Synthesis of spiropyrrolidines and spiropyrrolizidines by 1,3-dipolar cycloadditions of azomethine ylides to substituted α-methylene-γ-lactones

Article abstract of DOI:10.1016/S0040-4020(01)00807-9

1,3-Dipolar cycloadditions of (E)- and (Z)-substituted α-methylene-γ-lactones with azomethine ylides derived from N-methyl glycine and L-proline gave the corresponding spiropyrrolidine and spiropyrrolizidine cycloadducts in good to moderate yields with various extent of stereoselectivity and regioselectivity. Cycloadditions of the azomethine ylide derived from L-proline exhibited endo selectivity especially in the case of (Z)-isomers of starting methylene lactones. Reactivity and regioselectivity were rationalized by a comparison with quantum chemical calculations (AM1). Structures of derivatives prepared were determined by NMR spectroscopy and by X-ray.

Full text of DOI:10.1016/S0040-4020(01)00807-9

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 8339±8347
Synthesis of spiropyrrolidines and spiropyrrolizidines
by 1,3-dipolar cycloadditions of azomethine ylides
to substituted a-methylene-g-lactones
a
Jakub Castulõk, Jaromõr Marek and Ctibor Mazal
b
a,p
Ï
Â
Â
a
ÂÏ
Â
Department of Organic Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
ÂÏ Â
Department of Inorganic Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic
b
Received 26 April 2001;accepted 8 August 2001
AbstractÐ1,3-Dipolar cycloadditions of )E)- and )Z)-substituted a-methylene-g-lactones with azomethine ylides derived from N-methyl
glycine and l-proline gave the corresponding spiropyrrolidine and spiropyrrolizidine cycloadducts in good to moderate yields with various
extent of stereoselectivity and regioselectivity. Cycloadditions of the azomethine ylide derived from l-proline exhibited endo selectivity
especially in the case of )Z)-isomers of starting methylene lactones. Reactivity and regioselectivity were rationalized by a comparison with
quantum chemical calculations )AM1). Structures of derivatives prepared were determined by NMR spectroscopy and by X-ray. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
a-Methylene-g-lactone derivatives attract research
chemists' attention not only as desired target molecules
which offer various biological activities,1 but also as a start-
ing material of further possible synthetic utilization.2
Recently, several reports on the reactivity of methylene
lactones in 1,3-dipolar cycloadditions have been published
dealing with additions of diazomethane,3,4 nitrile oxides,5±7
nitrile imines,8,9 nitrones,10 and nitrile ylides.11,12 Among
increasing number of studies, only two isolated examples
of azomethine ylide cycloadditions to unsubstituted
a-methylene-g-butyrolactone could be found,13,14 despite
the fact that azomethine ylides represent one of the most
reactive and versatile classes of 1,3-dipoles and react readily
with a range of dipolarophiles forming substituted pyrro-
lidines.15 Their role in pyrrolizidine and indolizidine syn-
thesis has been reviewed recently.16,17 Since we have been
involved in a-methylene lactone chemistry for several
years, we decided to look more closely at their reactivity
in the 1,3-dipolar cycloaddition reactions with azomethine
ylides. In this paper we report our investigation of the
cycloadditions of two different azomethine ylides to )E)-
and )Z)-isomers of substituted a-methylene-g-lactones.
Azomethine ylides can be prepared by a number of methods
from more or less easy available starting materials. The
`decarboxylation route' generates them in situ by thermal
decarboxylation of mixtures of a-amino acids and alde-
hydes.18 Reactive azomethine ylides can then be trapped
by various dipolarophiles. This convenient method was
also adopted in our study using N-methylglycine )1) and
l-proline )2) which were transformed into dipoles 3 and 4
by the reactions with paraformaldehyde in boiling toluene
)Scheme 1).
A set of methylene lactone derivatives was on hand from our
previous research.19±21 Substitution at their exocyclic
double bond covered a wide range of electronic effects
offering a good opportunity of investigation of the reactivity
towards the dipoles 3 and 4. According to the general
knowledge that electron rich dipolarophiles do not undergo
Keywords: cycloadditions;methylene lactones;azomethine ylides;regio-
selectivity;stereoselectivity.
p
Corresponding author. Fax: 1420-5-41211214;
e-mail: mazal@chemi.muni.cz
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00807-9

Ï
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J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
8340
Reactivity of the dipolarophiles 5±9 towards 3 decreased in
the following order of substituents: tosyloxy.ethynyl.
2-thienyl. The )Z)-isomers were less reactive than the corre-
sponding )E)-isomers. Except for the thienyl derivatives, the
lactones used were more reactive than the unsubstituted
methylene lactone 9 )entry 9). Reaction times ranged from
2.5 h for tosylates )E)-5 and )Z)-5, having the most electron
Scheme 2.
Table 1. 1,3-Dipolar cycloadditions of dipole 3 with lactones 5±9
Entry
Lactone
R
R0
R. time )h)
Product
Yield )%)
1
2
3
4
5
6
7
8
9
)E)-5
)Z)-5
)E)-6
)Z)-6
)E)-7
)Z)-7
)E)-8
)Z)-8
9
Tosyloxy
H
2-Thienyl
H
CuCPh
H
CuCTMS
H
H
H
Tosyloxy
H
2-Thienyl
H
CuCPh
H
CuCTMS
2.5
4.0
10.0
48
4.0
6.0
4.5
6.5
8.0
10a
10b
10c
10d
10e
10f
10g
10h
10i
63
65
75
65
66
64
68
66
62
H
cycloaddition reactions with azomethine ylides,22 lactones
substituted with electron-donor groups such as amino,
alkoxy, alkyl, and aryl were indeed found to be unreactive.
On the other hand, the thermal 1,3-dipolar cycloaddition of
3 with methylene lactones 5±8 bearing suf®ciently electron
withdrawing substituents )tosyloxy, 2-thienyl, and alkynyl,
respectively) on the double bond, as well as the unsubsti-
tuted methylene lactone 9, gave corresponding cyclo-
adducts, racemic spiropyrrolidines 10, in good yield
)Scheme 2, Table 1).
de®cient double bond )entries 1 and 2), to two days for
thienyl derivative )Z)-6 )entry 4). Interestingly, 2-furyl
derivatives, which have been tested as well, were found to
be unreactive. In the reactions of propynylidene lactones
))E)-7, )E)-8, )Z)-7, and )Z)-8), the dipole 3 selectively
added to the exocyclic double bond ignoring the triple
bond;alkynyl substituted spiropyrrolidines
10e±h
were thus exclusively obtained )entries 5±8). Formation
of different diastereomers in the reactions of corresponding
geometric isomers of the lactones 5±8 indicated that the
stereochemistry of the exocyclic double bond has been
retained during the cycloaddition of the dipole 3.
Cycloaddition reactions of the azomethine ylide 4 were
studied with the same set of lactone dipolarophiles. As in
the above case, the lactones substituted by electron-donor
groups were found to be unreactive. The lactones 5±9,
however, reacted smoothly yielding a set of four different
racemic spiropyrrolizidine cycloadducts in each reaction.
The products obtained in the reactions of )E)-isomers
differed from those prepared from the corresponding )Z)-
isomers. This fact, caused by a lower symmetry of the dipole
4, is apparent from Scheme 3 where 4 adds to methylene
lactones with retention of starting con®guration of the di-
polarophile double bond. Different mutual orientations of
Scheme 3.
Table 2. 1,3-Dipolar cycloadditions of dipole 4 with lactones 5±9
Entry
Lactone
R
R0
R. time )h)
Yielda )%)
Isomer ratiob )%)
11
57
72
54
75
47
51
43
45
63
12
13
29
20
39
16
43
43
39
47
31
14
6c
a
b
c
d
e
f
g
b
i
)E)-5
)Z)-5
)E)-6
)Z)-6
)E)-7
)Z)-7
)E)-8
)Z)-8
9
Tosyloxy
H
2-Thienyl
H
CuCPh
H
CuCTMS
H
H
H
Tosyloxy
H
2-Thienyl
H
CuCPh
H
CuCTMS
2.0
3.0
6.0
15.0
4.0
5.0
3.5
4.5
9.0
60
62
68
66
62
65
70
67
60
8c
3c
5c
)4/3)
)5/4)
)6/4)
)4/3)
9
)4/3)
)5/4)
)6/4)
)4/3)
9
)5/3)
)4/2)
)5/3)
)4/2)
H
a
Overall isolated yields.
Detected in crude reaction mixtures;values in parentheses show the ratios of peaks of the minor isomers detected by GC-MS without assignment them to t he
b
structures 12 and 14.
