Selective ring contraction of 5-spirocyclopropane isoxazolidines mediated by acids

Article abstract of DOI:10.1021/jo034003g

Thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines 16, 18-21, 33, 34, 38a, and 61, in the presence of a protic acid at 70-110 °C, yielded 3,4-cis ring-fused azetidin-2-ones 22-26, 41, 42, 46, and 62 with concomitant extrusion of ethylene

Full text of DOI:10.1021/jo034003g

Selective Rin g Con tr a ction of 5-Sp ir ocyclop r op a n e Isoxa zolid in es
Med ia ted by Acid s
Franca M. Cordero,*,† Federica Pisaneschi,† Maria Salvati,† Valentina Paschetta,†
J ean Ollivier,‡ J acques Salau¨n,*,‡ and Alberto Brandi*,†
Dipartimento di Chimica Organica “Ugo Schiff”, Universita` degli Studi di Firenze, via della Lastruccia
13, I-50019 Sesto Fiorentino (Fi), Italy, and Laboratoire des Carbocycles (CNRS), Institut de Chimie
Mole´culaire et des Mate´riaux d’Orsay, Baˆt. 420, Universite´ de Paris-Sud, 91405 Orsay, France
franca.cordero@unifi.it
Received J anuary 2, 2003
Thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines 16, 18-21, 33, 34, 38a , and
61, in the presence of a protic acid at 70-110 °C, yielded 3,4-cis ring-fused azetidin-2-ones 22-26,
41, 42, 46, and 62 with concomitant extrusion of ethylene, in good yields. So far, the collected
evidences strongly support a mechanism started by a homolytic cleavage of the protonated N-O
bond for the rearrangement of 5-spirocyclopropane isoxazolidines to â-lactams. Some different
competitive pathways can then follow depending on the stability or the stereoelectronic properties
of cationic diradical intermediates. The two-step process, intramolecular 1,3-dipolar cycloaddition/
thermal rearrangement under acidic conditions, represents a general synthesis of a new class of
3,4-cis-fused bicyclic azetidin-2-ones starting from easily available compounds such as amino acids,
hydroxy acids, and dicarbonyl or amino alcohol derivatives.
SCHEME 1
In tr od u ction
5-Spirocyclopropane isoxazolidines 1 can be easily
synthesized by 1,3-dipolar cycloaddition of nitrones and
methylenecyclopropane derivatives1 and are character-
ized by a unique reactivity caused by the presence of the
strained three-membered ring spiro-fused on the adjacent
position of the weak N-O bond. Isoxazolidines 1 undergo
a thermally induced ring expansion to tetrahydropyridin-
4-ones 4 through a homolytic cleavage of the N-O bond,
followed by the opening of the cyclopropane ring and
formation of the relatively more stable oxoethyl diradical
3. The intermediate 3 can then evolve to 4 by radical ring
closure (Scheme 1).2,3
substituted piperidines including indolizidine and quino-
lizidine alkaloids.1a,5
We report here a new specific behavior of 5-spirocy-
clopropane isoxazolidines 1. In particular, cycloadducts
1 can be selectively converted into â-lactam derivatives
through ring contraction and concomitant extrusion of
ethylene by heating at 70-110 °C in the presence of a
protic acid.6
The temperature necessary to trigger the rearrange-
ment in solution phase usually ranges from 110 to 180
°C, except for N-aryl-substituted 5-spirocyclopropane
isoxazolidines which undergo the N-O cleavage also at
room temperature.4 The two-step process 1,3-dipolar
cycloaddition/thermal rearrangement has been success-
fully applied to the synthesis of several selectively
Resu lts a n d Discu ssion
Recently, new tri- and tetracyclic spirocyclopropane
isoxazolidines 8 were prepared starting from the 1-vin-
ylcyclopropyl tosylate (5), which underwent Pd0-cata-
lyzed nucleophilic substitution of R-amino and R-hydroxy
* To whom correspondence should be addressed. Fax: +39 055
4573531//+33 1 69156278.
(5) (a) Cordero, F. M.; Brandi, A.; Querci, C.; Goti, A.; De Sarlo, F.;
Guarna, A. J . Org. Chem. 1990, 55, 1762-1767. (b) Brandi, A.; Du¨ru¨st,
Y.; Cordero, F. M.; De Sarlo, F. J . Org. Chem. 1992, 57, 5666-5670.
(c) Cordero, F. M.; Anichini, B.; Goti A.; Brandi, A. Tetrahedron 1993,
49, 9867-9876. (d) Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi, A.
Tetrahedron Lett. 1994, 35, 949-952. (e) Brandi, A.; Cicchi, S.; Cordero,
F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J . Org. Chem. 1995,
60, 6806-6812. (f) Cordero, F. M.; Brandi A. Tetrahedron Lett. 1995,
36, 1343-1346. (g) Machetti, F.; Cordero, F. M.; De Sarlo, F.; Guarna,
A.; Brandi, A. Tetrahedron Lett. 1996, 37, 4205-4208.
(6) For preliminary communications, see: (a) Cordero,F. M.; Pisan-
eschi, F.; Goti, A.; Ollivier, J .; Salau¨n, J .; Brandi, A. J . Am. Chem.
Soc. 2000, 122, 8075-8076. (b) Paschetta, V.; Cordero, F. M.; Paugam,
R.; Ollivier, J .; Brandi, A.; Salau¨n, J . Synlett 2001, 1233-1236.
† Universita` degli Studi di Firenze.
‡ Universite` de Paris-Sud.
(1) (a) Brandi, A.; Garro, S.; Guarna, A.; Goti, A.; Cordero, F.; De
Sarlo, F. J . Org. Chem. 1988, 53, 2430-2434. (b) For a review, see:
Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr. Chem. 1996, 178, 1-97.
(2) Brandi, A.; Cordero, F. M.; Goti, A.; De Sarlo, F.; Guarna, A.
Synlett 1993, 1, 1-8.
(3) For a theoretical study of the rearrangement mechanism, see:
Ochoa, E.; Mann, M.; Sperling, D.; Fabian, J . Eur. J . Org. Chem. 2001,
4223-4231.
(4) (a) Cordero, F. M.; Goti, A.; De Sarlo, F.; Guarna, A.; Brandi, A.
Tetrahedron 1989, 45, 5917-5924. (b) Cordero, F. M.; Barile, I.; De
Sarlo, F.; Brandi, A. Tetrahedron Lett. 1999, 40, 6657-6660.
10.1021/jo034003g CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003
J . Org. Chem. 2003, 68, 3271-3280
3271

Cordero et al.
SCHEME 2
SCHEME 3
acid derivatives to afford exclusively alkylidenecyclopro-
panes 6. The esters 6 were easily converted into the
corresponding nitrones 7 which spontaneously evolved
to 8 (Scheme 2).7
Alternatively, the treatment of 5 with diethylzinc, in
the presence of a catalytic amount of Pd0, afforded the
zinc complex 11,8 which underwent selective electrophilic
addition of aldehyde 12 to give alkylidenecyclopropane
13. This process represents a nice example of “umpolung
of reactivity”9 for the synthesis of alkylidenecyclopro-
panes. After acetylation and hydrolysis of the acetal
moiety, aldehyde 14 was treated with N-methylhydrox-
ylamine to generate the alkylidenecyclopropane nitrone
15, which underwent intramolecular cycloaddition to give
an equimolecular mixture of diastereomers exo-16a and
endo-16b (Scheme 3).6b As in the previous examples,7 the
presence of the short three-atom chain between the two
reacting sites affected the cycloaddition mode by dis-
favoring the formation of bridged regioisomeric cyclo-
adducts.
SCHEME 4
The assignment of the relative configuration of adducts
1
exo-16a and endo-16b was based on the H NMR reso-
nances of 5-H. In particular, 5-H in exo-16a (δ ) 5.28
ppm, quintet, J ) 4.7 Hz) has a downfield chemical shift
with respect to the corresponding proton in endo-16b
(δ ) 4.97 ppm, quintet, J ) 6.5 Hz) in accord with the
more congested endo position. The structural assignment
was confirmed by the analysis of the NOESY spectrum
of endo-16b which exhibited a correlation between 5-H
(δ ) 4.97 ppm) and the hydrogen atoms of the bridge
3a-H (δ ) 2.87-2.75 ppm) and 6a-H (δ ) 3.59-3.55 ppm).
The adducts exo-8, exo-16a , and endo-16b rearranged
into the corresponding pyridones by simple heating in
refluxing xylenes (Schemes 2 and 3). In particular, each
adduct exo-87 gave the exo-9 as a unique product. On the
contrary, both isoxazolidines exo-16a and endo-16b were
converted into a mixture of two diastereomeric pyridones
exo-17a and endo-17b in a 5.4:1 ratio (63%) and a 1:5.5
ratio (26%), respectively. The epimerization at C-6 likely
occurred during the rearrangement process as the iso-
lated exo-17a and endo-17b did not interconvert under
the rearrangement reaction conditions. In contrast to
unsubstituted octahydro-1-methyl-4H-cyclopenta[b]py-
ridin-4-one5f and some octahydro-1H-pyrrolo[3,4-b]pyri-
din-4-ones,10 pyridones 17 do not seem to isomerize to
the corresponding trans-fused compounds.
The thermal behavior of 5-spirocyclopropane isoxazo-
lidines, after protonation, was completely different.6 The
enantiopure compounds exo-18-20 and the racemic 21
in the presence of trifluoroacetic acid (TFA) underwent
a clean reaction at 70-110 °C to afford 6-azabicyclo[3.2.0]-
heptan-7-ones 22-25 with conservation of the relative
and absolute configuration (Scheme 4).6 Under the same
conditions, both exo-16a and endo-16b were converted
into a diastereomeric mixture of exo-26a and endo-26b
in a 1.6:1 ratio (96%) and a 1:2 ratio (82%), respectively.11
Analogously to the products of the rearrangement in
neutral conditions, such as exo-17a and endo-17b, both
the isolated â-lactams exo-26a and endo-26b were stable
under the reaction conditions. An explanation of this
epimerization of acetates is not available at the moment.
(7) (a) Estieu, K.; Paugam, R.; Ollivier, J .; Salau¨n, J .; Cordero, F.
