Application of azomethine ylides in the synthesis of carbohydrate-derived spiroheterocycles

Article abstract of DOI:10.1055/s-0030-1260226

A series of sugar-fused spiro-pyrrolidine, -pyrrolizidine, and -indolizidine heterocycles were synthesized through a unique application of a 1,3-dipolar cycloaddition reaction of an azomethine ylide with a carbohydrate-derived olefin. The 1,3-dipoles synthesized from secondary α-amino acids (sarcosine, proline, or pipecolinic acid) and 1,2-diketones (isatin or acenaphthoquinone), upon reaction with the olefin, gave the corresponding cycloaddition products in good-to-very good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260226

PAPER
3563
Application of Azomethine Ylides in the Synthesis of Carbohydrate-Derived
Spiroheterocycles
C
arbohydrate-
i
D
erive
y
d Spirohetero
a
cycles li Deb Barman, 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 700032, India
Fax +91(33)24735197; E-mail: ashisbanerjee@iicb.res.in
Received 28 June 2011; revised 25 July 2011
Et
H
Abstract: A series of sugar-fused spiro-pyrrolidine, -pyrrolizidine,
H
N
N
H
and -indolizidine heterocycles were synthesized through a unique
application of a 1,3-dipolar cycloaddition reaction of an azomethine
ylide with a carbohydrate-derived olefin. The 1,3-dipoles synthe-
sized from secondary a-amino acids (sarcosine, proline, or pipe-
colinic acid) and 1,2-diketones (isatin or acenaphthoquinone), upon
reaction with the olefin, gave the corresponding cycloaddition prod-
ucts in good-to-very good yields.
OMe
CO2Me
H
O
O
O
N
N
CO2Me
H
H
rhynchophylline
formosanine
OH
Key words: heterocycles, spiro compounds, carbohydrates, ylides,
cycloadditions
Me
N
HN
O
N
H
Carbohydrate-based heterocycles have always attracted
the attention of organic chemists and biologists1 because
of their promising bioactivities,2 which include antiviral,3
antimicrobial4 and antitumor5 activities. Such heterocy-
cles have also been shown to be potentially useful as drugs
for the treatment of several diseases, such as influenza
H1N1,6 HIV,7 or cancer.8 The synthesis of newer classes
of carbohydrate-based heterocycles has therefore recently
become an interesting field of research. Spiro-pyrrolidine-
oxindole heterocycles are found in a range of bioactive
entities of both synthetic and natural origin.9 They occur
as important motifs in a number of naturally occurring al-
kaloids, such as rhynchophylline,10a formosanine,10b hors-
filine,10c elacomine,10d and spirotryprostatins A and B10e,f
(Figure 1), which are known to possess moderate-to-high
biological activities. In addition, some spiro-oxindole an-
alogues are also known to display inhibitory activities
against poliovirus, rhinovirus 3C-proteinase, and aldose
reductase.11 Although the synthesis of the spiro-oxindole
core has been realized in a number of ways, the most no-
table advance was made by Grigg and his co-workers,12
who were first to demonstrate a new approach to the syn-
thesis of such spiro-pyrrolidine-oxindole skeletons by uti-
lizing the well-known 1,3-dipolar azomethine ylide
cycloaddition reaction. Since then, the azomethine ylide
cycloaddition reaction has become one of the most popu-
lar approaches to the construction of the spiro-pyrroli-
dine-oxindole ring system, and a number of natural
products such as ( )-horsfiline, ( )-coerulescine, and
spirotryprostatin B, as well as some sugar-based spiro-
oxindoles have been successfully synthesized by utilizing
this key step.13
MeO
O
N
H
horsfiline
elacomine
O
N
N
H
O
O
N
O
O
HN
N
H
N
O
H
OMe
spirotryprostatin A
spirotryprostatin B
Figure 1 Some spiro-oxindole-containing alkaloids
Prompted by reports on the structural features and biolog-
ical activity of these molecules, we contemplated fusing
structurally unique spiro-pyrrolidine-oxindole motifs
with properly functionalized glycoside derivatives, on the
assumption that fusion might lead to a new class of carbo-
hydrate-based heterocycles with potential biological ac-
tivities. Towards this end, we report, for the first time, a
simple and short approach to a new series of sugar-fused
spiro-oxindole and spiro-acenaphthylenone derivatives
by using secondary a-amino acids (sarcosine, proline, or
pipecolinic acid) and 1,2-diketones (isatin or acenaphtho-
quinone) to generate azomethine ylides that react with a
sugar-derived precursor (Scheme 1).
