.52 (m, 2 H), 1.43–1.27 (m, 2 H), 0.88–0.85 (m, 3
H).
13C NMR (75 MHz, CDCl3): d = 204.7, 180.1, 162.8, 160.9, 140.8,
138.0, 129.6, 129.4, 129.7, 126.4, 123.6, 115.5, 115.3, 110.4, 102.4,
80.2, 75.8, 74.7, 73.9, 73.4, 69.1, 67.9, 36.1, 34.9, 31.6, 30.9, 22.6,
17.4, 14.1.
E-Isomeric a,b-Unsaturated b-C-Glycosidic Ketones 9a–j; Gen-
eral Procedure
To a soln of b-C-glycosidic ketone 7a–c (1 mmol) in anhyd CH2Cl2
was added pyrrolidine (30 mol%) and substituted benzaldehyde 8a–
h (1.2 mmol). The mixture was stirred r.t. for 4–15 h, and then it was
evaporated under reduced pressure and extracted using EtOAc–
H2O. The EtOAc layer was dried (anhyd Na2SO4) and concentrated
to dryness. The product thus formed was further purified by flash
column chromatography.
Spirooxindole-pyrrolidine or -pyrrolizidine Derivatives 12a–h
or 13a–f; General Procedure
Anal. Calcd for C30H35FN2O7 (554.6): C, 64.97; H, 6.36; N, 5.05.
Found: C, 64.54; H, 6.61; N, 4.93.
A soln of a,b-unsaturated b-C-glycosidic ketones 9a–j (1 mmol),
isatin (1 mmol), and sarcosine 10 or L-proline 11 (1 mmol), in tolu-
ene–MeCN (1:1, 20 mL) was refluxed for the time in Tables 2 or 4
(TLC monitoring). The solvent was removed under reduced pres-
sure and the crude product was subjected to flash column chroma-
tography (petroleum ether–EtOAc).
3¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-
methyl-4¢-(quinolin-2-yl)spiro[indole-3,2¢-pyrrolidin]-2(1H)-
one (12d)
White solid; yield: 0.45 g (77%); mp 138–140 °C; Rf = 0.82
(MeOH–CHCl3, 0.2:9.8).
1H NMR (300 MHz, CDCl3): d = 8.77 (s, 1 H), 8.19–8.07 (m, 2 H),
7.81–7.68 (m, 2 H), 7.67 (t, J = 8.25 Hz, 1 H), 7.53–7.47 (m, 2 H),
7.22 (d, J = 7.5 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.92–6.85 (dd,
J = 7.8, 13.2 Hz, 1 H), 4.65 (t, J = 8.4 Hz, 1 H), 4.67–4.53 (m, 1 H),
4.35–4.31 (m, 1 H), 3.77–3.69 (m, 2 H), 3.66–3.35 (m, 5 H), 3.34–
3.19 (m, 1 H), 3.13–2.97 (m, 4 H), 2.18 (s, 3 H), 1.56–1.52 (m, 2 H),
1.37–1.26 (m, 2 H), 0.91–0.83 (m, 3 H).
4¢-(4-Allyloxyphenyl)-3¢-[2-(4,6-O-butylidene-b-D-glucopyrano-
syl)-1-oxoethyl]-1¢-methylspiro[indole-3,2¢-pyrrolidin]-2(1H)-
one (12a)
White solid; yield: 0.47 g (79%); mp 104–106 °C; Rf = 0.87
(MeOH–CHCl3, 0.2:9.8).