M.; Goti, A.; Brandi, A. J . Org. Chem. 1997, 62, 8276-8277. (b) Ferrara,
M.; Cordero, F. M.; Goti, A.; Brandi, A.; Estieu, K.; Paugam, R.; Ollivier,
J .; Salau¨n, J . Eur. J . Org. Chem. 1999, 2725-2739.
(8) Ollivier, J .; Girard, N.; Salau¨n, J . Synlett 1999, 1539-1542.
(9) Seebach, D. Angew. Chem. 1979, 91, 259-278; Angew. Chem.,
Int. Ed. Engl. 1979, 18, 239.
(10) Pisaneschi, F.; Cordero, F. M.; Goti, A.; Paugam, R.; Ollivier,
J .; Brandi, A.; Salau¨n, J . Tetrahedron: Asymmetry 2000, 11, 897-909.
(11) An equimolecular mixture of exo-16a and endo-16b was con-
verted in equimolecular amounts of exo- and endo-â-lactams in only
63% yield under the same reaction conditions (TFA, CH3CN, reflux
temperature, 15 min).
3272 J . Org. Chem., Vol. 68, No. 8, 2003

Ring Contraction of 5-Spirocyclopropane Isoxazolidines
SCHEME 5
SCHEME 6
selectivity and in good yields (64-98%). In the last case,
the use of a tertiary amine as a base allowed to carry
out the reaction in the presence of the unprotected
hydroxyl group. The alkylidenecyclopropanes 29, 30, and
36 were converted into the corresponding aldehydes 31,
32, and 37 and then treated with N-methylhydroxyl-
amine to generate the nitrone moiety, which underwent
the intramolecular 1,3-dipolar cycloaddition. The cis-
fused cycloadducts 33 and 34 were obtained at 110 °C in
high yields (90-91%) and with complete control of regio-
and stereochemistry. The nitrone derived from 37 reacted
at room temperature and produced a mixture of adducts
38a ,b and the bridged-regioisomer 39 in 8:3:1 ratio and
59% overall yield (Scheme 5). Major compound 38a was
assigned the cis ring fusion on the basis of the bridged
hydrogen coupling constant value (J H-H ) 4.6 Hz com-
pared to J H-H ) 11.4 for 38b). The higher selectivity
showed by the aromatic compounds can be ascribed to
the lower flexibility inferred by the aromatic ring to the
four-atom chain linking the two reactive sites.
The thermal behavior of 5-spirocyclopropane isoxazo-
lidines 33, 34, and 38a ,b was studied either in neutral
and acidic conditions.
Compounds exo-22, exo-23, rac-25, exo-26a , and endo-
26b could be easily purified and were obtained in fair
yield after chromatography on silica gel. Unfortunately,
the tricylic lactam exo-24 could be only partially purified
by treatment with Dowex 50WX8-200 ion-exchange resin
or by reversed-phase HPLC, although its structure could
be fully determined by spectroscopical means. â-Lactams
22-25 and 26a ,b were characterized by distinctive
spectral data such as IR stretching (νCO ) 1740-1756
cm-1) and 13C NMR resonances (δCO ) 170.7-165.4 ppm).
Furthermore, the values of the coupling constants be-
tween vicinal C-H were consistent with the depicted
stereochemistry (22, 23, 25, 26: H1-H5 J ) 3.5-4.0 Hz;
22, 23: H4-H5 J ) 0 Hz; 24: H2a-H6a J ) 3.9 Hz and
The adducts 33 and 34 failed to give pyridones 40 by
heating (Scheme 6) up to 120 °C where they proved to
be stable, but decomposed at higher temperatures. On
the contrary, the cis- and trans-fused isoxazolidines 38a
and 38b underwent the usual rearrangement by heating
in refluxing xylenes, and both afforded the thermo-
dynamically more stable trans-fused bicyclic ketone 45
in 40 and 38% yield, respectively (Scheme 7).
A rather different behavior was observed in acidic
conditions. The tetracyclic isoxazolidines 33 and 34
underwent a clean reaction at 110 °C in the presence of
a small excess of TFA. Under these conditions, the cis-
fused â-lactams 41 and 42 were obtained in good yields
(60-72%) by ring contraction and loss of ethylene (Scheme
6). The same reaction occurred by heating 33 and 34 in
toluene in the presence of p-toluenesulfonic acid (TsOH)
or in refluxing ethanol with HCl or on treating directly
the aldehydes 31 and 32 with MeNHOH‚HCl in refluxing
ethanol in absence of triethylamine. It has to be stressed
that all these reactions had to be carried out in strictly
anhydrous conditions; otherwise, a 2:1 mixture of â-lac-
tams 41, 42 and ethyl ketones 43, 44 were obtained when
traces of H2O were present.
H
2a-H2b J ) 0 Hz). The optical purity of 22 and 23 was
ascertained by 1H NMR analysis in the presence of
increasing amount of Eu(hfc)3.
Finally, the exact structure of the C2 fragment, elimi-
nated in the acid-induced reorganization of 5-spirocyclo-
propane isoxazolidines, was unequivocally established by
1
analyzing the H NMR spectra of the CD3CN solution of
protonated 18-21 after heating at 70 °C. In particular,
the presence of the intense singlet at 5.41 ppm, besides
the â-lactam 22-25 signal set, was a clear evidence of
ethylene formation during the reaction.
The same strategy previously used to prepare the
spirofused isoxazolidines 18-21 was applied to the
syntheses of their superior homologues 33, 34, and 38a ,b,
starting from the anthranilic acid derivatives 27 [Z )
2-nitrobenzenesulfonyl (Ns)], 28 [Z ) Tosyl (Ts)], and the
amino alcohol 35, respectively (Scheme 5).
The Pd0-catalyzed nucleophilic substitution of 5 oc-
curred either with 27, 28, or 35 with complete regio-
The structures of 41 and 42 were unambiguously
established as for 22-25 and 26a ,b from spectroscopic
J . Org. Chem, Vol. 68, No. 8, 2003 3273

Cordero et al.
SCHEME 7
SCHEME 8
SCHEME 9
data. Especially diagnostic were IR stretching νCO (1750
and 1752 cm-1 for 41 and for 42, respectively), 13C NMR
resonances δCO (166.2 and 166.9 ppm for 41 and for 42,
1
respectively), and H NMR resonances of H8b (δ ) 4.45
ppm, d, J ) 5.1 Hz for 41 and δ ) 4.29 ppm, d, J ) 5.1
Hz for 42).
The two isomeric cis- and trans-fused isoxazolidines
38a and 38b showed a different thermal behavior in the
presence of TFA. In particular, the cis isomer 38a was
converted into the corresponding â-lactam 46 in high
yields (87%) (46: δCO ) 168.3 ppm; νCO ) 1754 cm-1),
while the isomer 38b failed to give the more strained
trans-fused bicyclic azetidin-2-one and underwent a
different rearrangement to a new ketone to which the
structure of 1,6-naphthyridinone 47 was assigned (Scheme
7). The bicyclic ketone 47 is clearly a structural isomer
of 45, the rearrangement product in neutral conditions,
with a methyl group shifted from N-1 (in 45) to C-3 (in
47). Compound 47 was recovered as a TFA salt after
In a preliminary attempt to rationalize the mechanism
of â-lactam formation from 5-spirocyclopropane isoxazo-
lidines 1, the possible involvement of piperidin-4-ones 4,
as reaction intermediates, was examined and discarded
when proved that they are stable under the acidic
rearrangement conditions.
The protonation of the isoxazolidine nitrogen atom,
unequivocally demonstrated by the significant downfield
1
shift of signals in the H NMR spectra of adducts 1 in
1
the presence of protic acids, must be the initial step of
the formation of â-lactams 53. The protonated isoxazo-
lidine 48, then, undergoes a thermally induced cleavage
of the weak protonated N-O bond that might occur either
in a homo- (Scheme 9, path A) or in a heterolytic (Scheme
9, path B) mode.
chromatography on silica gel, and the H NMR spectrum
showed the R-carbonyl protons of 47‚TF A were lacking
probably for a rapid keto-enolic exchange under the
acidic conditions. The free ketone 47 could be obtained
by treatment with a basic ion-exchange resin. The
12
synthesis of the trideuteriomethyl derivative 38b-d 3
In the first hypothesis,13 the diradical cation 49 could
evolve to the relatively more stable ionic diradical 50, in
analogy to the process in neutral condition. The lack of
any trace of tetrahydropyridones in acidic conditions
could be explained by the formation of a strong intra-
molecular hydrogen bond in 50 that should prevent the
radical ring closure to piperidone 52. At the same time,
allowed us to establish that the N-methyl group of 38b
becomes the 2-methylene in 47 (Scheme 8). In fact, the
1H NMR spectra of 47‚TF A and 47-d 2‚TF A were analo-
gous except for the resonances corresponding to the two
H atoms on C-2 (δ: 3.07 ppm, br s) which were not
present in the spectrum of the deuterated compound. The
new and unexpected behavior of the protonated trans-
fused bicyclic 5-spirocyclopropane isoxazolidine 38b pro-
vided a significant piece of information for the elucidation
of the mechanism of â-lactam formation (see below).
(13) This hypothesis recalls the first step of the Hoffman Loffler
Freitag reaction that is the thermal induced homolysis of N-X bond
in the presence of strong protic acid, where X is a chlorine or bromine
atom: (a) Corey, E. J .; Hertler, W. R. J . Am. Chem. Soc. 1960, 82,
1657-1668. (b) Wolff, M. E. Chem. Rev. 1963, 63, 55-64. (c) Stella, L.
Angew. Chem., Int. Ed. Engl. 1983, 22, 337-350.
(12) 38b-d 3 was obtained starting from aldehyde 37 and CD3NHOH
and following the same procedure used for the synthesis of 38b.
3274 J . Org. Chem., Vol. 68, No. 8, 2003

Ring Contraction of 5-Spirocyclopropane Isoxazolidines
SCHEME 10
SCHEME 11
the hydrogen bond might keep the nitrogen and CdO
group close enough and with the correct orbital over-
lapping required for the closure of a four-membered ring
with formation of a N-CO bond. Finally, the â-lactam
53 could be formed from 51 by radical fragmentation and
deprotonation (path A).