To begin with, the a,b-unsaturated carbohydrate-derived
ester 114 was exposed to the azomethine ylide generated in
situ from isatin (2a) and sarcosine (3a) to give the spiro
heterocycle 4a (Scheme 2). The effects of solvents on this
particular [3+2] cycloaddition reaction were studied, tak-
ing ester 1, isatin (2a), and sarcosine (3a) as the model
SYNTHESIS 2011, No. 21, pp 3563–3568
x
x.
x
x
.
2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260226; Art ID: Z64611SS
© Georg Thieme Verlag Stuttgart · New York

3564
P. D. Barman et al.
PAPER
substrates. Whereas no reaction occurred in methanol or spective cycloaddition products 4b and 4c were isolated
acetonitrile (Table 1, entries 4 and 5), the use of toluene as and characterized (Scheme 2). It was interesting to note
the solvent gave the corresponding cycloadduct 4a in 83% that the presence of an electron-withdrawing substituent
yield (entry 1), compared with 30% in N,N-dimethylform- in the isatin moiety reduced the overall yield slightly,
amide and 51% in benzene (entries 2 and 3).
whereas an electron-donating substituent produced a mar-
ginal improvement in the yield of the glycospiro-pyrroli-
dine-oxindole adduct (Table 2, entries 1–3).
R
Table 2 Synthesis of Sugar-Fused Spiro-Heterocycles through
[3+2] Cycloaddition Reactions
O
X
MeO2C
a
CO2Me
O
O
O
Entry
1,2-Diketone
a-Amino Product Time
Yield
(%)b
O
N
O
acida
(h)
12
14
11
11
11
12
11
10
14
14
carbohydrate-derived
precursor
O
n
1
2
2a (X = H)
2b (X = F)
2c (X = OMe)
2d
3a
4a
4b
4c
4d
5a
5b
5c
5d
6a
7a
83
78
85
82
81
75
83
79
81
70
(X = N, C; R = F, OMe; n = 1, 2)
glycospiroheterocycles
3a
Scheme 1 Reagents and conditions: (a) cis-1,2-diketone 2a, a-ami-
no acid 3a, toluene, reflux.
3
3a
4
3a
O
R
5
2a (X = H)
2b (X = F)
2c (X = OMe)
2d
3b
3b
3b
3b
3c
O
R
CO2Me
O
6
N
H
HN
CO2Me
O
2a–c
7
O
Me
H
N
O
8
N
CO2H
O
O
Me
H
O
3a
9
2a (X = H)
2a (X = H)
1
4a–c
10
3b
(a: R = H; b: R = F; c: R = OMe)
O
O
a All reactions were performed in refluxing toluene.
b Isolated yield.
Similar observations were made when sarcosine was re-
placed with L-proline 3b (Scheme 3) and the reactions
with 2a–c were performed under optimal conditions to
generate a series of glycospiro-pyrrolizidine-oxindoles
5a–c (Table 2, entries 5–7) in reduced yields. We assume
that an increase in steric crowding due to the presence of
a five-membered ring is the yield-determining factor.
2d
3a
CO2Me
O
H
O
N
O
N
CO2H
Me
Me
H
O
4d
Scheme 2 Synthesis of glycospiro-pyrrolidine-oxindoles and a
spiro-pyrrolidine-acenaphthylenone
O
R
R
Table 1 Effects of the Solvent on the Yield of the Cycloaddition
Reaction
O
CO2Me
N
HN
O
CO2Me
O
H
Solventa
toluene
benzene
DMF
Temp (°C)
reflux
reflux
120
Time (h)
Yield (%)b
2a–c
Entry
O
O
N
O
1
2
3
4
5
12
10
10
12
12
83
51
30
nrc
nr
CO2H
O
H
O
H
N
H
1
3b
5a–c
(a: R = H; b: R = F; c: R = OMe)
O
O
MeCN
MeOH
reflux
reflux
CO2Me
O
2d
3b
a All the reactions were performed by using 1, 2a, and 3a.
b Isolated yield.