1H NMR (300 MHz, CDCl3): d = 8.48 (s, 1 H), 7.37–7.24 (dd,
J = 6.3, 8.4 Hz, 2 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.15–7.11 (dd,
J = 4.2, 6.6 Hz, 1 H), 7.07–6.97 (m, 1 H), 6.91–6.84 (m, 3 H), 6.11–
5.98 (m, 1 H), 5.40 (d, J = 17.1 Hz, 1 H), 5.28 (d, J = 10.5 Hz, 1 H),
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

2502
A. Hemamalini et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 204.4, 179.6, 161.3, 147.4, 137.0,
129.8, 129.6, 128.5, 128.9, 128.7, 127.5, 127.2, 126.3, 126.2, 123.2,
121.4, 102.2, 80.2, 76.2, 74.6, 74.3, 73.9, 70.2, 68.0, 64.5, 59.0,
45.9, 36.2, 36.1, 35.0, 31.6, 22.6, 17.4, 13.9.
4¢-(5-Bromo-3-pyridyl)-3¢-[2-(4,6-O-butylidene-b-D-glucopyra-
nosyl)-1-oxoethyl]-1¢-methylspiro[indole-3,2¢-pyrrolidin]-
2(1H)-one (12h)
White solid; yield: 0.52 g (84%); mp 130–132 °C; Rf = 0.7 (MeOH–
CHCl3, 0.5:9.5).
[a]D28 –1.30 (c 1.0, CHCl3).
Anal. Calcd for C33H37N3O7 (587.7): C, 67.45; H, 6.35; N, 7.15.
Found: C, 67.85; H, 6.21; N, 6.96.
1H NMR (300 MHz, CDCl3): d = 8.57–8.52 (m, 3 H), 8.43–8.01
(dd, J = 9.6, 9.3 Hz, 1 H), 7.97 (d, J = 9.3 Hz, 1 H), 6.89 (t, J = 6.6,
7.2 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1 H), 4.52 (t, J = 5.1, 5.1 Hz, 1 H),
4.42–4.38 (m, 1 H), 4.33–4.24 (q, 1 H), 4.10–4.05 (q, 1 H), 3.87–
3.76 (m, 2 H), 3.66–3.60 (m, 1 H), 3.53–3.34 (m, 4 H), 3.31–3.12
(m, 1 H), 3.03–2.99 (m, 2 H), 2.17 (s, 3 H), 1.63–1.55 (m, 2 H),
1.43–1.29 (m, 2 H), 0.91–0.86 (t, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.8, 179.5, 149.2, 147.8, 140.9,
138.1, 129.9, 126.7, 123.5, 110.0, 102.5, 80.3, 78.2, 76.3, 76.1,
74.7, 74.0, 73.6, 72.7, 70.6, 68.7, 67.1, 45.4, 36.2, 34.7, 30.9, 29.7,
17.4, 13.9.
4¢-[4-(Allyloxy)phenyl]-3¢-[2-(2,3-di-O-acetyl-4,6-O-butylidene-
b-D-glucopyranosyl)-1-oxoethyl]-1¢-methylspiro[indole-3,2¢-
pyrrolidin]-2(1H)-one (12e)
White solid; yield: 0.52 g (77%); mp 153–155 °C; Rf = 0.6
(EtOAc–hexane, 7.5:2.5).
1H NMR (300 MHz, CDCl3): d = 7.59 (s, 1 H), 7.32 (d, J = 8.7 Hz,
2 H), 7.27–7.20 (m, 2 H), 7.09–7.00 (m, 2 H), 6.85 (d, J = 8.7 Hz, 2
H), 6.11–5.81 (m, 1 H), 5.40 (d, J = 18.0 Hz, 1 H), 5.27 (d, J = 10.5
Hz, 1 H), 4.98 (t, J = 9.45 Hz, 1 H), 4.54–4.48 (m, 3 H), 4.35 (t,
J = 5.1 Hz, 1 H), 4.23–4.15 (q, J = 16.8 Hz, 1 H), 3.75 (d, J = 8.7
Hz, 1 H), 3.62–3.55 (m, 2 H), 3.47 (t, J = 9.15 Hz, 1 H), 3.33 (t,
J = 8.25 Hz, 1 H), 3.17 (t, J = 9.15 Hz, 1 H), 3.10–3.03 (m, 2 H),
2.16 (s, 3 H), 1.98 (s, 3 H), 1.82 (s, 3 H), 1.59–1.47 (m, 2 H), 1.43–
1.17 (m, 2 H), 0.86 (t, J = 7.35 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.4, 179.3, 170.1, 169.7, 157.5,
140.6, 133.8, 133.4, 129.1, 128.9, 127.1, 126.6, 123.2, 117.7, 114.8,
109.8, 102.4, 78.2, 75.3, 72.7, 72.5, 72.0, 70.4, 69.2, 68.9, 67.6,
60.7, 44.5, 43.0, 35.9, 34.6, 20.7, 20.6, 17.4, 13.8.