In the second hypothesis, the heterolysis of the N-O
bond could be assisted by the concomitant C3-C4 ring
expansion of a cyclopropyloxonium ion in analogy with
the cyclopropylcarbinyl cation behavior. The formed
oxetane cation 55 might be intramolecularly trapped by
nitrogen to form a highly strained oxaazaspiroheptane
56. This strained intermediate could evolve to 53 and
ethylene through a formal retro Paterno`-Buchi reaction
and deprotonation (path B).
SCHEME 12
The different behaviors of the cis- and trans-fused
isoxazolidines 38a and 38b appear to be in accord with
the illustrated diradical pathway. In the cis-intermediate
57, the relative orientation of the orbitals is suitable for
the attack of the radical nitrogen to the carbonyl as
shown diagrammatically in Scheme 10. In the trans-
intermediate 59, there is an unfavorable stereoelectronic
orientation for the overlapping of nitrogen and CdO
orbitals. This fact should cause a relatively longer lifetime
for the diradical cation 59 which undergoes different
reaction pathways. The diradical 59, via intra- or inter-
molecular H-shift, could give rise to the iminium ion 60
which is exactly the expected precursor of ketone 47 via
an intramolecular Mannich reaction (Scheme 10).
The formation of an iminium intermediate can also
explain the formation of ethyl ketones 43 and 44 in the
presence of traces of H2O. Hydrogen bonding with
molecules of H2O destabilizes the intramolecular hydro-
gen bond in the intermediates 65 and 66 hampering the
four-membered ring closure (Scheme 11). Therefore, the
diradical cations 67 and 68 could evolve to the iminium
ions 69 and 70, respectively, analogues of 60. The
â-iminium ketones 69 and 70 preferentially undergo
either elimination to 43, or hydrolysis to aldehydes 63
and 64 and the corresponding amine, which successively
produces 43 by a retro-Michael addition. A confirmation
of this hypothesis came by treating the aldehyde 31 with
a slight excess of N-benzylhydroxylamine chlorhydrate
in absolute ethanol (ca. 99.8%) (Scheme 11). After 3 h at
the reflux temperature the reaction mixture consisted of
the â-lactam 62, the ethyl ketone 43, benzaldehyde (64),
and a small amount of N-benzyl-C-phenyl nitrone derived
from the condensation of benzaldehyde with the excess
of hydroxylamine.
temperature and in the presence of TsOH, the mixture
of isoxazolidines 71 provided a complex mixture of the
â-lactam 73,14 styrene (74), the cis- and trans-quinoliz-
idinones 7515 (trans/cis ratio 2:1), and the enone 7616
which slowly underwent intramolecular cyclization to 75
(Scheme 12).
The formation of all the observed products can be
rationalized starting from the common diradical inter-
mediate 72 which could evolve to the â-lactam 73 and
styrene (74) through ring closure and fragmentation
(Scheme 9, path A), but the relatively more stable benzyl
radical could also undergo an 1,5-hydrogen shift to give,
after deprotonation, the conjugated enone 76.
Con clu sion
A novel chemoselective reaction of 5-spirocyclopropane
isoxazolidines has been reported. These compounds can
selectively undergo ring contraction to â-lactams, with
concurrent extrusion of ethylene, or ring expansion to
tetrahydropyridones, depending on the preliminary treat-
ment with or without a protic acid.
The two-step process 1,3-dipolar cycloaddition/acidic
thermal rearrangement represents a useful strategy to
(14) Brunwin, D. M.; Lowe, G.; Parker, J . J . Chem. Soc. C 1971,
3756-3762.
(15) The diastereomeric mixture of 5-spirocyclopropane isoxazo-
lidines 71 was converted into the cis- and trans-quinolizidinones 76
in 28% and 52% isolated yield, respectively, by heating at 110 °C under
neutral conditions.
Finally, more support for the proposed homolytic
mechanism derived from the study of the rearrangement
of the spirocyclopropane isoxazolidines 71. At room
(16) Quick, J .; Meltz, C. J . Org. Chem. 1979, 44, 573-578.
J . Org. Chem, Vol. 68, No. 8, 2003 3275

Cordero et al.
The two phases were separated, and the organic layer was
washed sequentially with a saturated solution of NaHCO3 and
a saturated solution of NaCl. The resulting crude product was
purified by chromatography on silica gel (pentane/diethyl ether
75:25). Aldehyde 14 was obtained as a colorless oil (905 mg,
72%).
14: Rf ) 0.25; 1H NMR (200 MHz) δ 9.73 (t, J ) 2.2 Hz,
1H), 5.70 (tp, J ) 7.1, 2.1 Hz, 1H), 5.39 (quintet, J ) 6.2 Hz,
1H), 2.64 (dd, J ) 6.2, 2.2 Hz, 2H), 2.55-2.43 (m, 2H), 2.01 (s,
3H), 1.13-0.98 (m, 4H); 13C NMR (66 MHz) δ 199.5 (d), 170.3
(s), 126.4 (s), 112.0 (d), 68.9 (d), 47.4 (t), 36.4 (t), 21.1 (q), 2.8
(t), 1.9 (t); IR (CDCl3) ν 2981, 1734 cm-1; MS (CI with NH3)
m/z 200 (71, MNH4+), 183 (100, MH+), 182 (34, M+), 140 (60),
123 (92).
synthesize new classes of 3,4-cis-fused bicyclic azetidin-
2-ones, starting from easily available alkylidenecyclo-
propanes obtained from R-amino or R-hydroxy acids, 1,3-
dicarbonyl, â-amino alcohol, and acid derivatives.
Two different hypotheses have been formulated to
rationalize the formation of â-lactam and ethylene, but
the formation of transient cation diradical intermediates
from the homolytic cleavage of the protonated N-O bond
was shown to be consistent with the observed behavior
of 5-spirocyclopropane isoxazolidines under acidic condi-
tions.
(3a R*,5R*,6a S*)- a n d (3a R*,5S*,6a S*)-1,3a ,4,5,6,6a -
Hexa h yd r o-1-m eth ylsp ir o[3H-cyclop en t[c]isoxa zole-3,1′-
cyclop r op a n ]-5-yl Aceta te (16a a n d 16b). N-Methylhydrox-
ylamine hydrochloride (468 mg, 5.6 mmol) and pyridine (453
µL, 5.6 mmol) were added to a solution of the aldehyde 14 (850
mg, 4.7 mmol) in diethyl ether (235 mL) at rt. The mixture
was stirred at rt overnight, and the salts were eliminated by
filtration through a short pad of Celite. The solvent was
removed under reduced pressure, and the crude mixture (16a /
16b ) 1:1) was separated by chromatography on silica gel
(pentane/diethyl ether 25:75) to obtain 16a as a colorless oil
(379 mg, 32%) and 16b as a colorless oil (379 mg, 32%).
16a : Rf ) 0.25; 1H NMR (400 MHz) δ 5.28 (quintet, J ) 4.8
Hz, 1H), 3.74 (br d, J ) 6.7 Hz, 1H), 3.04 (q, J ) 8.2 Hz, 1H),
2.78 (s, 3H), 2.07 (br s, 2H), 2.01 (s, 3H), 2.00-1.94 (m, 1H),
1.89-1.83 (m, 1H), 1.04 (ddd, J ) 11.5, 6.0, 1.6 Hz, 1H), 0.88
(quintet, J ) 6.3 Hz, 1H), 0.76 (quintet, J ) 5.2 Hz, 1H), 0.63
(dt, J ) 10.5, 6.3 Hz, 1H); 13C NMR (66 MHz) δ 170.4 (s), 76.5
(d), 73.2 (d), 66.6 (s), 48.4 (d), 45.4 (q), 38.2 (t), 36.3 (t), 21.1
(q), 14.4 (t), 4.7 (t); IR (CDCl3) ν 2960, 1736 cm-1; MS (EI) m/z
211 (5, M+), 94 (28), 66 (100), 43 (73); HRMS found 211.1212,
Exp er im en ta l Section
Gen er a l Rem a r k s. All the reactions requiring anhydrous
conditions were carried out under nitrogen or argon, and the
solvents were appropriately dried before use. NMR spectra
were recorded in CDCl3 (except were indicated), and the data
are reported in δ (ppm) from TMS. Multiplicity of the 13C NMR
was determined by means of APT experiments. In mass
spectra, relative percentages are shown in brackets. Rf values
refer to TLC on 0.25 mm silica gel plates and were measured
(except were indicated) using the same eluant employed in the
purification of the corresponding compounds.
5-Cyclopr opyliden e-1,1-dieth oxy-3-pen tan ol (13). A mix-
ture of Pd(OAc)2 (11.2 mg, 5% mol) and PPh3 (31.4 mg, 12%
mol) was degassed under reduced pressure for 1 h. Then THF
(5 mL) was added under Ar, and the solution was stirred for
5 min. A solution of 5 (286 mg, 1.2 mmol) in THF (5 mL) was
added, and when the solution had turned green, a solution of
aldehyde 12 (146.2 mg, 1 mmol) in THF (5 mL) was added.
After the mixture was stirred for 5 min, diethylzinc (224 mg,
2 mmol) was added and the mixture was stirred at rt for 3 h.
The mixture was quenched with a 6 M solution of NH4Cl/NH4-
OH (2 mL) and filtered through Celite and Na2SO4. The solvent
was removed under reduced pressure, and the crude 13 was
purified by chromatography on silica gel (CH2Cl2/diethyl ether
9:1) to obtain 13 as a colorless oil (135 mg, 63%).
C
11H17NO3 required 211.1208.
16b: Rf ) 0.14 (pentane/diethyl ether 25:75); 1H NMR (400
MHz) δ 4.94 (quintet, J ) 7.3 Hz, 1H), 3.57 (br d, J ) 6.9 Hz,
1H), 2.85 (t, J ) 6.5 Hz, 1H), 2.77 (s, 3H), 2.39-2.32 (m, 1H),
2.16 (quintet, J ) 6.9 Hz, 1H), 2.04 (s, 3H), 1.89-1.77 (m, 2H),
1.04 (quintet, J ) 5.6 Hz, 1H), 0.94-0.84 (m, 1H), 0.79-074
(m, 1H), 0.62 (dt, J ) 10.5, 6.1 Hz, 1H); 13C NMR (50 MHz) δ
171.0 (s), 74.3 (d), 72.3 (d), 66.7 (s), 48.0 (d), 45.6 (q), 37.5 (t),
13: Rf ) 0.38; 1H NMR (250 MHz) δ 5.70 (m, 1H), 4.65 (t, J
) 5.7 Hz, 1H), 3.38 (m, 1H), 3.67-3.42 (m, 4H), 3.13 (d, J )
2.4 Hz, 1H), 2.30 (m, 2H), 1.74-1.68 (m, 2H), 1.15 (t, J ) 7.1
Hz, 6H), 0.98 (m, 4H); 13C NMR (66 MHz) δ 124.2 (s), 114.0
(d), 102.0 (d), 68.1 (d), 62.0 (t), 61.2 (t), 39.6 (t), 15.2 (q), 15.1
(q), 2.5 (t), 1.6 (t); MS (EI) m/z 213 (0.08), 101 (68), 75 (37), 73
(90), 45 (100).