Determined by H NMR.
c
1

Ï
J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
Â
8341
Figure 2. ORTEP representation of 11b.
corresponding regioisomers and to determine the product
ratio.
Unfortunately, similar NMR analyses of the other reaction
mixtures )entries c±i) were impossible because H10 signals
in the spectra overlapped with another signals of CH2
groups. However, as proven by GC-MS analyses, in each
reaction mixture, as expected, there were four different
compounds present with molecular weights equal to 1:1
adducts of 4 and the corresponding lactones. Of course,
this information was not suf®cient to assign the minor
peaks to the structures 12 and 14. Therefore, only peak
ratios are listed in the Table 2 at corresponding columns
)cf. note b of Table 2).
Scheme 4.
the dipole and the lactone resulted in formation of two
diastereomers of each possible regioisomer. Compounds
11 and 12 are formed by an endo and exo approach of the
dipole 4 oriented by its exocyclic methylene to exocyclic
methylene of the lactone, respectively. The pre®xes endo
and exo refer to the lactone carbonyl group. The endo and
exo approaches of 4 oriented by its exocyclic methylene
towards the annular carbon of the lactone double bond
lead then to cycloadducts 13 and 14, respectively )Scheme
3).
1
3. Assignment of con®gurations by means of H NMR
spectroscopic data
The ratios of the cycloadducts in the reaction mixtures have
been determined by 1H NMR spectroscopy )Table 2, entries
a and b) or by GC )entries c±i). The major isomers 11a±i
and 13a±i have successfully been isolated by column
chromatography on alumina and fully characterized. Our
attempts to isolate the minor isomers 12 and 14 were unsuc-
cessful;therefore, all information about their structures has
been obtained by analyses of the corresponding reaction
mixtures. Since the presence of tosyloxy group in com-
pounds 12a,b and 14a,b shifted the signals of hydrogen
1D and 2D NMR experiments have been the main tools of
elucidation of the major cycloadduct structures. The basic
differences identifying the both types of regioisomers )A vs
B, Scheme 4), the multiplicity of H10 NMR signals, have
already been mentioned. Splitting of H5 signals was an
additional feature characterizing the regioisomers. These
signals were triplets due to coupling with H6a and H6b in
the compounds of the type A, whereas an additional
coupling with H10 resulted in appearance of more complex
multiplets observed in B type regioisomers. Supporting
evidence for the B type isomers is the presence of AB
systems of H9a and H9b protons, which gave, on the
other hand, more complicated multiplets in the spectra of
the regioisomers A.
1
atoms H10 down®eld )for numbering cf. Scheme 4), H
NMR spectra have been used to analyze the reaction
mixtures in those cases. Four signals of different H10
protons have been found in the NMR spectra of each
mixture. Different shapes of the signals )dd for structures
11 and 12 vs d for 13 and 14) helped to assign them to the
Stereochemistry of the isolated cycloadducts was studied by
NOESY experiments. All major regioisomers of the type A
were found to have structure 11. Our assignment was mainly
based on positive NOE between hydrogens H5 and H3a )for
numbering cf. Scheme 4) detected in NOESY spectra of
these diastereomers. No interactions, which would support
the structure 12, were observed. The NMR based structure
assignments were also con®rmed by X-ray analyses of the
tosyloxy substituted spiropyrrolizidines 11a and 11b. )Figs.
1 and 2, respectively)
Structures of the B type major regioisomers were assigned
by means of NOE between H3a and H9b, and between H5
and H9b protons. Positive NOE detected these protons to be
located on the same side of the pyrrolizidine ring system,
Figure 1. ORTEP representation of 11a.

Ï
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J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
8342
Table 3. Dihedral angles F)H5±C5±C10±H10) calculated by AM1 and a
comparison of the vicinal coupling constants J)H5±H10) determined by
that exhibits a slightly higher reactivity than that expected
from its LUMO energy. The reason lies probably in the
lower steric demand of its less substituted double bond.
3
NMR )3Jexp) and calculated from the Karplus equation )3Jcalcd) in 13a±h
Cycloadduct
3Jexp )Hz)
F )8) )AM1)
3Jcalcd )Hz)
An examination of orbital coef®cients ciH and ciL of inter-
acting HOMO)dipole) and LUMO)dipolarophile), respec-
tively, at the reacting atoms )i) predicts, according to
second-order perturbation theory,26 the regioselectivity of
the dipole 4 cycloadditions in a good agreement with experi-
ment. The prediction failed only with propynylidene lactone
)Z)-8 but the difference was in the range of experimental
error.
13a
13b
13c
13d
13e
13f
7.3
4.7
9.9
8.7
9.6
7.1
9.9
7.0
150.9
36.3
169.7
25.2
172.4
25.5
171.6
24.5
7.4
5.2
8.9
6.6
9.1
6.6
9.0
6.7
13g
13h
which corresponded to the structure of the diastereomer 13
)Scheme 4).
Both regioisomeric approaches of the ylide 4 preferred
remarkably the endo orientation, relatively to the lactone
carbonyl, which resulted in the formation of the major
diastereomers 11 and 13. This endo selectivity could be
explained by a repulsion of methylene hydrogens of ylide
and hydrogens located in the b and g-positions of the
lactone ring in the exo transition state. The endo transition
states yielding diastereomers 11 could, moreover, be
stabilized by a weak hydrogen bond of ylide protons with
lactone carbonyl oxygen.27,28 No additional experiments or
calculations were carried out to prove this presumption,
however.
The relative con®guration of proton H10 in the major
isomers has also been obvious from NOESY spectra.
Signi®cant H10±H3b NOE interactions have been found
in all the derivatives prepared from )Z)-substituted di-
polarophiles, while H10±H6a NOEs were detected in the
cycloadducts isolated from the reactions of )E)-substituted
lactones. Different geometry of starting lactone could also
be traced with the help of vicinal spin±spin coupling
constants of protons H5 and H10 in the adducts 13a±h.
The )Z)-isomer adducts gave lower coupling constants
than the )E)-isomer. The constants are in good agreement
with those calculated from the Karplus equation23 using
dihedral angles obtained from AM1 optimized models24 of
13 )Table 3).
5. Conclusion
The results obtained in this study show that spiropyrro-
lidines and spiropyrrolizidines can be prepared in 1,3-di-
polar cycloadditions of azomethine ylides to a-methylene-
g-lactones either unsubstituted, or substituted on the double
bond with suf®ciently electron withdrawing substituents. In
these reactions, the con®guration of the dipolarophile
double bond is retained. The unsymmetrical azomethine
ylide derived from l-proline remarkably prefers the endo
access to the dipolarophile. This endo preference increases
in the reactions of )Z)-isomers of the substituted methylene
lactones. Regiochemistry of the cycloadditions is in good
agreement with semiempirical quantum chemical calcu-
lations at the AM1 level.
4. Comparison of quantum chemical results
We also compared our experimentally obtained results with
predictions based on semiempirical quantum-chemical
calculations )AM1).24 It is a generally accepted estimation
that 1,3-dipolar cycloaddition reactions of unstabilized
azomethine ylides are controlled by HOMO)dipole)±
LUMO)dipolarophile) interactions.25 Our results )Table 4)
con®rmed this, too. The calculated HOMO energy of the
ylide 4 is higher than that of 3 according to the higher
reactivity of 4 in the cycloadditions. The order of the
methylene lactone dipolarophile reactivities follows their
LUMO energies: the lower LUMO energy the higher reac-
tivity. An exception is the unsubstituted methylene lactone 9
6. Experimental
6.1. General
Table 4. HOMO and LUMO energies )EHO and ELU, respectively) of the
dipoles 3 and 4, and the dipolarophiles 5±9;absolute values of coef®cients
Melting points were obtained on a Ko¯er block and are
of the corresponding orbitals )cH and cL ) at interacting atoms i
1
i
i
uncorrected. H and 13C NMR spectra were obtained on
an Avance Bruker DRX 500 )500 MHz) and Avance Bruker
300 )300 MHz) spectrometer in deuteriochloroform with
tetramethylsilane as an internal standard. Ultraviolet spectra
were recorded on an UV±VIS spectrophotometer UV-101
Shimadzu in ethanol. IR spectra were measured on a
Genesis series FTIR, ATI Matson spectrometer in the KBr
)pellets) or neat. Elemental analyses were performed by
LACHEMA Brno. Toluene was dried by azeotropic distil-
lation and stored over sodium. Literature procedures were
used for the preparations of )E)- and )Z)-3-)tosyloxymethyl-
ene)tetrahydrofuran-2-ones.21 Commercially available
N-methyl glycine and l-proline )Aldrich) were used as
purchased, without further puri®cation.