Anal. Calcd for C29H34BrN3O7 (616.5): C, 56.50; H, 5.56; N, 6.82.
Found: C, 56.29; H, 5.72; N, 6.71.
1¢-(4-Bromophenyl)-2¢-[2-(4,6-O-butylidene-b-D-glucopyrano-
syl)-1-oxoethyl]-1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-
pyrrolizidin]-2(1H)-one (13a)
White solid; yield: 0.45 g (70%); mp 132–134 °C; Rf = 0.7 (EtOAc–
hexane, 60:40).
Anal. Calcd for C37H44N2O10 (676.8): C, 65.67; H, 6.55; N, 4.14.
Found: C, 65.80; H, 6.46; N, 4.01.
[a]D28 +9.84 (c 0.1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 9.20 (d, 1 H), 7.46–7.42 (m, 2 H),
7.33–7.27 (m, 2 H), 7.21–7.19 (m, 2 H), 7.06 (t, J = 7.5 Hz, 1 H),
6.91 (t, J = 7.2 Hz, 1 H), 4.46–4.41 (q, J = 5.4, 15.6 Hz, 1 H), 4.26–
4.22 (dd, J = 10.2, 13.8 Hz, 1 H), 4.08–3.94 (m, 2 H), 3.79–3.61 (m,
3 H), 3.57–3.47 (m, 2 H), 3.24–3.18 (t, 1 H), 3.31–2.96 (m, 4 H),
2.63–2.49 (m, 2 H), 2.01–1.93 (m, 2 H), 1.87–1.79 (m, 2 H), 1.62–
1.55 (m, 2 H), 1.43–1.37 (m, 3 H), 0.91–0.86 (t, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.1, 202.1, 180.8, 179.6, 141.0,
138.6, 136.2, 131.7, 129.9, 129.8, 129.6, 127.2, 125.8, 123.7, 120.9,
111.1, 102.4, 80.3, 79.4, 78.4, 74.8, 74.2, 73.2, 71.9, 70.3, 68.1,
67.1, 51.6, 47.8, 36.2, 30.9, 17.4, 13.9.
3¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-
methyl-4¢-phenylspiro[indole-3,2¢-pyrrolidin]-2(1H)-one (12f)
Yellow solid; yield: 0.43 g (80%); mp 128–130 °C; Rf = 0.76
(MeOH–CHCl3, 0.2:9.8).
1H NMR (300 MHz, CDCl3): d = 9.30 and 9.17 (s, 1 H), 7.46–7.42
(dd, J = 3.6, 3.3 Hz, 2 H), 7.33–7.28 (m, 2 H), 7.24–7.13 (m, 3 H),
7.03 (t, J = 7.2 Hz, 1 H), 6.90–6.87 (dd, J = 2.1, 2.4, 7.7 Hz, 1 H),
4.35 (t, J = 4.1 Hz, 1 H), 4.29 (d, J = 8.7 Hz, 1 H), 3.91 (t, J = 9.2
Hz, 1 H), 3.55–3.35 (m, 5 H), 3.03–2.88 (m, 4 H), 2.14 (d, J = 1.5
Hz, 3 H), 2.05–2.03 (m, 2 H), 1.55–1.51 (m, 2 H), 1.39–1.34 (m, 2
H), 1.23–1.19 (m, 3 H).