3-(Acet yloxy)-5-cyclop r op ylid en ep en t a n a l (14). (1)
Acetyla tion of th e Hyd r oxyl Gr ou p . Acetic anhydride (55
µL, 0.59 mmol) was added dropwise at 0 °C to a solution of
the alcohol 13 (1.76 g, 8.2 mmol) and DMAP (53 mg, 0.43
mmol) in diethyl ether (2 mL). The solution was stirred at rt
for 1.5 h. The resulting mixture was concentrated under
reduced pressure, diluted with hexane, filtered through a
sintered glass funnel, and concentrated. After purification of
the crude mixture by chromatography on silica gel (pentane/
diethyl ether 8:2), the acetyl derivative was obtained as a
colorless oil (1.77 g, 84%).
35.7 (t), 21.1 (q), 15.1 (t), 4.9 (t); IR (CDCl3) ν 2955, 1736 cm-1
;
MS (EI) m/z 211 (10, M+), 94 (28), 66 (100), 57 (11), 43 (93);
HRMS found 211.1201, C11H17NO3 required 211.1208.
(4a R*,6R*,7a S*)- a n d (4a R*,6S*,7a S*)-6-(Acetyloxy)-
octah ydr o-1-m eth yl-4H-cyclopen ta[b]pyr idin -4-on es (17a
a n d 17b). A solution of the adduct 16a (51 mg, 0.24 mmol) in
xylenes (30 mL) was refluxed for 6 h. After being cooled at rt,
the solution was passed through a short pad of silica gel,
eluting first with petroleum ether to remove the high boiling
solvent and then with MeOH to recover the product. The
solvent was removed under reduced pressure to give a mixture
of 17a and 17b in a 5.4:1 ratio. The crude residue was purified
by chromatography on silica gel (MeOH/diethyl ether 1:9) to
obtain 17a as a colorless oil (27 mg, 53%) and 17b as a colorless
oil (5 mg, 10%).
Starting from 16b (50 mg, 0.24 mmol) and following the
same procedure, a mixture of the two diastereomers 17a and
17b (ratio 1:5.5) was obtained in 26% overall yield.
3-(Ace t yloxy)-5-cyclop r op ylid e n e -1,1-d ie t h oxyp e n -
ta n e: Rf ) 0.43; H NMR (200 MHz) δ 5.70 (tp, J ) 7.1, 2.1
1
Hz, 1H), 5.08 (quintet, J ) 6.2 Hz, 1H), 4.54 (t, J ) 5.9 Hz,
1H), 3.60 (m, 2H), 3.48 (m, 2H), 2.44 (t, J ) 6.4 Hz, 2H), 2.01
(s, 3H), 1.86 (t, J ) 6.0 Hz, 2H), 1.18 (t, J ) 7.1 Hz, 6H), 1.03
(m, 4H); 13C NMR (66 MHz) δ 170.4 (s), 125.0 (s), 112.8 (d),
100.3 (d), 70.9 (d), 61.7 (t), 61.0 (t), 37.8 (t), 36.8 (t), 21.2 (q),
15.3 (q), 15.2 (q), 2.7 (t), 1.8 (t); IR (CDCl3) ν 2977, 2930, 1739
cm-1; MS (EI) m/z 213 (0.1), 103 (55), 96 (15), 79 (13), 75 (29),
43 (100); MS (CI with NH3) m/z 274 (1, MNH4+), 211 (100).
(2) Dep r otection of th e Ald eh yd e. A 0.2 M aqueous
solution of H2SO4 (100 mL) was added to a solution of the
acetal (1.77 g, 6.9 mmol) in THF (80 mL) at rt. The mixture
was stirred for 7 h, and then diethyl ether (80 mL) was added.
1
17a : Rf ) 0.35; H NMR (400 MHz) δ 5.24 (t, J ) 5.8 Hz,
1H), 3.15 (q, J ) 7.2 Hz, 1H), 2.97-2.92 (m, 1H), 2.91 (quintet,
J ) 8.4 Hz, 1H), 2.75-2.59 (m, 2H), 2.50-2.41 (m, 2H), 2.34
(s, 3H), 2.03 (s, 3H), 1.98-1.87 (m, 3H); 13C NMR (66 MHz) δ
210.2 (s), 170.4 (s), 74.4 (d), 66.6 (d), 52.9 (t), 49.7 (d), 43.4 (q),
39.2 (t), 37.4 (t), 33.0 (t), 21.2 (q); IR (CDCl3) ν 2952, 2841,
1736 cm-1; MS (EI) m/z 211 (15, M+), 152 (48), 124 (44), 110
(60), 96 (12), 82 (20), 68 (12), 42 (100); HRMS found 234.11025,
C
11H17NNaO3 required 234.11061.
17b: Rf ) 0.35; 1H NMR (400 MHz) δ 5.08 (quintet, J ) 6.2
Hz, 1H), 3.11 (q, J ) 7.1 Hz, 1H), 3.00-2.93 (m, 1H), 2.79-
3276 J . Org. Chem., Vol. 68, No. 8, 2003

Ring Contraction of 5-Spirocyclopropane Isoxazolidines
2.61 (m, 3H), 2.49 (ddt, J ) 16.2, 1.0, 5.0 Hz, 1H), 2.38 (s, 3H),
2.35 (dt, J ) 1.1, 6.8 Hz, 1H), 2.23 (quintet, J ) 6.8 Hz, 1H),
2.16-2.08 (m, 1H), 2.04 (s, 3H), 1.69 (quintet, J ) 6.7 Hz, 1H);
13C NMR (66 MHz) δ 210.9 (s), 170.9 (s), 73.4 (d), 65.7 (d),
51.8 (t), 49.5 (d), 43.4 (q), 39.4 (t), 35.0 (t), 32.0 (t), 29.7 (q); IR
(CDCl3) ν 2926, 1721, 1467, 1362, 1253, 1048 cm-1; MS (EI)
m/z 211 (5, M+), 151 (100), 134 (16), 124 (58), 108 (23), 85 (32),
82 (64); HRMS found 234.11002, C11H17NNaO3 required
234.11061.
(1R*,3R*,5S*)- an d- (1R*,3S*,5S*)-3-(Acetyloxy)-6-m eth -
yl-6-a za bicyclo[3.2.0]h ep ta n -7-on e (26a a n d 26b). TFA (15
µL, 0.2 mmol) was added dropwise to a solution of pure 16a
(21 mg, 0.1 mmol) in CH3CN (2.5 mL). The mixture was
refluxed for 15 min, and after cooling to rt, the solvent was
removed at reduced pressure to give a 1.6:1 mixture of 26a
and 26b. The two diastereomers were separated by chroma-
tography on silica gel (MeOH/diethyl ether 1: 9) to obtain 26a
as a yellow oil (10 mg, 56%) and 26b as a yellow oil (6.6 mg,
36%).
Meth yl 2-[(2-Cyclopr opyliden eeth yl)[(4-m eth ylph en yl)-
su lfon yl]a m in o]ben zoa te (30). The same procedure was
followed, starting from 28, to obtain 30 as a yellow solid in
90% yield.
1
30: Rf ) 0.22 (CH2Cl2); mp 71-72 °C; H NMR (200 MHz)
δ 7.87-7.79 (m, 1H), 7.54 (d, J ) 8.3 Hz, 2H), 7.40-7.32 (m,
2H), 7.25 (d, J ) 8.3 Hz, 2H), 6.94-6.87 (m, 1H), 5.88 (tp, J )
6.9, 1.9 Hz, 1H), 4.39 (d, J ) 6.9 Hz, 2H), 3.82 (s, 3H), 2.42 (s,
3H), 1.03-0.90 (m, 2H), 0.80-0.68 (m, 2H); 13C NMR (50 MHz)
δ 166.4 (s), 142.9 (s), 137.9 (s), 136.8 (s), 132.6 (s), 131.5 (d),
130.9 (d), 130.6 (d), 129.2 (d, 2C), 127.8 (d), 127.4 (s), 127.3 (d,
2C), 112.8 (d), 53.0 (t), 52.1 (q), 21.5 (q), 2.7 (t), 1.5 (t); IR
(CDCl3) ν 3061, 2986, 2954, 1722, 1596, 1433, 1341, 1297, 1255,
1155 cm-1; MS (EI) m/z 340 (1), 318 (4), 216 (70), 184 (100),
156 (13), 132 (27), 91 (67), 77 (20), 65 (14); MS (CI with NH3)
m/z 372 (90, MH+). Anal. Calcd for C20H21NO4S (371.45): C,
64.67; H, 5.70; N, 3.77. Found: C, 64.37; H, 5.85; N, 3.76.
N-(2-Cyclop r op ylid en eeth yl)-N-(2-for m ylp h en yl)-2-n i-
tr oben zen esu lfon a m id e (31). (1) Red u ction of th e Ester
Gr ou p to Alcoh ol. A 1 m solution of DIBALH in CH2Cl2 (9.2
mL, 9.2 mmol) was added dropwise to solution of ester 29 (1.28
g, 3.1 mmol) in CH2Cl2 (16 mL) at -30 °C. The mixture was
stirred for 2 h at low temperature, and then it was allowed to
reach rt and treated first with methanol and then with a
saturated solution of sodium and potassium tartrate. The two
phases were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic extracts were dried over
Na2SO4. Evaporation of the solvent gave the crude alcohol
(983.9 mg, 86%) as a yellow oil, which was used in the next
step without further purification.
Starting from 16b (20 mg, 0.09 mmol) and following the
same procedure a ca. 1:2 mixture of 26a and 26b was obtained
(26a : 5 mg, 26b: 9 mg; 82% overall yield).