Compound
EHO )eV)
cH
cH
ELU )eV)
cL
cL
4
1
2
3
3
4
27.12
26.88
29.81
29.94
29.31
29.18
29.29
29.01
210.06
29.93
210.80
±
0.39
±
±
±
±
±
±
±
±
0.42
±
±
±
±
±
±
±
1.16
1.06
±
±
±
±
)E)-5
)Z)-5
)E)-6
)Z)-6
)E)-7
)Z)-7
)E)-8
)Z)-8
9
21.42
21.14
21.00
20.91
21.02
20.95
20.93
20.89
20.88
0.27
0.31
0.26
0.39
0.18
0.31
0.22
0.55
0.14
0.19
0.23
0.21
0.31
0.14
0.29
0.19
0.51
0.09
±
±
±
±
For atom numbering see Schemes 1 and 3.

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J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
Â
8343
6.2. General procedure for cycloaddition of azomethine
ylide 3 to methylene lactones 5±9
60.73;H, 6.37;N, 5.90%.];
n
max)liquid ®lm) 2938, 2785,
1766, 1474, 1372, 1246, 1177, 1025, 701 cm21
;
dH)500 MHz) 7.17 )1H, dd, Jˆ4.9, 1.3 Hz, H5-thienyl),
6.97 )1H, br d, Jˆ3.6 Hz, H3-thienyl), 6.93 )1H, dd, Jˆ
4.9, 3.6 Hz, H4-thienyl), 4.17±4.07 )1H, m, OCHaHb),
4.03±3.93 )1H, m, OCHaHb), 3.71 )1H, dd, Jˆ10.9,
6.6 Hz, CH), 3.22 )1H, dd, Jˆ9.2, 6.6 Hz, CHCHaHbN),
3.06 )1H, d, Jˆ10.2 Hz, CCHaHbN), 3.03 )1H, d, Jˆ
10.2 Hz, CCHaHbN), 2.95 )1H, dd, Jˆ10.9, 9.2 Hz, CH2),
2.48 )2H, m, OCH2CH2), 2.45 )3H, s, Me); dC)75.47 MHz)
178.8, 139.2, 127.4, 126.0, 124.7, 65.4, 65.2, 62.8, 54.3,
51.2, 42.1, 37.2; lmax 309.4, 250.6 nm.
A 100 ml round bottom ¯ask, equipped with a condenser
and an air moisture-impermeable seal, was charged with
lactone )2 mmol), sarcosine )0.35 g, 4 mmol) and para-
formaldehyde )0.24 g, 8 mmol). The reaction mixture was
re¯uxed in dry toluene )60 ml) until the starting lactone was
consumed. Toluene was removed in vacuo. Residue was re-
dissolved in chloroform, the solution ®ltered to remove a
precipitate and dried over MgSO4. After ®ltration and
solvent removal at reduced pressure, the crude product
was separated by column chromatography on alumina
usually in diethyl ether )other eluents are noted below).
6.2.5. 35Rp,9Sp)-7-Methyl-9-32-phenylethynyl)-2-oxa-7-
azaspiro[4.4]nonan-1-one 310e). Yield 0.34 g )66%),
colorless oil;[Found: C, 75.06;H, 6.82;N, 5.91.
6.2.1. 35Rp,9Sp)-7-Methyl-1-oxo-2-oxa-7-azaspiro[4.4]-
non-9-yl tosylate 310a). Yield 0.41 g )63%) of a white
solid, mp 91±928C;[Found: C, 55.05;H, 6.12;N, 4.42.
C15H19NO5S requires C, 55.37;H, 5.89;N, 4.30%];LC in
dichloromethane; nmax)KBr) 2959, 2792, 1766, 1595, 1454,
1363, 1236, 1181, 1019, 819, 664, 554 cm21; dH 7.79 )2H,
d, Jˆ7.8 Hz, o-H-Ts), 7.36 )2H, d, Jˆ7.8 Hz, m-H-Ts), 5.02
)1H, dd, Jˆ6.3, 3.5 Hz, CH), 4.34 )1H, m, CH2O), 4.23 )1H,
m, CH2O), 2.89 )2H, m, CHCH2N), 2.86 )1H, m,
OCH2CHaHb), 2.81 )2H, m, CCH2N), 2.70 )3H, s, N-Me),
2.46 )3H, s, Me), 2.22 )1H, m, OCH2CHaHb);
dC)75.47 MHz) 178.4, 145.5, 132.8, 130.1, 128.0, 81.9,
66.5, 64.2, 61.0, 52.6, 41.5, 30.5, 21.7; lmax 273, 263,
226 nm.
C16H17NO2 requires C, 75.26;H, 6.71;N, 5.49%];
nmax)li-
quid ®lm) 2941, 2785, 2227, 1770, 1489, 1444, 1373, 1166,
1025, 758, 691 cm21; dH)500 MHz) 7.40±7.37 )2H, m, o-
H-Ph), 7.28±7.32 )3H, m, p,m-H-Ph), 4.46±4.40 )1H, m,
OCHaHb), 4.22±4.25 )1H, m, OCHaHb), 3.65 )1H, t, Jˆ
7.7 Hz, CH), 3.11 )1H, pt, Jˆ8.8 Hz, CHCHaHbN), 3.01
)2H, d, Jˆ9.5 Hz, CCHaHbN), 2.95±2.88 )1H, m,
OCH2CHaHb), 2.88 )1H, dd, Jˆ8.9, 7.7 Hz, CHCHaHbN),
2.65 )2H, d, Jˆ9.5 Hz, CCHaHbN), 2.40 )3H, s, Me), 2.25
)1H, m, OCH2CHaHb); dC)75.47 MHz) 180.2, 131.6, 128.4,
128.3, 122.9, 86.7, 85.4, 66.4, 65.5, 62.2, 51.5, 41.8, 38.6,
33.2; lmax 251.3, 245.1 nm.
6.2.6. 35Rp,9Rp)-7-Methyl-9-32-phenylethynyl)-2-oxa-7-
azaspiro[4.4]nonan-1-one 310f). Yield 0.33 g )64%),
colorless oil;[Found: C, 74.99;H, 6.66;N, 5.28.
C16H17NO2 requires C, 75.26;H, 6.71;N, 5.49%]; nmax
)liquid ®lm) 2940, 2911, 2789, 2227, 1768, 1487, 1448,
1372, 1175, 1024, 758, 693, 534 cm21; dH)500 MHz)
7.43±7.36 )2H, m, o-H-Ph), 7.30±7.24 )3H, m, p,m-H-
Ph), 4.45±4.26 )2H, m, CH2O), 3.25 )1H, d, Jˆ11.6 Hz,
CHCHaHbN), 3.23 )1H, d, Jˆ12 Hz, CHCHaHbN), 3.01
)1H, d, Jˆ9.9 Hz, CCHaHbN), 2.97 )1H, d, Jˆ9.9 Hz,
CCHaHbN), 2.68 )1H, dd, Jˆ11.5, 12.6 Hz, CH)
2.49±2.42 )2H, m, OCH2CH2), 2.42 )3H, s, Me);
dC)75.47 MHz) 178.5, 131.9, 128.43, 128.39 122.9, 85.5,
85.3, 65.6, 64.3, 61.8, 53.9, 41.8, 41.7, 37.9; lmax 255.1,
272.7, 279.3 nm.
6.2.2. 35Rp,9Rp)-7-Methyl-1-oxo-2-oxa-7-azaspiro[4.4]-
non-9-yl tosylate 310b). Yield 0.42 g )65%) of white
solid, mp 88±898C )petroleum ether);[Found: C, 55.28;
H, 5.83;N, 4.16. C 15H19NO5S requires C, 55.37;H, 5.89;
N, 4.30%];LC in dichloromethane; nmax)KBr) 2972, 2801,
1775, 1596, 1453, 1362, 1186, 1017, 888, 662, 558 cm21
;
dH 7.78 )2H, d, Jˆ7.8 Hz, o-H-Ts), 7.35 )2H, d, Jˆ7.8 Hz,
m-H-Ts), 4.91 )1H, t, Jˆ6.6 Hz, CH), 4.26 )2H, m, CH2O),
3.04 )1H, dd, Jˆ9.9, 6.6 Hz, CHCHaHbN), 3.02 )1H, d,
Jˆ9.6 Hz, CCHaHbN), 2.72 )1H, d, Jˆ9.5 Hz, CCHaHbN),
2.63 )1H, dd, Jˆ9.9, 6.6 Hz, CHCHaHbN), 2.44 )3H, s, Me),
2.41 )1H, m, OCH2CHaHb), 2.34 )1H, m, OCH2CHaHb),
2.33 )3H, s, NMe); dC)75.47 MHz) 175.1, 145.5, 132.9,
130.0, 128.0, 82.9, 65.1, 63.2, 60.2, 52.2, 41.7, 35.8, 21.7;
lmax 274.0, 263.4, 224.6 nm.