Anal. Calcd for C32H37BrN2O7 (641.6): C, 59.91; H, 5.81; N, 4.37.
Found: C, 60.22; H, 5.97; N, 4.14.
13C NMR (75 MHz, CDCl3): d = 204.5, 179.9, 142.1, 140.8, 129.6,
128.6, 128.0, 126.8, 123.3, 110.4, 102.3, 80.2, 75.8, 74.9, 74.8,
74.1, 73.9, 73.5 (2 C), 70.2, 69.1, 67.9, 66.7, 65.9, 60.9, 60.7, 36.1,
35.0, 17.5, 13.9.
2¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-(4-
fluorophenyl)-1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyr-
rolizidin]-2(1H)-one (13b)
White solid; yield: 0.26 g (44%); mp 150–153 °C; Rf = 0.8 (EtOAc–
hexane, 60:40).
Anal. Calcd for C30H36N2O7 (536.6): C, 67.15; H, 6.76; N, 5.22.
Found: C, 67.41; H, 6.93; N, 5.35.
[a]D28 –8.3 (c 0.36, CHCl3).
3¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-
methyl-4¢-[3,4-(methylenedioxy)phenyl]spiro[indole-3,2¢-pyr-
rolidin]-2(1H)-one (12g)
Yellow solid; yield: 0.40 g (69%); mp 150–154 °C; Rf = 0.8
(MeOH–CHCl3, 0.1:9.8).
1H NMR (300 MHz, CDCl3): d = 9.52 (s, 1 H), 7.19 (d, J = 7.2 Hz,
1 H), 7.12–6.70 (m, 5 H), 6.64 (d, J = 7.2 Hz, 1 H), 5.90 (s, 2 H),
4.38 (d, J = 3.0 Hz, 1 H), 4.22 (t, J = 6.9 Hz, 1 H), 4.16–4.09 (dd/
ABq, J = 7.2, 6.9, 14.3 Hz, 1 H), 3.71–3.60 (m, 2 H), 3.52–3.26 (m,
5 H), 3.05–2.95 (m, 3 H), 2.29 (d, 1 H), 2.12 (s, 3 H), 1.54–1.52 (m,
2 H), 1.38–1.19 (m, 3 H), 0.8 (t, J = 7.05 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.8, 179.7, 147.3, 145.8, 140.5,
135.3, 129.1, 126.1, 122.8, 122.7, 120.7, 107.7, 101.9, 100.5, 80.0,
75.4, 74.2, 73.6, 73.5, 73.0, 69.8, 68.4, 67.5, 66.6, 65.9, 60.2, 43.0,
35.7, 34.5, 17.0, 13.4.
1H NMR (300 MHz, CDCl3): d = 9.42 (s, 1 H), 7.41–7.32 (m, 2 H),
7.24–7.20 (m, 1 H), 7.08–6.96 (m, 3 H), 6.90 (t, 1 H), 4.44–4.39 (q,
J = 4.2, 13.8 Hz, 1 H), 4.27–4.22 (dd, J = 9.6, 14.1 Hz, 1 H), 4.09–
3.95 (m, 2 H), 3.77–3.64 (m, 3 H), 3.56–3.43 (m, 3 H), 3.3 (t, 1 H),
3.23–3.16 (t, 1 H), 3.02–2.95 (m, 3 H), 3.09–3.05 (m, 2 H), 2.62–
2.52 (m, 2 H), 2.01–1.93 (m, 2 H), 1.61–1.53 (m, 2 H), 1.43–1.34
(m, 3 H), 0.90–0.85 (t, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.8, 202.9, 181.5, 181.1, 141.1,
140.9, 135.3, 129.9, 129.5, 129.4 (2C), 129.3, 127.2, 127.1, 125.2,
125.0, 122.8, 122.6, 115.5, 115.3, 111.1, 102.4, 80.4, 75.5, 74.7,
74.3, 74.1, 73.3, 72.5, 72.1, 70.3, 68.1, 68.0, 67.2, 51.5, 51.4, 47.8,
45.9, 44.5, 36.2, 31.2, 31.0, 30.9, 27.7, 27.5, 17.5, 13.9.