Starting from a 1:1 mixture of 16a and 16b and following
the same procedure a 1:1 mixture of 26a and 26b was obtained
in 63% overall yield.
1
26a : Rf ) 0.53; H NMR (400 MHz) δ 5.16 (tt, J ) 9.9, 3.3
Hz, 1H), 3.98 (t, J ) 4.5 Hz, 1H), 3.57 (dd, J ) 8.8, 4.0 Hz,
1H), 2.76 (s, 3H), 2.52 (t, J ) 6.7 Hz, 1H), 2.47 (t, J ) 5.3 Hz,
1H), 2.06 (s, 3H), 1.62 (ddd, J ) 13.3, 10.0, 8.8 Hz, 1H), 1.43
(ddd, J ) 14.3, 9.5, 4.8 Hz, 1H); 13C NMR (66 MHz) δ 170.4 (s;
C-7), 168.7 (s; COCH3), 73.2 (d; C-3), 56.3, 52.3 (d; C-1, C-5),
31.8, 29.8 (t; C-2, C-4), 26.3 (q; NCH3), 21.0 (q; COCH3); IR
(CDCl3) ν 2961, 1742 cm-1; MS (EI) m/z 183 (0.4, M+), 125 (2),
66 (75), 43 (100); MS (CI with NH3) m/z 201 (35, MNH4+),
184 (MH+); HRMS found 206.0793, C9H13NNaO3 required
206.07931.
N-(2-Cyclop r op ylid en eet h yl)-N-[2-(h yd r oxym et h yl)-
p h en yl]-2-n itr oben zen esu lfon a m id e: Rf ) 0.18 (petroleum
1
ether/diethyl ether 1:2); H NMR (200 MHz) δ 7.74-7.48 (m,
5H), 7.35 (dt, J ) 1.2, 7.5 Hz, 1H), 7.13 (dt, J ) 1.9, 8.1 Hz,
1H), 6.78 (dd, J ) 8.0, 1.1 Hz, 1H), 5.81 (tp, J ) 7.3, 2.0 Hz,
1H), 4.85-4.63 (m, 2H), 4.51-4.40 (m, 1H), 4.31-4.20 (m, 1H),
2.75-2.62 (m, 1H), 1.17-0.66 (m, 3H), 0.52-0.38 (m, 1H); 13
C
1
26b: Rf ) 0.32; H NMR (400 MHz) δ 5.39 (t, J ) 4.9 Hz,
NMR (75 MHz) δ 148.2 (s), 142.3 (s), 135.5 (s), 133.8 (d), 132.1
(d), 131.8 (s), 131.1 (d), 130.8 (d), 130.1 (s), 129.6 (d), 129.5
(d), 128.4 (d), 123.9 (d), 111.5 (d), 60.8 (t), 54.9 (t), 2.8 (t), 1.4
1H), 4.08 (t, J ) 3.8 Hz, 1H), 3.59 (dd, J ) 8.4, 3.2 Hz, 1H),
2.73 (s, 3H), 2.30 (d, J ) 15.1 Hz, 1H), 2.25 (dd, J ) 15.7, 1.6
Hz, 1H), 2.02 (s, 3H), 1.84 (ddd, J ) 15.1, 8.4, 5.0 Hz, 1H),
1.70 (dt, J ) 15.7, 5.1 Hz, 1H); 13C NMR (50 MHz) δ 170.7 (s),
170.1 (s), 76.9 (d), 58.5 (d), 54.5 (d), 31.9 (d), 31.7 (t), 26.4 (q),
21.1 (q); IR (CDCl3) ν 3689, 2958, 1740, 1676, 1601, 1395, 1250
cm-1; MS (EI) m/z 184 (0.4, MH+), 125 (2), 66 (75), 43 (100);
MS (CI with NH3) m/z ) 184 (6, MH+), 122 (19), 93 (18),
65 (100); HRMS found 206.07928, C9H13NNaO3 required
206.07931.
(t); IR (CDCl3) ν 3550, 3063, 2960, 2926, 1543, 1364, 1160 cm-1
;
MS (EI) m/z 374 (0.1, M+), 291 (4), 277 (7), 188 (57), 186 (44),
170 (100), 158 (52), 91 (28).
(2) Sw er n Oxid a tion . A solution of DMSO (0.6 mL) in CH2-
Cl2 (2 mL) was added to a solution of oxalyl chloride (320 µL)
in CH2Cl2 (8 mL) at -78 °C, and then a solution of the crude
alcohol (983.9 mg, 3.07 mmol) in CH2Cl2 (2 mL) was added
dropwise to the mixture. After the mixture was stirred at -60
°C for 20 min, TEA (2.1 mL) was added, and then the mixture
was allowed to reach rt and poured into an equal volume of
water. The aqueous phase was extracted twice with CH2Cl2.
The collected organic phases were dried over Na2SO4 and
concentrated to give the crude aldehyde 31. After purification
by chromatography on silica gel (petroleum ether/diethyl ether
1:3), 31 was obtained as a yellow solid (980 mg, 81%).
31: Rf ) 0.53; mp 140-142 °C; 1H NMR (200 MHz) δ 10.14
(s, 1H), 7.95-7.90 (m, 1H), 7.72-7.68 (m, 2H), 7.58-7.47 (m,
4H), 7.27-7.12 (m, 1H), 5.89 (tp, J ) 7.3, 1.9 Hz, 1H), 4.85-
4.65 (m, 1H), 4.60-4.32 (m, 1H), 1.00-0.80 (m, 2H), 0.40-
0.80 (m, 2H); 13C NMR (50 MHz) δ 189.7 (d), 147.9 (s), 140.0
(s), 135.6 (s), 134.4 (d), 134.0 (d), 131.8 (d), 131.7 (s), 131.3
(d), 131.1 (s), 131.0 (d), 129.3 (d), 128.4 (d), 124.0 (d), 111.3
(d), 55.2 (t), 2.9 (t), 1.5 (t); IR (KBr) ν 3089, 2979, 2916, 1689,
1597, 1545, 1369, 1356, 1171, 773 cm-1; MS (EI) m/z 372 (0.7,
M+), 319 (2), 186 (100) 168 (9), 158 (12), 143 (12), 77 (15);
HRMS found 372.0774, C18H16N2O5S requires 372.0779.
N-(2-Cyclopr opyliden eeth yl)-N-(2-for m ylph en yl)-4-m e-
th ylben zen esu lfon a m id e (32). The same procedure was
followed starting from 30 to obtain 32 as a colorless solid in
96% yield.
E t h yl 2-[(2-Cyclop r op ylid en eet h yl)-[(2-n it r op h en yl)-
su lfon yl)]a m in o]ben zoa te (29). A mixture of Pd(dba)2 (134
mg, 0.23 mmol) and dppe (111 mg, 0.28 mmol) was degassed
under vacuum for 1 h and then treated with a solution of
1-tosyloxy-1-vinylcyclopropane (5) (928 mg, 3.9 mmol) in THF
(10 mL) under N2. After 10 min the mixture, which had turned
green, was added to a mixture of the amino ester 27 (1.5 g,
4.3 mmol) and NaH (93.6 mg, 5.8 mmol) in THF (20 mL). The
reaction mixture was stirred at rt overnight and filtered
through a short pad of Celite, and then the solvent was
removed under reduced pressure. The crude residue was
purified by chromatography on silica gel (CH2Cl2/petroleum
ether 9:1) to obtain 29 as a white waxy solid (1.76 g, 98%).
29: Rf ) 0.42 (CH2Cl2); 1H NMR (200 MHz) δ 7.89 (dd, J )
6.1, 3.4 Hz, 1H), 7.70-7.50 (m, 4H), 7.47-7.38 (m, 2H), 7.07
(dd, J ) 5.9, 3.4 Hz, 1H), 5.96 (tp, J ) 7.3, 2.0 Hz, 1H), 4.85-
4.35 (m, 2H), 4.19 (q, J ) 7.2 Hz, 2H), 1.33 (t, J ) 7.2 Hz,
3H), 1.04-0.50 (m, 4H); 13C NMR (50 MHz) δ 165.8 (s), 147.9
(s), 136.6 (s), 133.3 (d), 132.6 (d), 132.4 (s), 131.9 (d), 131.5
(d), 131.2 (d), 131.1 (d), 128.7 (s), 128.6 (d), 123.6 (d), 112.8
(d), 61.3 (t), 53.9 (t), 13.9 (q), 2.5 (t), 1.3 (t); IR (CDCl3) ν 2987,
2935, 1713, 1544, 1365, 1255, 1164, 1125 cm-1; MS (EI) m/z
350 (2), 230 (32), 184 (100). Anal. Calcd for C20H20N2O6S
(416.45): C, 57.68; H, 4.84; N, 6.73. Found: C, 57.65; H, 5.24;
N, 6.43.
N-(2-Cyclop r op ylid en eet h yl)-N-[2-(h yd r oxym et h yl)-
p h en yl]-4-m eth ylben zen esu lfon a m id e: yellow solid; Rf )
J . Org. Chem, Vol. 68, No. 8, 2003 3277

Cordero et al.
1
0.18 (petroleum ether/diethyl ether 1:1); H NMR (250 MHz)
mmol) in toluene (5 mL). The mixture was heated to reflux
for 45-60 min, stirred at rt in the presence of K2CO3 overnight,
and filtered. The solvent was removed under reduced pressure,
and the crude product was purified by chromatography on
silica gel.
δ 7.58 (d, J ) 8.2 Hz, 2H), 7.55 (dd, J ) 7.3, 1.6 Hz, 1H), 7.32
(td, J ) 7.4, 1.2 Hz, 1H), 7.32 (d, J ) 8.2 Hz, 2H), 7.11 (td, J
) 7.6, 1.6 Hz, 1H), 6.46 (dd, J ) 8.1, 1.2 Hz, 1H), 5.70 (m,
1H), 4.98 (dd, J ) 11.9, 2.7 Hz, 1H), 4.62 (dd, J ) 13.2; 5.8
Hz, 1H), 4.48 (t, J ) 11.0 Hz, 1H), 3.90 (dd, J ) 13.1; 8.4 Hz,
1H), 3.06 (dd, J ) 9.9, 3.6 Hz, 1H), 2.47 (s, 3H), 1.04-0.76 (m,
3H), 0.58-0.44 (m, 1H); 13C NMR (62.5 MHz) δ 143.8 (s), 142.3
(s), 137.1 (s), 134.8 (s), 130.6 (d), 129.5 (d, 2C), 128.9 (s), 128.8
(d), 128.0 (d), 127.9 (d, 2C), 127.5 (d), 111.4 (d), 61.1 (t), 53.5
(t), 21.5 (q), 2.6 (t), 1.3 (t); MS (EI) m/z ) 290 (6), 188 (46),
186 (10), 170 (62), 158 (23), 130 (22), 118 (45), 106 (27), 91
(100), 77 (31), 65 (27); MS (CI with NH3) m/z 344 (100, MH+).