O
N
c nr = No reaction.
O
CO2H
N
H
O
H
5d
H
With this initial success, we decided to replace 2a (R = H)
with other derivatives 2b (R = F) and 2c (R = OMe) while
keeping the amino acid unchanged. Upon reaction, the re-
Scheme 3 Synthesis of glycospiro-pyrrolizidine-oxindoles and a
spiro-pyrrolizidine-acenaphthylenone
Synthesis 2011, No. 21, 3563–3568 © Thieme Stuttgart · New York

PAPER
Carbohydrate-Derived Spiroheterocycles
3565
To establish the generality of the method, we replaced the
isatin derivatives with acenaphthoquinone (2d); the prod-
ucts isolated were 4d (82% with sarcosine) (Scheme 2)
and 5d (79% with proline) (Scheme 3) (Table 2, entries 4
and 8, respectively). When sarcosine and proline were re-
placed with N-benzylglycine (3c) or pipecolonic acid
(3d), the cycloaddition products with isatin were identi-
fied as 6a (81%) and 7a (70%), respectively (Scheme 4;
Table 2, entries 9 and 10).
O
iminium ion
MeO
formation
H
N
CO2H
O
Me
N
H
3a
2c
O
Me
O
Me
H
N
CH2
N
MeO
O
O
MeO
O
O
O
CO2Me
N
N
H
H
O
1
azomethine ylide
O
MeO2C
N
HN
O
O
CO2Me
O
H
H
2a
O
O
O
O
Bn
Me
O
[3+2] cycloaddition
N
N
O
O
CO2H
H
CO2Me
OMe
O
HN
3c
HN
O
6a
1
4c
O
N
Scheme 5 Probable mechanistic pathway
H
HN
CO2Me
O
2a
O
quantum coherence spectroscopy (HSQC), and H–13C
heteronuclear multiple-bond correlation spectroscopy
(HMBC) permitted the clear identification of most of the
signals, thereby establishing the disposition of the atoms
in the pentacyclic framework in 4c. The spiro carbon (d =
79.2 ppm) showed an HMBC correlation with Hb (d =
3.42 ppm), Hc (d = 3.51 ppm), N-methyl protons (d = 2.20
ppm), and methoxycarbonyl protons (d = 3.46 ppm). Fur-
thermore, a similar correlation of Ha (d = 3.83 ppm) with
methylene carbon (d = 54.5 ppm) and ester carbonyl (d =
170.3 ppm) confirmed the structure of the product. Cru-
cial evidence for the stereochemistry was obtained by nu-
clear Overhauser effect spectroscopy (NOESY). The
aromatic Hf (d = 6.70 ppm) showed a NOESY relationship
with the methoxycarbonyl protons (d = 3.46 ppm)
(Figure 2), indicating that the aromatic moiety and the es-
ter group are disposed in the same plane. A few more
characteristic NOESY correlations of Ha with Hb, of Hc
with Hd, and of Hd with Hc are clearly visible, indicating
the close proximity of these atoms in space.
1
N
O
H
O
N
CO2H
H
H
7a
3d
Scheme 4 Synthesis of glycospiro-pyrrolidine-oxindole and spiro-
indolizidine-oxindole
From mechanistic considerations, it is accepted that an in-
termediate imminium ion12 is formed by the reaction of 2c
with 3a (Scheme 5); this is followed by rapid decarboxy-
lation to form the azomethine ylide, which undergoes cy-
cloaddition reaction with dipolarophile 1 to give the
cycloadduct 4c. The azomethine ylide probably attacks 1
from the face opposite to that of the acetal linkage to avoid
steric crowding, thereby projecting the ester group and Ha
on the a-face. Furthermore, to avoid dipolar repulsion be-
tween the amide carbonyl and the ester carbonyl in 4c, the
amide keto group will go to the b-face, and the product is
expected to have the structure shown in Figure 2.