6.2.7. 35Rp,9Sp)-7-Methyl-9-32-trimethylsilylethynyl)-2-
oxa-7-azaspiro[4.4]nonan-1-one 310g). Yield 0.34 g
)68%), colorless oil;[Found: C, 62.08;H, 8.82;N, 5.71.
C13H21NO2Si requires C, 62.11;H, 8.42;N, 5.57%]; nmax
)liquid ®lm) 2981, 2856, 2773, 2222.6, 1776, 1577, 1436,
1389, 1253, 1175, 1126, 856, 769, 691 cm21; dH)300 MHz)
4.38±4.26 )2H, m, CH2O), 3.15 )1H, dd, Jˆ8.7, 6.7 Hz,
CHCHaHbN), 3.10 )1H, dd, Jˆ9.9, 6.0 Hz, CHCHaHbN),
3.05 )1H, d, Jˆ9.3 Hz, CCHaHbN), 2.93 )1H, d, Jˆ
9.3 Hz, CCHaHbN), 2.59 )1H dd, Jˆ10.1, 8.8 Hz, CH),
2.43±2.39 )m, 2H, OCH2CH2), 2.39 )3H, s, NMe), 0.15 )s,
9H, TMS); dC)75.47 MHz) 179.5, 105.5, 93.9, 66.4, 63.7,
62.9, 56.1, 43.1, 42.1, 33.8, 0.08; lmax 272.1, 252.0,
244.1 nm.
6.2.3.
spiro[4.4]nonan-1-one 310c). Yield 0.36 g )75%), colorless
oil;[Found: C, 60.63;H, 6.28;N, 6.12. C 12H15NO2S
35Rp,90Sp)-7-Methyl-9-32-thienyl)-2-oxa-7-aza-
requires C, 60.73, H, 6.37, N, 5.90%]; nmax)liquid ®lm)
2937, 2784, 1766, 1449, 1371, 1169, 1024, 700 cm21; dH
7.20 )1H, d, Jˆ4.9 Hz, H5-thienyl), 6.95 )1H, m, H4-thie-
nyl), 6.89 )1H, d, Jˆ3.3 Hz, H3-thienyl), 4.08 )2H, m,
CH2O), 3.88 )1H, m, CH), 3.13 )1H, m, CHCHaHbN),
3.03 )1H, m, CHCHaHbN), 2.99 )1H, d, Jˆ9.4 Hz,
CCHaHbN), 2.82 )1H, d, Jˆ9.4 Hz, CCHaHbN), 2.45 )3H,
s, Me), 2.02 )2H, m, OCH2CH2); dC)75.47 MHz) 179.4,
141.2, 125.5, 125.1, 123.8, 65.4, 65.0, 61.3, 52.6, 45.6,
40.8, 32.2; lmax 309.4, 250.6 nm.
6.2.8. 35Rp,9Rp)-7-Methyl-9-32-trimethylsilylethynyl)-2-
oxa-7-azaspiro[4.4]nonan-1-one 310h). Yield 0.33 g
)67%) colorless oil;[Found: C, 62.31;H, 8.28;N, 5.53.
6.2.4. 35Rp,90Rp)-7-Methyl-9-32-thienyl)-2-oxa-7-azaspiro-
[4.4]nonan-1-one 310d). Yield 0.30 g )65%), colorless oil;
[Found: C, 60.53;H, 6.62;N, 5.68. C 12H15NO2S requires C,

Ï
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J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
8344
C13H21NO2Si requires C, 62.11;H, 8.42;N, 5.57%]; nmax
)liquid ®lm) 2959, 2742, 2787, 2181, 1772, 1476, 1451,
1372, 1175, 1120, 843, 651 cm21; dH)300 MHz) 4.29±
4.17 )2H, m, CH2O), 3.05 )1H, dd, Jˆ8.7, 6.7 Hz,
CHCHaHbN), 2.95 )1H, dd, Jˆ10.7, 6.6 Hz, CHCHaHbN),
2.87 )1H, d, Jˆ9.9 Hz, CCHaHbN), 2.82 )1H, d, Jˆ9.9 Hz,
CCHaHbN), 2.48 )1H, dd, Jˆ10.7, 8.8 Hz, CH), 2.40±2.31
)2H, m, OCH2CH2), 2.30 )3H, s, NMe), 0.05 )9H, s, TMS);
dC)75.47 MHz) 178.3, 102.5, 89.9, 65.4, 62.5, 61.7, 54.0,
42.1, 41.8, 37.8, 0.02; lmax 276.2, 251.0, 245.2 nm.
2.55 )3H, s, Me), 2.40±2.34 )1H, m, H-3b), 1.91±1.89 )3H,
m, H-6a,b, H-7a), 1.67±1.61 )1H, m, H-7b); dC)75.47 MHz)
176.8, 145.8, 132.2, 130.1, 128.2, 85.5, 68.2, 66.4, 61.2,
54.7, 53.8, 29.3, 28.5, 25.3, 21.7; lmax 274.0, 263.4,
243.5 nm.
6.3.3.
310Rp,20Rp,7a0Sp)-2-Oxohexahydrospiro[furan-
333H),10-pyrrolizine]-20-yl tosylate 311b). Yield 0.25 g
)35%), white solid, mp 114±1168C )petroleum ether);
[Found: C, 58.31;H, 6.22;N, 4.36. C 17H21NO5S requires
C, 58.10;H, 6.02;N, 3.99%]; nmax)KBr) 2953, 2864, 2811,
1756, 1339, 1190, 1019, 1173, 1113, 999, 863, 789,
566 cm21; dH)300 MHz) 7.76 )2H, d, Jˆ7.8 Hz, o-H-Ts),
7.32 )2H, d, Jˆ7.8 Hz, m-H-Ts), 5.13 )1H, dd, Jˆ9.8,
6.9 Hz, H-10), 4.32±4.26 )1H, m, OCHaHb), 4.18±4.11
)1H, m, OCHaHb), 3.49 )1H, t, Jˆ7.7 Hz, H-5), 3.07±2.99
)2H, m, H-9b,8b), 2.94±2.89 )1H, m, H-9a), 2.68±2.61 )1H,
m, H-8a), 2.55±2.45 )1H, m, H-3b), 2.42 )3H, s, Me), 2.25±
2.18 )1H, m, H-3a), 2.05±1.97 )1H, m, H-7a), 1.90±1.82
)1H, m, H-6b), 1.82±1.73 )1H, m, H-7b), 1.68±1.58 )1H, m,
H-6a); dC)75.47 MHz) 174.2, 145.3, 133.0, 129.9, 127.8,
83.8, 69.2, 65.3, 54.7, 54.6, 54.0, 31.1, 27.6, 27.3, 21.6;
6.2.9. 7-Methyl-2-oxa-7-azaspiro[4.4]nonan-1-one 310i).
Yield 0.19 g )62%), colorless oil;[Found: C, 61.71;H,
8.62;N, 8.87. C H13NO2 requires C, 61.91;H, 8.44;N,
8
9.03%]; nmax)liquid ®lm) 2945, 2789, 1769, 1451, 1373,
1249, 1175, 1152, 1021, 683 cm21; dH)300 MHz) 4.16±
4.01 )2H, m, CH2O), 2.70 )1H, dt, Jˆ8.3, 4.4 Hz,
CHCHaHbN), 2.58 )1H, d, Jˆ9.4 Hz, CCHaHbN), 2.49
)1H, d, Jˆ9.4 Hz, CCHaHbN), 2.35 )1H, pq, Jˆ8.2 Hz,
OCH2CH2,
CHCHaHbN),
2.25±2.04
)3H,
m,
CCHaHbCH2N), 2.21 )3H, t, NMe) 1.70 )1H, dt, Jˆ12.6,
7.6 Hz, CCHaHbCH2N); dC)75.47 MHz) 181.4, 65.8, 65.2,
56.1, 48.5, 41.9, 37.9, 36.6; lmax 314.4, 244.4 nm.
l
max 274.0, 263.4, 256.8 nm.
6.3.4.
310Rp,20Rp,7a0Rp)-2-Oxohexahydrospiro[furan-
6.3. Reactions of azomethine ylide 4 with lactones 5±9
333H),20-pyrrolizine]-10-yl tosylate 313b). Yield 0.063 g
)9%), white solid, mp 166±1678C )petroleum ether);
[Found: C, 58.22;H, 5.86;N, 3.89. C 17H21NO5S requires
C, 58.10;H, 6.02;N, 3.99%]; nmax)KBr) 2979, 2822, 1759,
The general procedure for the reactions of 3 was followed
using l-proline instead. Four spiropyrrolizidine isomers
11±14 were detected in each reaction mixture. The major
isomers 11 and 13 were isolated by column chromatography
on alumina using diethyl ether as an eluent if not stated
otherwise. Reaction times and isomer ratios in the crude
reaction mixtures are given in Table 2.