32: Rf ) 0.40 (petroleum ether/diethyl ether 1:2); mp 90-
91 °C; 1H NMR (250 MHz) δ 10.38 (s, 1H), 7.98-7.90 (m, 1H),
7.51 (d, J ) 8.2 Hz, 2H), 7.45-7.35 (m, 2H), 7.29 (d, J ) 8.2
Hz, 2H), 6.78-6.69 (m, 1H), 5.73 (tp, J ) 7.1, 1.9 Hz, 1H),
4.68 (br s, w1/2h ) 29.0 Hz, 1H), 4.02 (br s, w1/2h ) 25.3 Hz;
1H), 2.44 (s, 3H), 1.05-0.71 (m, 3H), 0.70-0.49 (m, 1H); 13C
NMR (62.5 MHz) δ 190.2 (d), 144.0 (s), 141.6 (s), 136.0 (s),
134.6 (s), 133.8 (d), 129.7 (s), 129.6 (d, 2C), 128.4 (d), 128.0
(d), 127.9 (d), 127.8 (d, 2C), 111.4 (d), 53.0 (t), 21.5 (q), 2.7 (t),
1.5 (t); IR (CDCl3) ν 3065, 2995, 2925, 2775, 1687, 1590, 1343,
1155 cm-1; MS (EI) m/z 341 (0.6, M+), 186 (100), 158 (10), 143
(14), 91 (73), 77 (25); HRMS found 341.1063, C19H19NO3S
requires 341.1085.
(3′a R*,9′b R*)-3′a ,4′,5′,9′b -Tet r a h yd r o-1′-m et h yl-5′-[(2-
n itr op h en yl)su lfon yl]-sp ir o[cyclop r op a n e-1,3′(1H)-isox-
a zolo[4,3-c]qu in olin e] (33). TEA (55.6 µL, 0.4 mmol) was
added to a mixture of aldehyde 31 (100 mg, 0.27 mmol) and
N-methylhydroxylamine hydrochloride (33.7 mg, 0.4 mmol) in
toluene (2 mL) cooled to 0 °C. The mixture was refluxed for
15 min, diluted with diethyl ether, dried over Na2SO4, and
filtered. The solvent was removed, and the crude mixture was
chromatographed on silica gel (CH2Cl2, then CH2Cl2/AcOEt
1:9) to give the isoxazolidine 33 as a yellow solid (97.3 mg,
90%).
(1R,4S,5R)-6-Met h yl-4-(1-m et h ylet h yl)-3-[(4-m et h yl-
ph en yl)su lfon yl)-3,6-diazabicyclo[3.2.0]h eptan -7-on e (22):
colorless solid; 63% yield; Rf ) 0.14 (ethyl acetate/petroleum
ether 2:1); mp 162-163 °C; [R]22 ) 74.4 (c ) 0.215, CH3OH);
D
1H NMR (200 MHz) δ 7.72 (d, J ) 8.0 Hz, 2H), 7.32 (d, J ) 8.0
Hz, 2H), 4.04 (d, J ) 12.4 Hz, 1H), 3.83 (d, J ) 3.7 Hz, 1H),
3.61 (d, J ) 6.6 Hz, 1H), 3.50 (dd, J ) 7.0, 3.7 Hz, 1H), 3.39
(dd, J ) 12.4, 7.0 Hz, 1H), 2.43 (s, 3H), 2.24 (s, 3H), 1.89 (octet,
J ) 6.7 Hz, 1H), 1.02 (d, J ) 7.0 Hz, 3H), 1.00 (d, J ) 6.6 Hz,
3H); 13C NMR (50 MHz) δ 165.4 (s), 143.3 (s), 136.7 (s), 129.6
(d, 2C), 127.0 (d, 2C), 63.9 (d), 60.6 (d), 55.3 (d), 46.2 (t), 31.0
(d), 26.4 (q), 21.5 (q), 19.3 (q), 18.7 (q); IR (CDCl3) ν 3034, 2967,
2877, 1756, 1341, 1151 cm-1; MS (EI) m/z ) 322 (3, M+), 279
(64), 222 (14), 155 (100), 91 (41). Anal. Calcd for C16H22N2O3S
(322.42): C, 59.60; H, 6.88; N, 8.69. Found: C, 59.60; H, 6.83;
N, 9.00.
(1R,4S,5R)-4-(1H-In d ol-3-ylm eth yl)-6-m eth yl-3-[(4-m e-
t h ylp h e n yl)su lfon yl]-3,6-d ia za b icyclo[3.2.0]h e p t a n -7-
on e (23): pale yellow glass; 57% yield; Rf ) 0.31 (ethyl acetate);
1
[R]23 ) 35.0 (c ) 0.575, CH3OH); H NMR (200 MHz) δ 8.15
D
(br s, 1H), 7.78-7.69 (m, 3H), 7.43-7.36 (m, 1H), 7.34-7.14
(m, 4H), 7.08 (d, J ) 2.2 Hz, 1H), 4.15 (dd, J ) 9.9, 4.0 Hz,
1H), 3.99 (d, J ) 12.1 Hz, 1H), 3.88 (d, J ) 3.7 Hz, 1H), 3.43
(dd, J ) 6.6, 3.7 Hz, 1H), 3.31 (dd, J ) 12.1, 6.6 Hz, 1H), 3.24
(dd, J ) 14.3, 4.0 Hz, 1H), 2.92 (dd, J ) 14.3, 9.9 Hz, 1H),
2.40 (s, 3H), 2.09 (s, 3H); 13C NMR (50 MHz) δ 165.8 (s), 143.3
(s), 137.0 (s), 136.3 (s), 129.7 (d, 2C), 127.3 (s), 126.9 (d, 2C),
122.7 (d), 122.4 (d), 120.0 (d), 118.7 (d), 111.3 (d), 110.8 (s),
61.8 (d), 58.4 (d), 54.8 (d), 45.3 (t), 28.2 (t), 26.3 (q), 21.5 (q);
IR (CDCl3) ν 3479, 3041, 2925, 1753, 1341, 1152 cm-1; MS (EI)
m/z 409 (10, M+), 279 (19), 254 (8), 222 (3), 130 (100), 91 (19);
HRMS found 409.1459, C22H23N3O3S requires 409.1460.
33: Rf ) 0.07 (CH2Cl2); mp 169-172 °C; 1H NMR (500 MHz,
280 K) δ 7.76-7.71 (m, 2H), 7.68 (dd, J ) 8.0, 1.2 Hz, 1H),
7.61 (dt, J ) 1.3, 7.7 Hz, 1H), 7.51-7.46 (m, 2H), 7.32-7.25
(m, 2H), 4.23 (dd, J ) 14.0, 5.9 Hz, 1H), 3.80 (d, J ) 7.5 Hz,
1H), 3.49 (t, J ) 13.3 Hz, 1H), 2.98 (s, 3H), 2.82 (dt, J ) 11.6,
6.6 Hz, 1H), 1.07-1.02 (m, 1H), 0.94-0.84 (m, 2H), 0.81-0.75
(m, 1H); 13C NMR (50 MHz) δ ) 147.8 (s), 136.1 (s), 134.0 (d),
133.0 (s), 131.7 (d), 130.1 (d), 129.9 (d), 129.1 (s), 128.2 (d),
126.2 (d), 124.2 (d), 123.9 (d), 66.7 (d), 64.4 (s), 46.8 (t), 46.2
(q), 44.4 (d), 12.4 (t), 4.1 (t); IR(CDCl3) ν 3040, 3005, 2957, 2879,
1598, 1484, 1450, 1347, 1158, 1078 cm-1; MS (EI) m/z 401(2,
M+), 344 (1), 215 (55), 186 (9), 159 (22), 130 (100); HRMS found
401.1041, C19H19N3O5S requires 401.1045.
(2a R*,8bR*)-2a ,3,4,8b-Tetr a h yd r o-1-m eth yl-4-[(2-n itr o-
p h en yl)su lfon yl]a zeto[3,2-c]qu in olin -2(1H)-on e] (41): col-
orless solid; 72% yield; Rf ) 0.18 (CH2Cl2/AcOEt 1:1); mp 206-
1
209 °C; H NMR (200 MHz) δ 8.21-8.14 (m, 1H), 7.80-7.63
(m, 4H), 7.58 (d, J ) 8.1 Hz, 1H), 7.42-7.23 (m, 2H), 4.56 (dd,
J ) 14.6, 1.8 Hz, 1H), 4.45 (d, J ) 5.1 Hz, 1H), 3.70 (br dd, J
) 5.1, 4.4 Hz, 1H), 3.50 (dd, J ) 14.6, 4.4 Hz, 1H), 2.44 (s,
3H); 13C NMR (50 MHz) δ 166.2 (s), 138.6 (s), 134.1 (d), 133.6
(s), 132.3 (d), 132.1 (d), 130.6 (d), 129.8 (d), 126.1 (d), 125.8 (s,
2C), 125.0 (d), 124.5 (d), 54.3 (d), 52.8 (d), 45.3 (t), 26.4 (q); IR
(CDCl3) ν 3078, 3029, 2930, 1750, 1603, 1542, 1486, 1361, 1166
cm-1; MS (EI) m/z 373 (13, M+), 299 (19), 277 (17), 215 (2),
186 (4), 130 (100), 77 (56). Anal. Calcd for C17H15N3O5S
(373.38): C, 54.69; H, 4.05; N, 11.25. Found: C, 55.01; H, 3.97;
N, 10.86.