The absence of a signal for an olefinic proton and the pres-
ence of two triplet signals at d = 3.42 and 3.51 ppm for the
N-methylene protons of the pyrrolidine moiety and anoth-
er triplet signal at d = 3.83 ppm for the adjacent methine
OMe
OMe
6.70
Hf
Hf
CO2Me
O
HN
1
HN
CO2Me
170.3
79.2
3.46
proton (ring-juncture) in the H NMR spectrum of 4c
3.46
O
Hf
O
He
O
proved that a cyclization involving the olefin and the
azomethine ylide had indeed taken place. This was con-
firmed by the presence of two other singlets at d = 2.20
and 3.46 ppm for the N-methyl and methoxycarbonyl
groups, respectively, of the fused pyrrolidine moiety. The
peaks at d = 50.7, 54.5, and 79.2 ppm in the 13C NMR
spectrum of 4c were characteristic of methylene, methane,
and spiro carbons, respectively; sharp and intense peaks at
d = 52.4 and 35.4 ppm were allocated to the methoxycar-
bonyl and N-methyl carbons, respectively. 1H–1H correla-
50.7
N
O
N
O
Me
Me
54.5
2.20
3.83
Hb
Ha
Hb
Ha
O
Hd
4.58
3.42
3.42
O
Hd
3.83
3.51
Hc
Hc
3.51
Figure 2 Characteristic HMBC (blue) and NOESY (red) correla-
tions of 4c
In conclusion, we have developed a simple synthesis of
glycospiro-pyrrolidines, -pyrrolizidines, and -indoliz-
idines from a carbohydrate-derived precursor by a 1,3-di-
polar cycloaddition reaction of a series of azomethine
ylides generated in situ in a one-pot sequence. The struc-
tion spectroscopy (COSY), H–13C heteronuclear single
1
Synthesis 2011, No. 21, 3563–3568 © Thieme Stuttgart · New York

3566
P. D. Barman et al.
PAPER
6.13 (d, J = 3.0 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 2.4
Hz, 1 H), 6.75 (dd, J = 3.0, 8.4 Hz, 1 H), 7.35 (br s, 1 H).
tural resemblance of the products to a number of naturally
occurring bioactive alkaloids may lead to the identifica-
tion of newer structural motifs with potential biological 13C NMR (150 MHz, CDCl3): d = 26.9 (CH3), 27.3 (CH3), 35.4
(CH3), 50.7 (CH), 52.4 (CH3), 54.5 (CH2), 55.8 (CH3), 79.2 (C),
activities. To the best of our knowledge, this is the first re-
83.4 (CH), 100.2 (C), 109.5 (CH), 110.3 (CH), 111.5 (CH), 113.5
port of the synthesis of sugar-fused spiroheterocycles with
an attached oxindole/acenaphthylenone core by means of
1,3-dipolar azomethine ylide cycloaddition reactions.
(C), 115.1 (CH), 126.7(C), 135.1 (C), 155.6 (C), 170.3 (C), 176.2
(C).
HRMS (ESI): m/z [M + Na]+ calcd for C20H24N2NaO7: 427.1481;
found: 427.1465.
Melting points were recorded in open capillaries and are uncorrect-
ed. 1H and 13C NMR spectra were recorded in CDCl3 using TMS as
Methyl (1S,3a¢S,4a¢R,7a¢S,7b¢S)-2¢,2¢,7¢-Trimethyl-2-oxo-
the internal standard. Mass spectra were recorded in ESI mode. Op-
tical rotations were measured at 589 nm. TLC was performed on
precoated plates (0.2 mm, silica gel 60 F254). All solvents were dis-
tilled and purified as necessary.