Anal. Calcd for C32H37FN2O7 (580.6): C, 66.19; H, 6.42; N, 4.82.
Found: C, 66.29; H, 6.52; N, 4.75.
Anal. Calcd for C31H36N2O9 (580.6): C, 64.13; H, 6.25; N, 4.82.
Found: C, 64.45; H, 6.39; N, 4.60.
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

PAPER
Sugar-Based Spirooxindole-pyrrolidines or -pyrrolizidines
2503
2¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-
phenyl-1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyrrolizi-
din]-2(1H)-one (13c)
Yellow solid; yield: 0.30 g (53%); mp 140–144 °C; Rf = 0.85
(EtOAc–hexane, 60:40).
Anal. Calcd for C32H37N3O9 (607.7): C, 63.25; H, 6.14; N, 6.92.
Found: C, 62.93; H, 6.28; N, 7.07.
1¢-(4-Bromophenyl)-2¢-[2-(2,3,4,6-tetra-O-acetyl-b-D-glucopyr-
anosyl)-1-oxoethyl]-1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-
pyrrolizidin]-2(1H)-one (13f)
White solid; yield: 0.61 g (80%); mp 130–132 °C; Rf = 0.55
(EtOAc–hexane, 60:40).
1H NMR (300 MHz, CDCl3): d = 8.25 (d, 1 H), 7.48–7.43 (m, 2 H),
7.29–7.15 (m, 4 H), 7.06–7.00 (m, 1 H), 6.91–6.897 (dd/q, 1 H),
5.02–4.85 (m, 3 H), 4.64–4.55 (q, 1 H), 4.21–4.10 (q, 1 H), 4.07–
3.94 (m, 3 H), 3.71–3.54 (m, 4 H), 3.40–3.36 (m, 1 H), 2.62–2.49
(m, 2 H), 2.39–2.30 (q, 1 H), 1.96–1.92 (m, 12 H), 0.90–0.83 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 202.7, 201.6, 179.9, 170.6, 170.1,
169.7, 169.4, 141.1, 138.8, 131.9, 131.8, 129.8, 129.6, 126.9, 125.4,
122.6, 121.0, 120.8, 110.5, 75.3, 75.2, 74.2, 73.8, 73.6, 72.8, 72.4,
72.3, 72.1, 71.1, 69.8, 68.2, 61.9, 61.7, 51.9, 47.7, 43.5, 31.9, 30.8,
30.0, 29.7, 29.4, 27.3, 22.7, 20.8, 20.6, 20.5, 20.4, 14.1.
[a]D28 –12.25 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 9.99 (d, J = 2.1 Hz, 1 H), 7.43–
7.19 (m, 7 H), 7.01–6.90 (m, 2 H), 4.40 (d, J = 3.9 Hz, 1 H), 4.35–
4.29 (dd, J = 5.1, 12.0 Hz, 1 H), 4.15–4.07 (dd, J = 6.3, 15.8 Hz, 1
H), 4.05–3.97 (dd, J = 6.6, 15.6 Hz, 1 H), 3.75–3.62 (m, 1 H), 3.54
(t, J = 8.1 Hz, 1 H), 3.44 (t, J = 8.9 Hz, 1 H), 3.26 (t, J = 7.8 Hz, 1
H), 3.17 (t, J = 10.2 Hz, 1 H), 3.08–2.88 (m, 2 H), 2.63–2.47 (m, 2
H), 2.39–2.14 (m, 2 H), 2.39–2.14 (m, 2 H), 1.99–1.94 (dd, J = 4.5,
11.1 Hz, 1 H), 1.90–1.82 (m, 2 H), 1.69–1.66 (m, 1 H), 1.56–1.50
(m, 2 H), 1.39–1.26 (m, 2 H), 0.87–0.82 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.0, 203.0, 181.6, 181.2, 141.1,
140.9, 139.5, 129.9, 128.6 (2C), 128.0, 127.8, 127.3, 127.1, 126.9,
125.3, 125.1, 122.8, 122.6, 111.2, 102.4 (2C), 80.4, 77.3, 76.8, 75.6,
74.6, 74.3, 74.1, 73.5, 72.6, 72.3, 70.3, 70.1, 68.0, 66.9, 52.2, 52.1,
47.9, 47.7, 46.0, 44.4, 36.2, 31.3, 31.1, 27.8, 27.5, 17.5, 17.4, 13.9.