(2a R*,8bR*)-2a ,3,4,8b-Tetr a h yd r o-1-m eth yl-4-[(4-m eth -
ylp h en yl)su lfon yl)]a zeto[3,2-c]qu in olin -2(1H)-on e] (42):
pale yellow solid; 60% yield; Rf ) 0.43 (petroleum ether/diethyl
ether 1:1); mp 108-112 °C; 1H NMR (300 MHz) δ 7.93 (d, J )
8.0 Hz, 1H), 7.63 (d, J ) 8.1 Hz, 2H), 7.42-7.34 (m, 1H), 7.22-
7.18 (m, 4H), 4.76 (dd, J ) 14.3, 2.2 Hz, 1H), 4.29 (d, J ) 5.1
Hz, 1H), 3.56 (dt, J ) 2.0, 4.8 Hz, 1H), 3.47 (dd, J ) 14.3, 4.7
Hz, 1H), 2.36 (s, 3H), 2.21 (s, 3H); 13C NMR (75 MHz) δ 166.9
(s), 143.6 (s), 138.2 (s), 136.5 (s), 130.4 (d), 129.6 (d), 129.3 (d,
2C), 127.8 (d, 2C), 126.3 (s), 125.5 (d), 124.4 (d), 54.4 (d), 52.6
(d), 44.6 (t), 26.1 (q), 21.5 (q); IR (KBr) ν 3071, 2949, 1752,
1596, 1335, 1157, 1078 cm-1; MS (EI) m/z 342 (2, M+), 277
(7), 187 (2), 130 (71), 91 (26), 84 (100); HRMS found 365.09356,
(3′a R*,9′b R*)-3′a ,4′,5′,9′b -Tet r a h yd r o-1′-m et h yl-5′-[(4-
m eth ylph en yl)su lfon yl]spir o[cyclopr opan e-1,3′(1H)-isox-
a zolo[4,3-c]qu in olin e] (34). The synthesis of 34 was per-
formed from 32 following the same procedure. Product 34 was
obtained as a yellow solid in 91% yield.
34: Rf ) 0.39 (petroleum ether/ethyl acetate 2:1); mp 132-
135 °C; 1H NMR (500 MHz, 280 K) δ 7.64 (d, J ) 7.5 Hz, 1H),
7.55 (d, J ) 8.1 Hz, 2H), 7.40 (d, J ) 7.6 Hz, 1H), 7.30 (dt, J
) 1.4, 7.7 Hz, 1H), 7.25 (d, J ) 8.1 Hz, 2H), 7.22 (dt, J ) 1.2,
7.5 Hz, 1H), 4.19 (dd, J ) 13.9, 5.9 Hz, 1H), 3.52 (d, J ) 7.5
Hz, 1H), 3.40 (t J ) 12.9 Hz, 1H), 2.87 (s, 3H), 2.54 (dt, J )
12.5, 6.3 Hz, 1H), 2.39 (s, 3H), 1.05-1.00 (m, 1H), 0.91-0.86
(m, 1H), 0.80-0.75 (m, 1H), 0.71-0.75 (m, 1H); 13C NMR (50
MHz) δ 143.8 (s), 137.0 (s), 136.7 (s), 129.6 (d, 3C), 128.6 (s),
128.0 (d), 127.0 (d, 2C), 125.6 (d), 124.3 (d), 66.5 (d), 64.2 (s),
46.4 (t), 46.0 (q), 43.7 (d), 21.4 (q), 12.3 (t), 3.9 (t); IR (CDCl3)
C
18H18N2NaO3S requires 365.09358.
ν 3070, 3037, 3004, 2927, 2861, 1599, 1484, 1447, 1348, cm-1
;
1-[1(2-Nitr oben zen su lfon yl)-1,2-d ih yd r oqu in olin -3-yl]-
MS (EI) m/z 370 (2, M+), 215 (36), 159 (24) 130 (100), 91 (66).
p r op a n -1-on e (43) a n d 41. A mixture of aldehyde 31 (80 mg,
0.21 mmol) and N-methylhydroxylamine hydrochloride (26.9
mg, 0.32 mmol) in absolute ethanol (1 mL) was refluxed for 3
h. The ethanol was removed at reduced pressure, CH2Cl2 was
added, and the solution was stirred over Na2CO3. After
HRMS found 393.12477, C20H22N2NaO3S requires 393.124885.
Syn t h esis of â-La ct a m s 22, 23, 41, a n d 42. Gen er a l
P r oced u r e. TFA (freshly distilled over P2O5) (1.2-2 equiv)
was added to a solution of isoxazolidine 18, 19, 33, or 34 (0.2
3278 J . Org. Chem., Vol. 68, No. 8, 2003

Ring Contraction of 5-Spirocyclopropane Isoxazolidines
filtration and concentration, the crude 2:1 mixture of 41 and
43 was separated by chromatography on silica gel (CH2Cl2/
AcOEt 1:1) to obtain 41 (45.1 mg, 62%) as a pale yellow solid
and 43 (21.9 mg, 28%) as a yellow solid.
(18), 91 (41), 84 (46), 69 (100), 57 (81), 55 (94). HRMS: the
observed peak corresponds to the M - 1 mass. The compound
polymerizes on storage. Found 126.0673, C6H8N2O2 requires
126.0555.
43: Rf ) 0.37 (CH2Cl2); mp 114-116 °C; 1H NMR (200 MHz)
δ 7.72-7.58 (m, 3H), 7.51-7.41 (m, 3H), 7.37-7.22 (m, 2H),
7.08 (br s, 1H), 4.72 (br s, 2H), 2.56 (q, J ) 7.3 Hz, 2H), 1.06
(t, J ) 7.3 Hz, 3H); 13C NMR (50 MHz) δ 198.3 (s), 135.6 (s),
134.1 (s, 2C), 133.9 (d), 132.6 (d), 131.7 (s), 131.1 (d), 131.0 (d,
2C), 129.0 (d), 128.3 (s), 127.4 (d), 126.4 (d), 123.7 (d), 44.3 (t),
30.3 (t), 8.2 (q); IR (CDCl3) ν 3075, 2981, 2929, 2857, 1662,
1543, 1365, 1167 cm-1; MS (EI) m/z 372 (0.5, M+), 355 (2), 260
(1), 232 (1), 204 (3), 186 (100), 156 (58), 130 (56); HRMS found
372.0781, C18H16N2O5S requires 372.0779.
(2a R*,8bR*)-2a ,3,4,8b-Tetr a h yd r o-1-ben zyl-4-[(2-n itr o-
p h en yl)su lfon yl]a zeto[3,2-c]qu in olin -2(1H)-on e] (62). A
mixture of aldehyde 31 (50 mg, 0.13 mmol) and N-benzylhy-
droxylamine hydrochloride (32 mg, 0.20 mmol) in absolute
ethanol (1.3 mL) was refluxed for 3 h. The ethanol was
removed at reduced pressure, and the 1H NMR of the crude
mixture showed the presence of â-lactam 62, aldehyde 31,
enone 43, benzaldehyde (64), and C,N-diphenylnitrone in ca.
18.8: 4.4:3.8:1.8:1 molecular ratio. The crude residue was
separated by chromatography on silica gel (AcOEt/petroleum
ether 3:1) to obtain 62 (40 mg, 74%) as a colorless solid.
62: Rf ) 0.17 (petroleum ether/AcOEt 1:1); mp 164-167 °C;
1H NMR (200 MHz) δ 8.25-8.21 (m, 1H), 7.80-7.75 (m, 3H),
7.75-7.73 (m, 1H) 7.72-7.20 (m, 5H), 7.16-7.12 (m, 2H),
7.02-6.97 (m, 1H), 4.61 (dd, J ) 14.6, 1.1 Hz, 1H), 4.38-4.30
(m, 2H), 3.68-3.64 (m, 1H), 3.53-3.40 (m, 2H); 13C NMR (50
MHz) δ 165.9 (s), 147.7 (s), 138.7 (s), 135.0 (s), 134.0 (d), 133.7
(s), 132.2 (d), 132.0 (d), 130.7 (d), 129.6 (d), 128.8 (d, 2C), 128.4
(d, 2C), 127.8 (d), 126.0 (d), 124.8 (d), 124.4 (d), 54.1 (d), 50.6
(d), 45.6 (t), 44.2 (t); IR (CDCl3) ν 3032, 2927, 1753, 1604, 1544,
1489, 1371, 1247, 1173 cm-1; MS (EI) m/z 449 (3, M+), 299
(23), 263 (14), 202 (22), 187 (17), 168 (32), 127 (100), 103 (93),
100 (62), 89 (75), 76 (100), 63 (82). Anal. Calcd for C23H19N3O5S
(449.48): C, 61.46; H, 4.26; N, 9.35. Found: C, 61.42; H, 4.16;
N, 9.18.
3-[Ben zyl(2-cyclopr opyliden eeth yl)am in o]-2,2-dim eth yl-
1-p r op a n ol (36). A mixture of Pd(dba)2 (144 mg, 0.25 mmol)
and PPh3 (157 mg, 0.60 mmol) was degassed under vacuum
for 1 h. Then, under nitrogen, a solution of 1-tosyloxy-1-
vinylcyclopropane 5 (1.19 g, 5 mmol) in CH2Cl2 (14 mL) was
added. In a different flask, TEA (1.66 mL, 12 mmol) was added
to a solution of amino alcohol 35 (1.07 g, 5.5 mmol) in CH2Cl2
(7 mL). After 10 min, when the mixture containing 5 and the
catalyst had turned orange, the solution of 35 was added to.
The mixture was stirred overnight, diluted with diethyl ether,
and filtered over Celite. Evaporation of the solvent and
chromatography on silica gel (petroleum ether/diethyl ether
3:1) of the residue gave 36 (903 mg, 70%) as a colorless oil.
36: Rf ) 0.13; 1H NMR (200 MHz) δ 7.35-7.26 (m, 5H),
5.91 (tp, J ) 6.8, 2.0 Hz, 1H), 5.71 (br s, 1H), 3.66 (s, 2H),
3.40 (s, 2H), 3.21 (d, J ) 7.0 Hz, 2H), 2.55 (s, 2H), 1.27-0.80
(m, 4H), 0.95 (s, 6H); 13C NMR (50 MHz) δ 138.6 (s), 129.1 (d,
2C), 128.4 (d, 2C), 127.2 (d), 126.5 (s), 114.1 (d), 73.4 (t), 65.2
(t), 60.8 (t), 56.5 (t), 35.6 (s), 24.4 (q, 2C), 2.5 (t), 1.9 (t); GC-
MS m/z ) 186 (M+, 11), 157 (1), 129 (4), 118 (1), 91 (100), 65
(6); IR (CDCl3) ν 3292, 3064, 3033, 2982, 2873, 1448, 1360,
1100, 1035 cm-1. Anal. Calcd for C17H25NO (259.39): C, 78.72;
H, 9.71; N, 5.40. Found: C, 78.56; H, 9.46; N, 5.55.