3a¢,7¢,7a¢,7b¢-tetrahydro-2H-spiro[acenaphthylene-1,6¢-[1,3]di-
oxolo[4,5]furo[3,2-b]pyrrole]-4a¢(5¢H)-carboxylate (4d)
Yellow gum; yield: 82%; [a]D25 –130.7 (c 0.14, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.33 (s, 6 H), 2.17 (s, 3 H), 3.20
(s, 3 H), 3.53 (t, J = 9.6 Hz, 1 H), 3.62 (t, J = 9.6 Hz, 1 H), 3.94 (t,
J = 9.0 Hz, 1 H), 4.65 (d, J = 2.4 Hz, 1 H), 6.07 (d, J = 3.0 Hz, 1 H),
7.39 (d, J = 7.2 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.71 (t, J = 7.8
Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1 H), 8.07
(d, J = 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 26.8 (CH3), 27.3 (CH3), 35.2
(CH3), 50.8 (CH), 52.0 (CH3), 55.0 (CH2), 81.9 (C), 83.5 (CH),
100.6 (C), 108.8 (CH), 113.5 (C), 121.2 (CH), 121.5 (CH), 125.4
(CH), 128.1 (CH), 128.3 (CH), 130.4 (C), 131.4 (CH), 132.3 (C),
135.4 (C), 142.7 (C), 170.4 (C), 204.2 (C).
Glyco Spiro Heterocycles 4–7; General Procedure
A mixture of diketone 2a–d (0.275 mmol, 1.1 equiv), a-amino acid
3a–d (0.275 mmol, 1.1 equiv), and the carbohydrate-derived olefin
1 (0.25 mmol, 1.0 equiv) in toluene (10 mL) was refluxed under N2
for 12 h. The mixture was cooled and the solvent was evaporated
under reduced pressure. The residue was purified by column chro-
matography [silica gel (100–200 mesh), EtOAc–PE (1:4)].
Methyl (3aS,4aR,6S,7aS,7bS)-2,2,7-Trimethyl-2¢-oxo-
1¢,2¢,3a,7,7a,7b-hexahydrospiro[1,3-dioxolo[4,5]furo[3,2-b]pyr-
role-6,3¢-indole]-4a(5H)-carboxylate (4a)
HRMS (ESI): m/z [M + Na]+ calcd for C23H23NaNO6: 432.1423;
found: 432.1409.
Yellow gum; yield: 83%; [a]D25 –73.8 (c 0.6, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.33 (s, 3 H), 1.37 (s, 3 H), 2.19
(s, 3 H), 3.40 (s, 3 H), 3.43 (t, J = 9.0 Hz, 1 H), 3.49 (t, J = 9.0 Hz,
1 H), 3.84 (t, J = 9.0 Hz, 1 H), 4.58 (d, J = 3.6 Hz, 1 H), 6.12 (d,
J = 3.0 Hz, 1 H), 6.75 (d, J = 7.8 Hz, 1 H), 6.98 (br t-like, J = 7.8
Hz, 1 H), 7.08 (br d, J = 7.2 Hz, 1 H), 7.21 (dt, J = 1.2, 7.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 26.9 (CH3), 27.3 (CH3), 35.3
(CH3), 50.6 (CH), 52.3 (CH3), 54.5 (CH2), 78.8 (C), 83.4 (CH),
100.2 (C), 109.4 (CH), 109.4 (C), 109.7 (CH), 113.5 (C), 122.3
(CH), 125.3 (CH), 129.7 (CH), 141.7 (C), 170.2 (C), 176.0 (C).
Methyl (3aR,4aS,5R,9aS,9bR,9cR)-2,2-Dimethyl-2¢-oxo-
1¢,2¢,7,8,9,9a,9b,9c-octahydrospiro[1,3-dioxolo[4,5]furo[3,2-
a]pyrrolizine-5,3¢-indole]-4a(3aH)-carboxylate (5a)
Yellow gum; yield: 81%; [a]D25 –85.3 (c 0.53, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.32 (s, 3 H), 1.35 (s, 3 H), 1.78–
1.84 (m, 1 H), 1.86–1.94 (m, 1 H), 2.03–2.08 (m, 1 H), 2.19–2.24
(m, 1 H), 2.73 (dt, J = 3.0, 7.8 Hz, 1 H), 3.03 (q, J = 8.4 Hz, 1 H),
3.37 (s, 3 H), 3.46 (d, J = 8.4 Hz, 1 H), 4.14 (m, 1 H), 4.61 (d,
J = 3.0 Hz, 1 H), 6.16 (d, J = 3.6 Hz, 1 H), 6.81 (d, J = 7.8 Hz, 1 H),
6.96 (t, J = 7.8 Hz, 1 H), 7.17 (d, J = 7.2 Hz, 1 H), 7.21 (t, J = 7.2
Hz, 1 H), 7.94 (br s, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C19H22N2NaO6: 397.1376;
found: 397.1362.