1595, 1360, 1178, 1127, 1021, 901, 675, 555 cm21
;
dH)300 MHz) 7.83 )2H, d, Jˆ7.8 Hz, o-H-Ts), 7.36 )2H,
d, Jˆ7.8 Hz, m-H-Ts), 4.80 )1H, d, Jˆ4.7 Hz, H-10),
4.34±4.28 )1H, m, OCHaHb), 4.19 )1H, pseudo q, Jˆ
9.0 Hz, OCHaHb), 3.81±3.75 )1H, m, H-5), 3.23 )1H, d,
Jˆ10.2 Hz, H-9a), 3.12 )1H, d, Jˆ10.2 Hz, H-9b), 2.94±
2.88 )1H, m, H-8a), 2.64±2.58 )1H, m, H-8b), 2.38 )3H, s,
Me), 2.32±2.28 )2H, m, H-3a,b), 1.95±1.62 )4H, H-6a,b,
H-7a,b); dC)75.47 MHz) 176.5, 145.3, 133.3, 130.0, 127.9,
85.9, 71.9, 65.8, 58.4, 55.8, 54.8, 30.9, 27.9, 27.8, 21.6; lmax
273.9, 263.6, 243.3 nm.
6.3.1.
310Rp,20Sp,7a0Sp)-2-Oxohexahydrospiro[furan-
333H),10-pyrrolizine]-20-yl tosylate 311a). Yield 0.21 g
)30%), white solid, mp 102±1038C )petroleum ether);
[Found: C, 58.23;H, 6.25;N, 3.83. C 17H21NO5S requires
C, 58.10;H, 6.02;N, 3.99%]; nmax)KBr) 2965, 2943, 2868,
2809, 1762, 1598, 1369, 1188, 1019, 899, 666, 560 cm21
;
dH)500 MHz) 7.71 )2H, d, Jˆ7.8 Hz, o-H-Ts), 7.29 )2H, d,
Jˆ7.8 Hz, m-H-Ts), 5.03 )1H, dd, Jˆ4.6, 2.9 Hz, H-10),
4.28 )1H, dt, Jˆ6.4, 2.6 Hz, OCHaHb), 4.08 )1H, m,
OCHaHb), 3.62 )1H, t, Jˆ7.3 Hz, H-5), 3.11 )1H, dd, Jˆ
12.1, 4.8 Hz, H-9a), 2.97 )1H, dd, Jˆ12.1, 2.8, H-9b), 2.94
)1H, m, H-8a), 2.64 )1H, m, H-3a), 2.49 )1H, m, H-8b), 2.38
)3H, s, Me), 2.11 )1H, m, H-3b), 1.99 )3H, m, H-6a,7ab),
1.86 )1H, m, H-6b); dC)75.47 MHz) 176.5, 145.3, 133.3,
130.0, 127.9, 85.9, 71.9, 65.8, 58.4, 55.8, 54.8, 30.9, 27.9,
27.8, 21.6; lmax 274.0, 263.0, 243.0 nm.
6.3.5. 310Rp,20Rp,7a0Rp)-20-32-Thienyl)hexahydrospiro-
[furan-333H),10-pyrrolizine]-2-one 311c). Yield 0.14 g
)26%), colorless oil;[Found: C, 63.93;H, 6.13;N, 5.65.
C14H17NO2S requires C, 63.85;H, 6.51;N, 5.32%]; nmax
)liquid ®lm) 2958, 2868, 1761, 1450, 1371, 1169, 1024,
850, 701 cm21; dH)500 MHz) 7.20 )1H, d, Jˆ4.9 Hz, H5-
thienyl), 6.97±6.93 )1H, m, H4-thienyl), 6.89 )1H, d, Jˆ
3.3 Hz, H3-thienyl), 4.16±4.06 )2H, m, CH2O), 4.00 )1H, t,
Jˆ8.2 Hz, H-10), 3.66 )1H, t, Jˆ6.2 Hz, H-5), 3.35±3.27
)2H, m, H-9a,b), 3.23±3.17 )1H, m, H-8a), 2.71±2.63
)1H, m, H-8b), 2.21±2.09 )1H, m, H-3a), 2.04±1.92
)2H, m, H-3b,6a), 1.92±1.80 )3H, m, H-6b,7a,b);
dC)75.47 MHz) 178.7, 140.5, 127.0, 125.7, 124.6, 72.9,
65.5, 59.2, 56.6, 56.0, 44.9, 31.9, 29.0, 26.9; lmax
251.5, 308.0 nm.
6.3.2.
310Rp,20Sp,7a0Sp)-2-Oxohexahydrospiro[furan-
333H),20-pyrrolizine]-10-yl tosylate 313a). Yield 0.08 g
)11%), white solid. mp 77±788C )petroleum ether);
[Found: C, 57.98;H, 6.19;N, 3.92. C 17H21NO5S requires
C, 58.10;H, 6.02;N, 3.99%]; nmax)KBr) 2969, 2876, 2822,
1767, 1599, 1362, 1183, 1030, 1005, 853, 670, 557 cm21
;
6.3.6. 310Rp,20Rp,7a0Sp)-10-32-Thienyl)hexahydrospiro-
[furan-333H),20-pyrrolizin]-2-one 313c). Yield 0.12 g
)22%), colorless oil;[Found: C, 63.69;H, 6.32;N, 5.60.
C14H17NO2S requires C, 63.85;H, 6.51;N, 5.32%]; nmax
)liquid ®lm) 2957, 2869, 1763, 1449, 1374, 1181, 1099,
1024, 799, 700, 649 cm21; dH)300 MHz) 7.22 )1H, d,
dH)300 MHz) 7.71 )2H, d, Jˆ7.8 Hz, o-H-Ts), 7.30 )2H, d,
Jˆ7.8 Hz, m-H-Ts), 4.57 )1H, d, Jˆ7.6 Hz, H-10), 4.34±
4.29 )1H, m, OCHaHb), 4.29±4.23 )1H, m, OCHaHb), 3.49
)1H, dd, Jˆ12.2, 7.0 Hz, H-5), 3.25 )1H, d, Jˆ10.6 Hz,
H-9a), 3.00 )1H, d, Jˆ10.6 Hz, H-9b), 3.00±2.93 )1H, m,
H-8a), 2.90±2.84 )1H, m, H-8b), 2.73±2.67 )1H, m, H-3a),

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J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
Â
8345
Jˆ4.9 Hz, H5-thienyl), 6.97 )1H, m, H4-thienyl), 6.91 )1H,
d, Jˆ3.3 Hz, H3-thienyl), 4.16±4.04 )1H, m, OCHaHb),
3.90±3.80 )1H, m, H-10), 3.69±3.62 )1H, m, OCHaHb),
3.62 )1H, d, Jˆ10.8 Hz, H-5), 3.27 )1H, d, Jˆ9.7 Hz, H-
9a), 3.04 )1H, d, Jˆ9.7 Hz, H-9b), 3.05±2.96 )1H, m, H-8a),
2.81±2.72 )1H, m, H-8b), 2.40±2.30 )1H, m, H-3a), 2.26±
2.17 )1H, m, H-3b), 2.05±1.82 )3H, m, H-6a,b, H-7a), 1.74±
1.62 )1H, m, H-7b); dC)75.47 MHz) 179.1, 139.1, 127.4,
126.0, 124.7, 69.5, 66.0, 64.1, 56.8, 55.3, 52.7, 30.7, 29.9,
26.0; lmax 251.0, 305.5 nm.