Anal. Calcd for C36H39BrN2O11 (755.6): C, 57.22; H, 5.20; N, 3.71.
Found: C, 56.97; H, 5.32; N, 3.95.
Anal. Calcd for C32H38N2O7 (562.6): C, 68.31; H, 6.81; N, 4.98.
Found: C, 68.07; H, 6.97; N, 5.10.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of HPLC profiles, spectral data, and correlation spectra
[1H-1H COSY and 1H-13C COSY].
2¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-
[3,4-(methylenedioxy)phenyl]-1¢,2¢,5¢,6¢,7¢,7a¢-hexahydro-
spiro[indole-3,3¢-pyrrolizidin]-2(1H)-one (13d)
Yellow solid; yield: 0.48 g (79%); mp 156–158 °C; Rf = 0.65
(EtOAc–hexane, 60:40).
1H NMR (300 MHz, CDCl3): d = 9.88 (s, 1 H), 7.13 (d, J = 7.8 Hz,
2 H), 6.97–6.34 (m, 5 H), 5.83 (s, 2 H), 4.34 (t, J = 2.6 Hz, 1 H),
4.21–4.14 (dd, J = 9.9, 10.2, 11.9 Hz, 1 H), 3.99–3.90 (dd/q, J = 6.6,
16.1 Hz, 1 H), 3.90–3.83 (dd, J = 7.5, 16.4 Hz, 1 H), 3.78–3.73 (dd,
J = 4.8, 10.2 Hz, 1 H), 3.68 (d, J = 6.3 Hz, 1 H), 3.60–3.46 (m, 3 H),
3.38 (t, J = 8.7 Hz, 1 H), 3.29–3.22 (dd, J = 3.6, 9.2 Hz, 1 H), 3.15
(t, J = 10.1 Hz, 1 H), 3.07–2.90 (m, 3 H), 2.55–2.39 (m, 1 H), 2.33–
2.13 (m, 1 H), 1.93–1.85 (m, 2 H), 1.78–1.71 (m, 2 H), 1.63–1.54
(m, 1 H), 1.51–1.43 (m, 2 H), 1.31–1.18 (m, 2 H), 0.80–0.74 (m, 3
H).
13C NMR (75 MHz, CDCl3): d = 204.1, 203.2, 181.5, 181.2, 147.8,
146.5, 146.4, 141.1, 141.0, 133.3, 133.2, 129.9, 127.2, 127.0, 125.3,
125.0, 122.7, 122.6, 121.5, 121.1, 111.2, 108.3, 107.9, 102.4, 101.0,
80.4, 75.7, 74.6, 74.3, 74.1, 73.4, 73.3, 72.5, 72.1, 70.4, 70.3, 69.8,
68.2, 68.0, 66.7, 52.0, 51.8, 47.9, 47.7, 46.0, 44.4, 36.2, 31.2, 30.9,
27.7, 27.5, 17.4, 13.9.
Acknowledgment
Authors acknowledge CSIR, New Delhi, India for financial support.