13C NMR (150 MHz, CDCl3): d = 26.1 (CH2), 26.5 (CH3), 26.8
(CH3), 29.8 (CH2), 46.9 (CH2), 52.2 (CH3), 58.2 (CH), 66.0 (CH),
77.3 (C), 82.9 (CH), 103.3 (C), 108.9 (CH), 110.0 (CH), 113.0 (C),
121.7 (CH), 124.9 (C), 126.6 (CH), 129.7 (CH), 141.8 (C), 170.9
(C), 177.0 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C21H24N2NaO6: 423.1532;
found: 423.1548.
Methyl (3aS,4aR,6S,7aS,7bS)-5¢-Fluoro-2,2,7-trimethyl-2¢-oxo-
1¢,2¢,3a,7,7a,7b-hexahydrospiro[1,3-dioxolo[4,5]furo[3,2-b]pyr-
role-6,3¢-indole]-4a(5H)-carboxylate (4b)
Light brown gum; yield: 78%; [a]D25 –94.0 (c 0.13, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.32 (s, 3 H), 1.38 (s, 3 H), 2.19
(s, 3 H), 3.41(t, J = 9.0 Hz, 1 H), 3.48 (m, 4 H), 3.82 (t-like, J = 8.4,
9.6 Hz, 1 H), 4.57 (d, J = 3.0 Hz, 1 H), 6.11 (d, J = 3.6 Hz, 1 H),
6.69 (dd, J = 4.2, 8.4 Hz, 1 H), 6.85 (dd, J = 2.4, 7.8 Hz, 1 H), 6.92
(dt, J = 2.4, 8.4 Hz, 1 H), 7.34 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 26.8 (CH3), 27.3 (CH3), 35.3
(CH3), 50.7 (CH), 52.4 (CH3), 54.4 (CH2), 79.1 (C), 83.2 (CH),
100.1 (C), 109.5 (CH), 110.2 (CH), 113.3 (CH), 113.6 (C), 116.2
(CH), 127.4 (C), 137.7 (C), 158.0 (C), 170.1 (C), 176.1 (C).
Methyl (3aR,4aS,5R,9aS,9bR,9cR)-5¢-Fluoro-2,2-dimethyl-2¢-
oxo-1¢,2¢,7,8,9,9a,9b,9c-octahydrospiro[1,3-dioxolo[4,5]fu-
ro[3,2-a]pyrrolizine-5,3¢-indole]-4a(3aH)-carboxylate (5b)
Light brown gum; yield: 75%; [a]D25 –59.1 (c 0.12, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.32 (s, 3 H), 1.35 (s, 3 H), 1.78–
1.82 (m, 1 H), 1.92–1.95 (m, 1 H), 2.08–2.10 (m, 1 H), 2.19–2.21
(m, 1 H), 2.72 (br t, J = 5.4, 7.8 Hz, 1 H), 3.03(q, J = 8.4 Hz, 1 H),
3.43 (d, J = 9.0 Hz, 1 H), 3.46 (s, 3 H), 4.15 (q, J = 7.2 Hz, 1 H),
4.59 (d, J = 3.0 Hz, 1 H), 6.13 (d, J = 3.0 Hz, 1 H), 6.73 (m, 1 H),
6.95 (m, 2 H), 7.43 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 25.9 (CH2), 26.5 (CH3), 26.9
(CH3), 29.7 (CH2), 46.4 (CH2), 52.4 (CH3), 58.3 (CH), 65.8 (CH),
77.2 (C), 82.6 (CH), 103.5 (C), 109.2 (CH), 110.3 (CH), 113.3 (C),
114.5 (CH), 116.2 (CH), 127.8 (C), 137.6 (C), 157.6 (C), 170.9 (C),
176.8 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C19H21FN2NaO6: 415.1281;
found: 415.1269.