6.3.10. 310Rp,20Rp,7a0Sp)-10-32-Phenylethynyl)hexahydro-
spiro[furan-333H),20-pyrrolizine]-2-one 313e). Yield
0.084 g )15%), colorless oil;[Found: C, 76.63;H, 6.79;N,
5.11. C18H19NO2 requires C, 76.84;H, 6.81;N, 4.98%];
n
max)liquid ®lm) 2976, 2920, 2838, 2199, 1772, 1486,
1395, 1222, 1189, 1105, 1058, 769, 681 cm21; dH)300
MHz) 7.43 )2H, m, o-H-Ph), 7.31 )3H, m, p,m-H-Ph),
4.50 )1H, dt, Jˆ6.1, 8.8 Hz, OCHaHb), 4.34 )1H, dt, Jˆ
6.1, 8.5 Hz, OCHaHb), 3.70±3.63 )1H, m, H-5), 3.26 )1H,
d, Jˆ9.9 Hz, H-9a), 3.13 )1H, d, Jˆ9.9 Hz, H-9b), 3.08±
2.99 )1H, buried m, H-8a) 3.06 )1H, d, Jˆ10.2 Hz, H-10),
2.88 )1H, ddd, Jˆ6.1, 8.2, 13.2 Hz, H-3a), 2.76 )1H, dt,
Jˆ10.5, 6.4 Hz, H-8b), 2.41±2.32 )1H, m, H-3b), 2.17±
1.81 )4H, br m, H-6a,b, H-7a,b); dC)75.47 MHz) 179.0,
132.0, 128.6, 128.5, 122.9, 85.5, 85.3, 71.1, 66.6, 64.0,
55.1, 55.0, 45.4, 31.3, 30.3, 25.4; lmax 283.1, 255.6,
240.4 nm.
6.3.7. 310Rp,20Sp,7a0Rp)-20-32-Thienyl)hexahydrospiro-
[furan-333H),10-pyrrolizine]-2-one 311d). Yield 0.21 g
)40%), colorless oil;[Found: C, 63.99;H, 6.68;N, 5.59.
C14H17NO2S requires C, 63.85;H, 6.51;N, 5.32%]; nmax
)liquid ®lm) 2937, 2869, 1758, 1451, 1374, 1291, 1214,
1171, 1027, 851, 702 cm21; dH)300 MHz) 7.16 )1H, dd,
Jˆ5.2, 1.1 Hz, H5-thienyl), 6.99 )1H, broad d, Jˆ3.2 Hz,
H3-thienyl), 6.93 )1H, dd, Jˆ3.3, 5.2 Hz, H4-thienyl), 4.02
)1H, dt, Jˆ6.4, 8.5 Hz, OCHaHb), 3.93 )1H, t, Jˆ9.6 Hz,
H-10), 3.88 )1H, t, Jˆ7.6 Hz, H-5), 3.79 )1H, dt, Jˆ6.4,
8.5 Hz, OCHaHb), 3.52 )2H, d, Jˆ9.6 Hz, H-9a,b), 3.19±
3.10 )1H, m, H-8a), 2.88 )1H, dt, Jˆ5.8, 9.4 Hz, H-8b),
2.50±2.38 )1H, m, H-3a), 2.35±2.20 )1H, m, H-3b), 2.20±
2.07 )1H, m, H-7a), 2.05±1.89 )2H, m, H-6a,7b), 1.76±1.61
)1H, m, H-6b); dC)75.47 MHz) 176.7, 137.2, 127.3, 126.4,
124.9, 73.3, 65.5, 58.4, 56.3, 54.4, 51.9, 31.8, 28.7, 27.2;
lmax 253.0, 306.5 nm.
6.3.11. 310Rp,20Sp,7a0Rp)-20-32-Phenylethynyl)hexahydro-
spiro[furan-333H),10-pyrrolizine]-2-one 311f). LC in
diethyl ether/acetone )6:1) yielded 0.15 g )26%) of white
solid, mp 36±39 8C )petroleum ether);[Found: C, 77.12;
H, 6.77;N, 4.89. C 18H19NO2 requires C, 76.84;H, 6.81;
N, 4.98%]; nmax)KBr) 2969, 2876, 2822, 1767, 1362,
1183, 1030, 1005, 853, 670, 557 cm21; dH)500 MHz)
7.40±7.35 )2H, m, o-H-Ph), 7.28±7.23 )3H, m, p,m-H-
Ph), 4.39 )1H, dt, Jˆ6.1, 8.4 Hz, OCHaHb), 4.22±4.12
)1H, m, OCHaHb), 3.67 )1H, t, Jˆ7.6 Hz, H-5), 3.45 )1H,
dd, Jˆ10.8, 6,7 Hz, H-9a), 3.39 )1H, t, Jˆ6.7 Hz, H-10),
3.29±3.15 )1H, m, H-9b), 3.02±2.92 )1H, m, H-8a), 2.75
)1H, dt, Jˆ9.0, 5.6 Hz, H-8b), 2.54±2.42 )1H, m, H-3a),
2.29±2.18 )m, 1H, H-3b), 2.13±2.00)1H, m, H-7a), 1.95±
1.78 )2H, m, H-7b,6a), 1.73±1.57 )1H, m, H-6b);
dC)75.47 MHz) 176.2, 131.8, 128.29, 128.24, 122.8, 85.1,
83.7, 72.3, 65.4, 57.8, 55.9, 54.5, 42.9, 32.8, 28.6, 27.4; lmax
274.0, 263.4, 243.5 nm.
6.3.8. 310Rp,20Sp,7a0Rp)-10-32-Thienyl)hexahydrospiro-
[furan-333H),20-pyrrolizine]-2-one 313d). Yield 0.041 g
)8%), colorless oil;[Found: C, 64.16;H, 6.46;N, 5.19.
C14H17NO2S requires C, 63.85;H, 6.51;N, 5.32%]; nmax
)liquid ®lm) 2972, 2933, 1763, 1463, 1363, 1215, 1179,
911, 531 cm21; dH)300 MHz) 7.15 )1H, dd, Jˆ1.2,
5.3 Hz, H5-thienyl), 6.90 )1H, br d, Jˆ3.5 Hz, H3-thienyl),
6.87 )1H, dd, Jˆ3.5, 5.3 Hz, H4-thienyl), 3.95±3.75 )2H, m,
OCH2), 3.91 )1H, buried d, Jˆ7.6 Hz, H-10), 3.54 )1H, d,
Jˆ9.1 Hz, H-9a), 3.49 )1H, pseudo q, Jˆ7.6 Hz, H-5), 3.47
)1H, d, Jˆ9.1 Hz, H-9b), 3.06±2.95 )1H, m, H-8a), 2.83±
2.75 )1H, m, H-8b), 2.50±2.39 )1H, m, H-3a), 2.30±2.21
)1H, m, H-3b), 2.20±2.10 )1H, m, H-7a), 1.91 )2H, m, H-6a,
H-7b), 1.78±1.66 )1H, m, H-6b); dC)75.47 MHz) 176.8,
137.9, 127.2, 126.3, 124.7, 73.6, 65.3, 58.8, 56.6, 54.5,
52.1, 32.1, 28.7, 27.4; lmax 251.5, 325.5 nm.
6.3.12. 310Rp,20Sp,7a0Rp)-10-32-Phenylethynyl)hexahydro-
spiro[furan-333H),20-pyrrolizine]-2-one 313f). Yield
0.10 g )18%), LC in diethyl ether/acetone )6:1), white
solid, mp 56±578C )petroleum ether);[Found: C, 77.09;
H, 6.95;N, 5.13. C 18H19NO2 requires C, 76.84;H, 6.81;
N, 4.98%]; nmax)KBr) 2963, 2924, 2854, 2228, 1775,
1491, 1383, 1216, 1192, 1094, 1028, 758, 693 cm21
;
dH)500 MHz) 7.45±7.41 )2H, m, o-H-Ph), 7.31±7.28 )3H,
m, p,m-H-Ph), 4.37 )2H, dd, Jˆ8.6, 5.1 Hz, CH2O), 3.90
)1H, pseudo q, Jˆ7.2 Hz, H-5), 3.36 )1H, d, Jˆ10.7 Hz,
H-9a), 3.32 )1H, d, Jˆ7.1 Hz, H-10), 3.12 )1H, d, Jˆ
10.7 Hz, H-9b), 3.13±3.09 )1H, buried m, H-8a), 3.00±
2.95 )1H, m, H-8b), 2.47±2.38 )2H, m, H-3a,b), 2.34±
2.26 )1H, m, H-6a), 2.17±2.10 )1H, m, H-7a), 1.95±1.83
)2H, m, H-6b, H-7b); dC)75.47 MHz) 176.9, 131.9, 128.4
)o,m-C-Ph), 123.1, 88.1, 85.1, 68.5, 65.3, 61.6, 56.5, 55.2,
43.2, 36.8, 28.2, 26.6; lmax 279.2, 252.3, 245.4 nm.