T.M. thanks DST, New Delhi for NMR facility to the Department
of Organic Chemistry, University of Madras, Chennai, India. S.N.
thanks CSIR, New Delhi for SRF and A.H. thanks CSIR, New Delhi
for JRF. We thank Prof. C. R. Ramanathan, Department of Chemi-
stry, Pondicherry University, Puducherry for HPLC analysis.
References
(1) (a) 1,3-Dipolar Cycloaddition Chemistry, Vols. 1-2; Padwa,
A., Ed.; Wiley: New York, 1984. (b) Grigg, R.; Sridharan,
V. In Advances in Cycloaddition, Vol. 3; Curran, D. P., Ed.;
JAI Press: London, 1993, 161. (c) Kumar, A.; Pandey, P. S.
Org. Lett. 2008, 10, 165. (d) Karthikeyan, K.; Kumar, R. S.;
Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2009,
50, 7175. (e) Chaulagain, M. R.; Aron, Z. D. J. Org. Chem.
2010, 75, 8271; and references cited therein.
Anal. Calcd for C33H38N2O9 (606.7): C, 65.33; H, 6.31; N, 4.62.
Found: C, 64.98; H, 6.47; N, 4.80.
(2) (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381. (b) Thomson, J. E.; Kyle, A. F.; Ling, K. B.;
Smith, S. R.; Slawin, A. M. Z.; Smith, A. D. Tetrahedron
2010, 66, 3801. (c) Girgis, A. S. Eur. J. Med. Chem. 2009,
44, 91. (d) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. (e) Galliford, C. V.; Scheidt, K. V. Angew.
Chem. Int. Ed. 2007, 46, 2. (f) Shanmugam, P.;
Viswambharan, B.; Selvakumar, K.; Madhavan, S.
Tetrahedron Lett. 2008, 49, 2611.
(3) (a) Monlineux, R. J. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1987,
Chap. 1. (b) Fujimori, S. JP 882912, 1988; Chem Abstr.
1990, 112, 98409.
(4) (a) Gasperi, T.; Loreto, M. A.; Migliorini, A.; Ventura, C.
Eur. J. Org. Chem. 2011, 385. (b) Chafeev, M.; Fu, J.;
Cadieux, J.-J. US 20100331386, 2010. (c) Prasanna, P.;
Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D.
Eur. J. Med. Chem. 2010, 45, 5653. (d) Cadieux, J.-J.;
Chafeev, M.; Chowdhury, S.; Douglas, A. F.; Fu, J.;
2¢-[2-(4,6-O-Butylidene-b-D-glucopyranosyl)-1-oxoethyl]-1¢-(2-
nitrophenyl)-1¢,2¢,5¢,6¢,7¢,7a¢-hexahydrospiro[indole-3,3¢-pyr-
rolizidin]-2(1H)-one (13e)
Yellow solid; yield: 0.51 g (84%); mp 116–120 °C; Rf = 0.8
(MeOH–CHCl3, 0.5:9.5).
1H NMR (300 MHz, CDCl3): d = 10.03 (s, 1 H), 8.17 (d, J = 6.6 Hz,
2 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.28–6.90
(m, 4 H), 4.38–4.34 (m, 2 H), 4.09–4.00 (m, 1 H), 3.83–3.44 (m, 5
H), 3.22–2.98 (m, 4 H), 2.57–2.51 (m, 2 H), 2.41–2.22 (m, 2 H),
2.10–1.80 (m, 4 H), 1.95–1.86 (m, 2 H), 1.66–1.33 (m, 3 H), 1.26
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.2, 202.5, 181.2, 180.8, 147.4,
147.0, 141.1, 140.9, 130.1, 129.0, 128.6, 126.9, 124.7, 123.8, 123.0,
111.2, 102.5, 80.3, 77.3, 75.5, 74.6, 74.3, 74.0, 73.2, 72.3, 72.0,
70.3, 67.9, 67.4, 52.1, 47.8, 45.6, 36.1, 31.0, 27.7, 27.5, 25.6, 17.4,
13.9.