Methyl (3aS,4aR,6S,7aS,7bS)-5¢-Methoxy-2,2,7-trimethyl-2¢-
oxo-1¢,2¢,3a,7,7a,7b-hexahydrospiro[1,3-dioxolo[4,5]furo[3,2-
b]pyrrole-6,3¢-indole]-4a(5H)-carboxylate (4c)
Light brown gum; yield: 85%; [a]D25 –65.1 (c 0.42, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.32 (s, 3 H), 1.37 (s, 3 H), 2.20
(s, 3 H), 3.42(t, J = 9.0 Hz, 1 H), 3.46 (s, 3 H), 3.51 (t, J = 9.0 Hz, 1
H), 3.76 (s, 3 H), 3.83 (t, J = 9.0 Hz, 1 H), 4.58 (d, J = 3.6 Hz, 1 H),
Synthesis 2011, No. 21, 3563–3568 © Thieme Stuttgart · New York

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HRMS (ESI): m/z [M + Na]+ calcd for C21H23FN2NaO6: 441.1438;
found: 441.1456.
1H NMR (300 MHz, CDCl3): d = 1.32 (s, 3 H), 1.36 (s, 3 H), 1.40–
1.56 (m, 4 H), 1.78–1.83 (m, 1 H), 2.01 (br d, J = 10.8 Hz, 1 H),
2.34–2.38 (m, 2 H), 3.34 (s, 3 H), 3.39 (m, 2 H.), 4.51 (d, J = 3.0 Hz,
1 H), 6.08 (d, J = 3.0 Hz, 1 H), 6.72 (d, J = 7.5 Hz, 1 H), 6.95 (t,
J = 7.5 Hz, 1 H), 7.06 (d, J = 7.2 Hz, 1 H), 7.18 (dt, J = 1.2, 7.5 Hz,
1 H), 7.23 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.7 (CH2), 25.2 (CH2), 26.7
(CH3), 27.3 (CH3), 31.5 (CH2), 45.9 (CH2), 52.0 (CH3), 57.1 (CH),
60.3 (CH), 78.9 (C), 82.0 (CH), 98.7 (C), 109.4 (CH), 109.5 (CH),
113.4 (C), 122.0 (CH), 125.1 (CH), 126.3 (C), 129.4 (CH), 142.0
(C), 170.3 (C), 176.5 (C).
Methyl (3aR,4aS,5R,9aS,9bR,9cR)-5¢-Methoxy-2,2-dimethyl-2¢-
oxo-1¢,2¢,7,8,9,9a,9b,9c-octahydrospiro[1,3-dioxolo[4,5]fu-
ro[3,2-a]pyrrolizine-5,3¢-indole]-4a(3aH)-carboxylate (5c)
Light brown gum; yield: 83%; [a]D25 –29.5 (c 0.12, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.31 (s, 3 H), 1.35 (s, 3 H), 1.76–
1.82 (m, 1 H), 1.88–1.93 (m, 1 H), 2.04–2.09 (m, 1 H), 2.17–2.22
(m, 1 H), 2.72 (dt, J = 3.0, 8.4 Hz, 1 H), 2.99 (q, J = 8.4 Hz, 1 H),
3.42 (s, 3 H), 3.45 (d, J = 9.0 Hz, 1 H), 3.76 (s, 3 H), 4.12 (q-like,
J = 6.6, 8.4 Hz, 1 H), 4.61 (d, J = 3.0 Hz, 1 H), 6.16 (d, J = 3.0 Hz,
1 H), 6.72–6.81 (m, 3 H), 7.94 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 26.2 (CH2), 26.5 (CH3), 26.8
(CH3), 29.8 (CH2), 46.5 (CH2), 52.2 (CH3), 55.9 (CH3), 57.9 (CH),
66.0 (CH), 77.4 (C), 82.9 (CH), 103.4 (C), 109.0 (CH), 110.3 (CH),
113.0 (C), 113.8 (CH), 114.4 (CH), 126.2 (C), 135.1 (C), 155.1 (C),
170.8 (C), 177.1 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C22H26N2O6Na: 437.1689;
found: 437.1699.
Acknowledgment
The authors (P.D.B. and I.S.) gratefully acknowledge receipt of Se-
nior Research Fellowships from the Council of Scientific and Indu-
strial Research.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26N2NaO7: 453.1638;
found: 453.1619.