6.3.9. 310Rp,20Rp,7a0Rp)-20-32-Phenylethynyl)hexahydro-
spiro[furan-333H),10-pyrrolizine]-2-one 311e). Yield
0.11 g )19%), colorless oil;[Found: C, 76.59;H, 6.65;N,
4.63. C18H19NO2 requires C, 76.84;H, 6.81;N, 4.98%];
n
max)liquid ®lm) 2952, 2900, 2863, 2178, 1765, 1431,
1356, 1232, 1199, 1066, 1029, 736, 690 cm21; dH)500
MHz) 7.43±7.37 )2H, m, o-H-Ph), 7.33±7.26 )3H, m,
p,m-H-Ph), 4.44 )1H, dt, Jˆ9.1, 2.3 Hz, OCHaHb), 4.25
)1H, dt, Jˆ6.4, 9.2 Hz, OCHaHb), 3.68 )1H, t, Jˆ7.3 Hz,
H-5), 3.60 )1H, dd, Jˆ9.7, 7.0 Hz, H-10), 3.30 )1H, dd,
Jˆ7.0, 11.4 Hz, H-9a), 3.24±3.16 )1H, m, H-8a), 3.17
)1H, dd, Jˆ7.0, 11.4 Hz, H-9b), 2.88 )1H, ddd, Jˆ8.8,
10.2, 12.9 Hz, H-3a), 2.64 )1H, m, H-8b), 2.24 )1H, ddd,
Jˆ2.3, 6.4, 12.9 Hz, H-3b), 2.05±1.70 )4H, m, H-6a,b,
H-7a,b); dC)75.47 MHz) 178.2, 131.9, 128.4 )o-C and
p-C), 123.0, 85.7, 85.6 )2Cu), 73.1, 65.8, 59.4, 55.8,
37.6, 33.0, 28.8, 26.8; lmax 269.2, 255.3, 242.4 nm.
6.3.13.
310Rp,20Rp,7a0Rp)-20-32-Trimethylsilylethynyl)-
hexahydrospiro[furan-333H),10-pyrrolizine]-2-one 311g).
Yield 0.11 g )20%), LC in dichloromethane, colorless oil;
[Found: C, 64.88;H, 8.23;N, 4.89. C 15H23NO2Si requires C,
64.94;H, 8.36;N, 5.05%]; nmax)liquid ®lm) 2960.7, 2903.3,
2876.5, 2169.9, 1767.5, 1376.0, 1249.9, 1026.1, 843.9,
761.0 cm21; dH)500 MHz) 4.45 )1H, dt, Jˆ9.1, 2.6 Hz,
OCHaHb), 4.27 )1H, dt, Jˆ6.4, 9.6 Hz, OCHaHb), 3.94

Ï
Â
J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
8346
Table 5. Crystallographic data and re®nement parameters of 11a and 11b
Parameters
11a
C12H21NO5S
351.41
150)2)
0.71073
11b
C12H21NO5S
351.41
150)2)
0.71073
Triclinic, P-1
0.50£0.30£0.20
6.521)1)
11.093)2)
11.761)2)
108.82)3)
90.03)3)
Empirical formula
Formula mass
Temperature )K)
Wavelength )A)
Crystal system, space group
Ê
Monoclinic, C2/c
0.50£0.40£0.40
Crystal size )mm)
Ê
a )A)
Ê
22,849)5)
12.642)2)
b )A)
Ê
c )A)
11.573)2)
90
97.05)2)
90
3317.7;8
1.407
0.222
1488
a )8)
b )8)
g )8)
95.10)3)
801.7
1.236
0.210
1488
Ê 3
Volume )A ); Z
)
D )g cm23
Absorption coef®cient )mm21
F000 )e)
)
Q range for data collection )8)
Range of hkl
Re¯ections collected/independent
Completeness Qˆ25.07 )%)
Re®nement method
2.48±25.07
227!26, 215!0, 0!13
2.48±25.07
0!7, 212!12, 213!13
3091/216
3105/2943
47.6
Full-matrix least-squares on F2
2943/302
0.988
Number of data/parameters
Goodness-of-®t on F2
1908/302
1.140
Final R indices [I.2s)I)]
R indices )all data)
Largest diff. peak and hole )e A )
R1ˆ0.0375, WR2ˆ0.0935
R1ˆ0.0598, WR2ˆ0.1058
0.350 and 20.344
R1ˆ0.0433
R1ˆ7.05
Ê 3
0.41 and 20.81
)1H, t, Jˆ7.3 Hz, H-5), 3.58±3.46 )2H, m, H-10, H-8a),
3.40±3.23 )2H, m, H-9a,b), 2.88±2.68 )2H, m, H-3a,8b),
2.38 )1H, ddd, Jˆ2.6, 6.4, 13.2 Hz, H-3b), 2.11±1.81
)4H, buried m, H-6a,b, H-7a,b), 0.15 )9H, s, TMS);
dC)75.47 MHz) 176.6, 99.7, 92.3, 72.9, 66.0, 58.2, 56.1,
54.5, 37.9, 32.0, 28.2, 26.6, 0.06; lmax 247.2, 292.3 nm.
0.13 )9H, s, TMS); dC)75.47 MHz) 176.1, 102.0, 88.9, 72.3,
65.8, 57.8, 56.1, 54.6, 43.6, 32.9, 28.8, 27.3, 0.08; lmax
247.4, 299.4 nm.
6.3.16.
310Rp,20Sp,7a0Rp)-10-32-Trimethylsilylethynyl)-
hexahydrospiro[furan-333H),20-pyrrolizine]-2-one 313h).
Yield 0.12 g )21%), LC in dichloromethane, white solid, mp
94±968C )petroleum ether);[Found: C, 65.09;H, 8.61;N,
4.98. C15H23NO2Si requires C, 64.94;H, 8.36;N, 5.05%];
6.3.14.
310Rp,20Rp,7a0Sp)-10-32-Trimethylsilylethynyl)-
hexahydrospiro[furan-333H),20-pyrrolizine]-2-one 313g).
Yield 0.078 g )14%), LC in dichloromethane, colorless oil;
[Found: C, 65.13;H, 8.62;N, 5.29. C 15H23NO2Si requires C,
n
max)KBr) 2959, 2922, 2868, 2175, 1775, 1482, 1251, 1029,
843, 716 cm21; dH)300 MHz) 4.31 )2H, dt, Jˆ1.0, 6.4, Hz,
OCH2), 3.78 )1H, pseudo q, Jˆ7.3 Hz, H-5), 3.27 )1H, d,
Jˆ11.0 Hz, H-9a), 3.11 )1H, d, Jˆ7.3 Hz, H-10), 3.08±3.02
)1H, buried m, H-8a), 2.04 )1H, d, Jˆ11.0 Hz, H-9b), 2.99±
2.92 )1H, m, H-8b), 2.37±2.33 )2H, m, H-3a,b), 2.25±2.16
)1H, m, H-7a), 2.12±2.03 )1H, m, H-7b), 1.86±1.78 )2H, m,
H-6a,b), 016 )9H, s, TMS); dC)75.47 MHz) 176.9, 101.9,
92.9, 68.4, 65.3, 61.6, 55.8, 55.2, 43.8, 36.9, 28.0, 22.3,
20.04; lmax 292.0, 247.7 nm.
64.94;H, 8.36;N, 5.05%];
2871, 2174, 1774, 1452, 1261, 1097, 1028, 801 cm21
nmax)liquid ®lm) 2962, 2903,
;
dH)300 MHz) 4.42 )1H, dt, Jˆ6.4, 8.5 Hz, OCHaHb), 4.29
)1H, dt, Jˆ6.0, 8.5 Hz, OCHaHb), 3.60±3.51 )1H, m, H-5),
3.21 )1H, d, Jˆ9.9 Hz, H-9a), 3.04±2.96)1H, buried m,
H-8a), 3.00 )1H, d, Jˆ9.9 Hz, H-9b), 2.89 )1H, d, Jˆ
9.6 Hz, H-10), 2.83±2.67 )2H, m, H-3a, H-8b), 2.37±2.25
)1H, m, H-3b) 2.12±1.73 )4H, m, H-6a,b, H-7a,b) 0.15 )9H,
s, TMS); dC)75.47 MHz) 179.0, 102.0, 90.4, 71.1, 66.6,
64.1, 55.1, 54.8, 45.6, 31.2, 30.1, 25.3, 0.2; lmax 249.2,
260.6 nm.
6.3.17.
310Rp,7a0Rp)-Hexahydrospiro[furan-333H),10-
pyrrolizine]-2-one 311i). Yield 0.09 g )25%), LC in di-
chloromethane/diethyl ether )1:4), colorless oil;[Found:
C, 66.19;H, 8.25;N, 7.46. C 10H15NO2 requires C, 66.27;
6.3.15.
310Rp,20Sp,7a0Rp)-20-32-Trimethylsilylethynyl)-
hexahydrospiro[furan-333H),10-pyrrolizine]-2-one 311h).