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York

2504
A. Hemamalini et al.
PAPER
(9) (a) Nagarajan, S.; Mohan Das, T. Carbohydr. Res. 2009,
Langille, J.; Sun, S.; Wood, M. WO 2010078307, 2010.
(e) Augustine, T.; Kanakam, C. C.; Vithiya, S. M.;
Ramkumar, V. Tetrahedron Lett. 2009, 50, 5906.
(f) Basavaiah, D.; Reddy, R. K. Org. Lett. 2007, 9, 57.
334, 1028. (b) Nagarajan, S.; Mohan Das, T.; Arjun, P.;
Raaman, N. J. Mater. Chem. 2009, 19, 4587. (c)Nagarajan,
S.; Mohan Das, T. New J. Chem. 2009, 33, 2391.
(d) Nagarajan, S.; Ravinder, P.; Subramanian, V.;
Mohan Das, T. New J. Chem. 2010, 34, 123. (e) Nagarajan,
S.; Anupa, K.; Babu, V.; Mohan Das, T. Carbohydr. Res.
2010, 345, 1077. (f) Karthik Kumar, K.; Elango, M.;
Subramanian, V.; Mohan Das, T. New J. Chem. 2009, 33,
1570. (g) Nagarajan, S.; Arjun, P.; Raaman, N.; Mohan Das,
T. Carbohydr. Res. 2010, 345, 1988. (h) Rajaganesh, R.;
Jayakumar, J.; Sivaraj, C.; Raaman, N.; Mohan Das, T.
Carbohydr. Res. 2010, 345, 1649. (i) Nagarajan, S.;
Shanmugam, M. J.; Mohan Das, T. Carbohydr. Res. 2011,
346, 722.
(5) (a) Pellegrini, C.; Weber, M.; Borschberg, H.-J. Helv. Chim.
Acta 1996, 79, 151. (b) Kamisaki, H.; Nanjo, T.; Tsukano,
C.; Takemoto, Y. Chem. Eur. J. 2011, 17, 626. (c) White, J.
D.; Li, Y.; Ihle, D. C. J. Org. Chem. 2010, 75, 3569.
(6) (a) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo,
B. J. Org. Chem. 1991, 56, 6527. (b) Deppermann, N.;
Thomanek, H.; Prenzel, A. H. G. P.; Maison, W. J. Org.
Chem. 2010, 75, 5994. (c) Klein, J. E. M. N.; Perry, A.;
Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2010, 12, 3446.
(d) Reddy, V. J.; Douglas, C. J. Tetrahedron 2010, 66, 4719.
(e) Reddy, V. J.; Douglas, C. J. Org. Lett. 2010, 12, 952.
(f) Jaegli, S.; Vors, J.-P.; Neuville, L.; Zhu, J. Synlett 2009,
2997.
(7) Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.;
Flower, K.; Vit, I.; Willing, R. I. Phytochemistry 1998, 48,
437.
(8) (a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651. (b) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot.
1996, 49, 832. (c) Abou-Gharbia, M. A.; Doukas, P. H.
Heterocycles 1979, 12, 637. (d) Kornet, M. J.; Thio, A. P.
J. Med. Chem. 1976, 19, 892.
(10) (a) Mellis, R. L.; Mehltretter, C. L.; Rist, C. E. J. Am. Chem.
Soc. 1951, 73, 294. (b) Bonner, T. G.; Bourne, E. J.; Lewis,
D. J. Chem. Soc. 1965, 7453.
(11) (a) Bragnier, N.; Scherrmann, M. C. Synthesis 2005, 814.
(b) Rodrigues, F.; Canac, Y.; Lubineau, A. Chem. Commun.
2000, 2049. (c) Riemann, I.; Papadopoulos, M. A.; Knorst,
M.; Fessner, W. D. Aust. J. Chem. 2002, 55, 147.
Synthesis 2011, No. 15, 2495–2504 © Thieme Stuttgart · New York