References
Methyl (1R,3a¢R,4a¢S,9a¢S,9b¢R,9c¢R)-2¢,2¢-Dimethyl-2-oxo-
7¢,8¢,9¢,9a¢,9b¢,9c¢-hexahydro-2H-spiro[acenaphthylene-1,5¢-
[1,3]dioxolo[4,5]furo[3,2-a]pyrrolizine]-4a¢(3a¢H)-carboxylate
(5d)
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830. (b) Beecham, A. F.; Hart, N. K.; Johns, S. R.;
Lamberton, J. A. Chem. Commun. 1967, 535. (c) Jossang,
Yellow gum; yield: 79%; [a]D25 –169.6 (c 0.57, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.30 (s, 3 H), 1.31 (s, 3 H), 1.86–
1.96 (m, 2 H), 2.05–2.11 (m, 1 H), 2.23–2.29 (m, 1 H), 2.78 (br t-
like, J = 6.6 Hz, 1 H), 3.19 (s, 3 H), 3.24 (m, 1 H), 3.54 (d, J = 9.0
Hz, 1 H), 4.26–4.33 (m, 1 H), 4.67 (d, J = 3.0 Hz, 1 H), 6.11 (d,
J = 3.0 Hz, 1 H), 7.49 (d, J = 6.9 Hz, 1 H), 7.59 (t, J = 7.8 Hz, 1 H),
7.71 (t, J = 7.5 Hz, 1 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.93 (d, J = 7.2
Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 25.9 (CH2), 26.5 (CH3), 26.8
(CH3), 29.8 (CH2), 47.6 (CH2), 51.9 (CH3), 59.1 (CH), 66.1 (CH),
80.7 (C), 82.9 (CH), 103.7 (C), 108.6 (CH), 113.0 (C), 122.1 (CH),
123.1 (CH), 125.6 (CH), 127.6 (CH), 128.3 (CH), 130.6 (C), 131.2
(CH), 132.0 (C), 135.0 (C), 142.3 (C), 171.5 (C), 202.4 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C25H25NO6Na: 458.1580;
found: 458.1570.
Methyl (3aR,4aS,5R,7aR,7bR)-6-Benzyl-2,2-dimethyl-2¢-oxo-
1¢,2¢,6,7,7a,7b-hexahydrospiro[1,3-dioxolo[4,5]furo[2,3-c]pyr-
role-5,3¢-indole]-4a(3aH)-carboxylate (6a)
Yellow gum; yield: 71%; [a]D25 –40.4 (c 0.22, CHCl3).
1H NMR (600 MHz, CDCl3): d = 1.31 (s, 3 H), 1.37 (s, 3 H), 3.25–
3.31 (m, 2 H), 3.38 (s, 3 H), 3.42 (d, J = 13.2 Hz, 1 H), 3.48 (d,
J = 13.2 Hz, 1 H), 3.78 (t, J = 9.6 Hz, 1 H), 4.48 (d, J = 2.4 Hz, 1
H), 6.14 (d, J = 3.0 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 6.99 (dt,
J = 0.6, 7.2 Hz, 1 H), 7.19–7.33 (m, 7 H).
13C NMR (150 MHz, CDCl3): d = 26.8 (CH3), 27.3 (CH3), 50.2
(CH), 50.9 (CH2), 52.2 (CH3), 52.9 (CH2), 78.8 (C), 83.2 (CH), 99.9
(C), 109.3 (CH), 109.6 (CH), 113.6 (C), 122.3 (CH), 125.4 (CH),
126.2 (C), 127.2 (CH), 128.3 (4 × CH), 129.7 (CH), 138.2 (C),
141.9 (C), 170.1 (C), 176.3 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C25H26N2NaO6: 473.1689;
found: 473.1675.
Methyl (3aR,4aS,5R,10aS,10bR,10cR)-2,2-Dimethyl-2¢-oxo-
1¢,2¢,3a,7,8,9,10,10a,10b,10c-decahydro-4aH-spiro[1,3-dioxo-
lo[4,5]furo[3,2-a]indolizine-5,3¢-indole]-4a-carboxylate (7a)
25
White solid; yield: 80%; mp: 244–246 °C; [a]D –150.9 (c 0.14,
CHCl3).
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P. D. Barman et al.
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