LC in dichloromethane yielded 0.12 g )21%) of white solid,
mp 51±538C )petroleum ether);[Found: C, 64.68;H, 8.22;
N, 5.38. C15H23NO2Si requires C, 64.94;H, 8.36;N, 5.05%];
H, 8.34;N, 7.73%]; nmax)liquid ®lm) 2955, 2780, 1772,
1431, 1352, 1249, 1195, 1149, 1028, 693 cm21; dH)300
MHz) 4.34±4.27 )1H, m, OCHaHb), 4.11 )1H, pseudo q,
8.8 Hz, OCHaHb), 3.45 )1H, t, Jˆ7.3 Hz, H-5), 3.13 )1H,
dt, Jˆ10.8, 6.6 Hz, H-9a), 3.07±3.03 )1H, m, H-8a), 2.97
)1H, dt, Jˆ10.8, 6.6 Hz, H-9b), 2.63 )1H, dt, Jˆ6.1, 9.0 Hz,
H-8b), 2.35 )1H, dt, Jˆ12.7, 6.6 Hz, H-10a), 2.29 )2H, dd,
Jˆ8.1, 5.6 Hz, H-3a,b), 2.01±1.94 )1H, m, H-6a), 1.89 )1H,
dt, Jˆ12.7, 6.6 Hz,H-10b), 1.85±1.75 )2H, m, H-6b, H-7a),
1.70±1.62 )1H, m, H-7b); dC)75.47 MHz) 179.6, 73.2, 65.5,
55.0, 53.4, 51.6, 36.5, 36.3, 28.4, 27.3; lmax 312.4,
251.4 nm.
n
max)KBr) 2959, 2913, 2870, 2172, 1767, 1450, 1249, 1173,
1106, 1035, 845, 760 cm21; dH)500 MHz) 4.38 )1H, dt,
Jˆ6.7, 8.5 Hz, OCHaHb), 4.17 )1H, dt, Jˆ5.9, 8.5 Hz,
OCHaHb), 3.64 )1H, t, Jˆ7.6 Hz, H-5), 3.37±3.25 )2H, m,
H-10, H-9a) 3.15 )1H, dd, Jˆ10.5, 7.3 Hz, H-9b), 3.02±2.95
)1H, m, H-8a), 2.80±2.72 )1H, m, H-8b), 2.50±2.39 )1H, m,
H-3a), 2.31±2.20 )1H, m, H-3b), 2.15±2.02 )1H, m, H-7a),
1.96±1.80 )2H, m, H-6b, H7a), 1.73±1.60 )1H, m, H-6b)

Ï
J. Castulõk et al. / Tetrahedron 57 42001) 8339±8347
Â
8347
320Rp,7a0Sp)-Hexahydrospiro[furan-333H),20-
Æ
3. Jonas, J.;Gøowiak, T.;Z ak, Z.;Trs ka, P.;Mazal, C. Collect.
Â
Ï
6.3.18.
Czech. Chem. Commun. 1991, 56, 973±983.
4. Otto, A.;Ziemer, B.;Liebscher, J. Synthesis 1999, 965±972.
pyrrolizine]-2-one 313i). Yield 0.025 g )7%), LC in
dichloromethane/diethyl ether )1:4), colorless oil;[Found:
C, 66.21;H, 8.35;N, 7.53. C 10H15NO2 requires C, 66.27;H,
8.34;N, 7.73%]; nmax)liquid ®lm) 2900, 2760, 1759, 1390,
1323, 1220, 1210, 1170, 1018, 685 cm21; dH)500 MHz)
4.39±4.30 )1H, m, OCHaHb), 4.22 )1H, pseudo q, Jˆ
8.1 Hz, OCHaHb), 3.56±3.48 )1H, m, H-5), 3.17 )1H, d,
Jˆ9.1 Hz, H-9a), 3.11±3.03 )1H, m, H-8a), 2.91 )1H, d,
Jˆ9.1 Hz, H9b), 2.66±2.58 )1H, m, H-8b), 2.37±2.30
)1H, m, H-10a), 2.30±2.22 )2H, m, H-3a,b), 1.97±1.90
)1H, m, H-6a), 1.85±1.77 )1H, m, H-10b), 1.72±1.56 )3H,
m, H-6b, H-7a,b); dC 178.2, 74.6, 64.8, 54.0, 52.8, 50.6,
36.4, 36.1, 28.0, 26.9; lmax 320, 258 nm.
Ï
Æ
Â
Â
5. Stverkova, S.;Z ak, Z.;Jonas, J. Liebigs Ann. Chem. 1993,
1169±1173.
6. Pereira, S. M.;Savage, G. P.;Simpson, G. W.;Greenwood,
R. J.;Mackay, M. F. Aust. J. Chem. 1993, 46, 1401±1412.
Â
Ï
7. Micuch, P.;Fis era, L.;Ondrus , V.;Ertl, P. Molecules 1997, 2,
Ï
57±61.
Ï
Æ
Â
Â
8. Stverkova, S.;Z ak, Z.;Jonas, J. Liebigs Ann. Chem. 1995,
477±480.
9. Dunstan, J. B. F.;Elsey, G. M.;Russel, R. A.;Savage, G. P.;
Simpson, G. W.;Tiekink, E. R. T. Aust. J. Chem. 1998, 51,
499±509.
10. de March, P.;Figueredo, M.;Font, J. Heterocycles 1999, 50,
1213±1226.
6.4. X-Ray crystallographic study
11. de March, P.;el Arrad, M.;Figueredo, M.;Font, J.
Tetrahedron 1998, 54, 11613±11622.
Crystals of 11a and 11b suitable for X-ray analysis were
obtained by a careful recrystallization from diethyl ether.
Experimental data were collected with a KUMA K4 kappa-
axis four-circle diffractometer with graphite-monochroma-
tized radiation. The data were corrected for Lp factor but no
absorption correction was applied. The structures were
solved by a direct method in a straightforward manner.
The H atoms were placed in calculated positions with the
temperature factors 1.2Ueq of the parent atoms and re®ned
by using a `ride-on' model. The structures were solved and
re®ned using the SHELX9729 program system and the
drawings were prepared by ORTEP.30 Crystal data and
other details concerning the data collection are summarized
in Table 5.
Ï
12. Castulõk, J.;Jonas, J.;Mazal, C.
Â
Collect. Czech. Chem.
Commun. 2000, 65, 708±716.
13. Yates, N. D.;Peters, D. A.;Allway, P. A.;Beddoes, R. L.
Heterocycles 1995, 40, 331±347.
14. Jenkins, S. M.;Wadsworth, H. J.;Bromidge, S. J. Med. Chem.
1992, 35, 2392±2406.
15. Padwa, A. Comprehensive Organic Synthesis;Trost, B. H.,
Flemming, W., Eds.;Pergamon: Oxford, 1991;Vol. 4, p. 1085.
16. Broggini, G.;Zecchi, G. Synthesis 1999, 905±917.
17. Subramaniyan, G.;Raghunathan, R. Tetrahedron 2001, 57,
2909±2913.
18. )a) Grigg, R.;Surendrakumar, S.;Thianpatamagul, S.;
Vipond, D. J. Chem. Soc., Perkin Trans. 1 1988, 2693±
2701. )b) Grigg, R.;Iddle, J.;McMeekin, P.;Vipond, D.
J. Chem. Soc., Perkin Trans. 1 1988, 2703±2713. )c) Tsuge,
O.;Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231±349.
19. Mazal, C.;Jurka, Z.;Jonas, J. Collect. Czech. Chem. Commun.
1984, 49, 2509±2519.
Crystallographic data )excluding structure factors) for the
structures 11a and 11b in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 162247 and 162248,
respectively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1 EZ, UK [fax: 144 )0) 1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Ï
Â
20. Castulõk, J.;Mazal, C. Tetrahedron Lett. 2000, 41, 2741±
2744.
21. Jonas, J. Collect. Czech. Chem. Commun. 1984, 49, 1907±
1913.
22. Lown, J. W. 1,3-Dipolar Cycloaddition Chemistry;Padwa, A.,
Ed.;Wiley: New York, 1984;Vol. 1 Chapter 6.
23. Karplus, M. J. Chem. Phys. 1959, 30, 11.
24. AM1 calculations were performed by MOPAC software
package.
Acknowledgements
Authors are indebted to Professor J. Jonas for the attention
he paid to this work. We thank Dr O. Humpa for NMR
measurements. This work was supported by grant no. 391/
99 from The Fund of the Development of Universities.
25. Padwa, A.;Dent, W. J. Org. Chem. 1987, 52, 235±244.
26. Salem, L. J. Am. Chem. Soc. 1968, 90, 543±552.
27. Domingo, L. R. J. Org. Chem. 1999, 64, 3922±3929.
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2000, 33, 658±664.
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