3-[Ben zyl(2-cyclop r op ylid en eeth yl)a m in o]-2,2-d im eth -
ylp r op a n a l (37). Activated powdered molecular sieves (4 Å,
500 mg), NMO (337 mg, 2.79 mmol), and TPAP (33 mg, 0.09
mmol) were added, under nitrogen atmosphere, to a solution
of 36 (483 mg, 1.86 mmol) in CH2Cl2 (3.7 mL). The mixture
was stirred at rt for 1 h and then filtered through a short pad
of silica gel. Evaporation of the solvent afforded the crude
aldehyde 37 (478 mg, 85%) as a colorless oil, which was used
in the next step without further purifications.
1
37: Rf ) 0.88 (petroleum ether/diethyl ether 1:1); H NMR
(200 MHz) δ 9.45 (s, 1H), 7.35-7.20 (m, 5H), 5.84 (tp, J ) 6.6,
1.8 Hz, 1H), 3.60 (s, 2H), 3.15 (d, J ) 6.9 Hz, 2H), 2.67 (s,
2H), 1.20-0.75 (m, 4H), 1.05 (s, 6H).
(2aR,2bS,6aR)-2-Meth yloctah ydr o-2,5a-diazacyclobu ta-
[a ]p en ta len -1-on e (24). TFA (32 µL) was added to a solution
of isoxazolidine 20 (41 mg, 0.21 mmol) in toluene (5.2 mL).
The reaction flask was dipped in an oil bath at 88 °C, and the
mixture was refluxed for 2 min. After the mixture was cooled
to rt, the solvent was removed under reduced pressure and
the crude product was treated with Dowex 50WX8-200 ion-
exchange resin. â-Lactam 24 was obtained as a colorless oil
(16.5 mg, 47%).
(3′a R*,7′a R*)-Oct a h yd r o-1′,7′,7′-t r im et h yl-5′-(p h en yl-
m e t h yl)sp ir o[cyclop r op a n e -1,3′-isoxa zolo[4,3-c]p yr i-
d in e] (38a ), (3′a R*,7′a S*)-Octa h yd r o-1′,7′,7′-tr im eth yl-5′-
(p h en ylm eth yl)sp ir o[cyclop r op a n e-1,3′-isoxa zolo[4,3-c]-
p yr id in e] (38b), a n d 5′,5′,7′-Tr im eth yl-3′-(p h en ylm eth yl)-
sp ir o[cyclop r op a n e-1,9′-[8]oxa [3,7]d ia za b icyclo[4.2.1]-
n on a n e (39). N-Methylhydroxylamine hydrochloride (324 mg,
2.89 mmol) and TEA (0.54 mL, 3.89 mmol) were added to a
solution of the aldehyde 37 (665 mg, 2.59 mmol) in toluene
(18.5 mL) at 0 °C. After being stirred overnight at rt, the
mixture was diluted with an equivalent volume of diethyl
ether, treated with Na2SO4, and filtered. The solvent was
removed under reduced pressure, and the crude mixture was
separated by chromatography on silica gel (petroleum ether/
AcOEt 6:1) to obtain 38a (300 mg, 40%) as a pale yellow oil,
38b (105 mg, 14%) as a white solid, and 39 (40 mg, 5%) as a
colorless oil.
24: 1H NMR (400 MHz) δ 3.95 (d, J ) 3.9 Hz, 1H), 3.70
(dd, J ) 3.8, 6.8 Hz, 1H), 3.56 (dd, J ) 10.4, 7.0 Hz, 1H), 3.32
(d, J ) 10.3 Hz, 1H), 3.06 (dt, J ) 12.7, 8.3 Hz, 1H), 2.97 (ddd,
J ) 12.7, 8.4, 3.7 Hz, 1H), 2.82 (s, 3H), 2.41 (dd, J ) 10.7, 6.8
Hz, 1H), 2.12-2.02 (m, 1H), 1.89-1.77 (m, 2H), 1.34 (dt, J )
5.4, 10.7 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 168.0 (s), 63.5
(d), 60.3 (d), 54.9 (d), 51.2 (t), 49.0 (t), 26.1 (q), 24.8 (t), 22.6
(t); IR (CDCl3) ν 2967, 2881, 1743, 1426, 1396, 1199, 1085 cm-1
;
GC-MS m/z 166 (24, M+), 138 (44), 123 (22), 108 (47), 95 (100),
80 (45), 70 (65), 68 (75), 55 (41), 42 (69).
1
38a : Rf ) 0.22; H NMR (500 MHz) δ 7.34-7.23 (m, 5H),
(1S*,5R*)-6-Meth yl-3-oxa -6-a za bicyclo[3.2.0]h ep ta n -7-
on e (25). TFA (10 µL, 0.13 mmol) was added to a solution of
isoxazolidine 21 (10 mg, 0.064 mmol) in CD3CN (200 µL) in
an NMR tube, and the mixture was heated at 70 °C for 6 min.
The NMR spectra of the mixture showed the disappearance
of 10 and the appearance of 25 and ethylene. Evaporation of
the solvent and purification on a short pad of silica gel (MeOH)
afforded â-lactam 25 as a colorless oil (5 mg, 60%).
3.54 (A part of an AB system, J ) 13.4 Hz, 1H), 3.45 (B part
of an AB system, J ) 13.4 Hz, 1H), 2.83 (s, 3H), 2.78 (dd, J )
9.3, 4.4 Hz, 1H), 2.75 (d, J ) 4.6 Hz, 1H), 2.34-2.26 (m, 2H),
2.20 (AB syst., J ) 11.3 Hz, 1H), 2.17 (AB syst, J ) 11.3 Hz,
1H), 1.12 (s, 3H), 0.90 (s, 3H), 0.86-0.77 (m, 2H), 0.60-0.50
(m, 2H); 13C NMR (50 MHz) δ 139.1 (s), 128.5 (d, 2C), 127.9
(d, 2C), 126.6 (d), 75.5 (d), 63.7 (s), 62.8 (t), 60.4 (t), 53.2 (t),
50.0 (d), 45.8 (q), 33.5 (s), 27.6 (q), 25.5 (q), 12.5 (t), 2.4 (t); MS
(70 eV) m/z 230 (4), 200 (2), 186 (3), 174 (8), 91 (100); IR
(CDCl3) ν 2961, 2815, 2786, 1452, 1361, 1251, 1165, 1122, 1036
cm-1. Anal. Calcd for C18H26N2O (286.41): C, 75.48; H, 9.15;
N, 9.78. Found: C, 75.25; H, 8.88; N, 9.82.
25: 1H NMR(200 MHz) δ 4.22 (d, J ) 9.9 Hz, 1H), 4.12 (dd,
J ) 3.8, 2.9 Hz, 1H), 4.05 (d, J ) 10.8 Hz, 1H), 3.68 (m, 1H),
3.38 (dd, J ) 9.9, 5.7 Hz, 1H), 3.25 (dd, J ) 10.9, 3.0 Hz, 1H),
2.77 (s, 3H); 13C NMR (50 MHz) δ 167.6 (s), 65.9 (t), 65.8 (t),
58.2 (d), 55.8 (d), 26.6 (q); IR (CDCl3) ν 2969, 2863, 1747, 1671,
1427, 1398, 1209, 1173, 1073 cm-1; MS m/z 127 (10, M+), 105
1
38b: Rf ) 0.11; H NMR (200 MHz) δ 7.37-7.24 (m, 5H),
3.59 (A part of an AB system, J ) 13.5 Hz, 1H), 3.51 (B part
J . Org. Chem, Vol. 68, No. 8, 2003 3279

Cordero et al.
of an AB system, J ) 13.5 Hz, 1H), 2.94 (td, J ) 11.2, 3.7 Hz,
1H), 2.82 (s, 3H), 2.66 (ddd, J ) 9.9, 3.7, 1.5 Hz, 1H), 2.46 (dd,
J ) 11.5, 1.4 Hz, 1H), 2.24 (d, J ) 11.4 Hz, 1H), 1.78 (t, J )
10.6 Hz, 1H), 1.77 (d, J ) 11.4 Hz, 1H), 1.16 (s, 3H), 0.93 (s,
3H), 0.95-0.83 (m, 1H), 0.64-0.45 (m, 3H); 13C NMR (50 MHz)
δ 138.6 (s), 128.3 (d, 2C), 128.1 (d, 2C), 126.8 (d), 81.4 (d) 65.3
(s), 62.5 (t), 62.1 (t), 53.8 (t), 48.9 (d), 43.9 (q), 34.2 (s), 27.4
(q), 19.2 (q), 8.6 (t), 4.4 (t); MS (70 eV) m/z 287 (3, M+), 272
(4), 235 (3), 230 (6), 200 (7), 195 (6), 174 (17), 120 (16), 91 (100),
84 (43); IR (CDCl3) ν 2970, 2933, 2811, 1599, 1453, 1366, 1244,
1108, 1058 cm-1; HRMS found 287.21221, C18H27N2O required
287.21234.
Evaporation of the solvent and purification of the crude
product by chromatography on silica gel (CH2Cl2/MeOH 30:1)
gave 46 (47 mg, 87%) as a colorless oil.
46: Rf ) 0.31; 1H NMR (200 MHz) δ 7.54-7.37 (m, 5H), 4.37
(A part of an AB system, J ) 12.4 Hz, 1H) 4.24 (B part of an
AB system, J ) 12.8 Hz, 1H), 3.74-3.57 (m, 1H), 3.57-3.44
(m, 2H), 3.40-3.24 (m, 1H), 3.32 (A part of an AB system, J )
12.6 Hz, 1H), 2.95 (s, 3H), 2.86 (B part of an AB system, J )
12.6 Hz, 1H), 1.19 (s, 3H), 1.10 (s, 3H); 13C NMR (50 MHz) δ
168.3 (s), 131.1 (d, 2C), 130.1 (d), 129.3 (d, 2C), 128.5 (s), 62.5
(t), 58.4 (q), 54.8 (t), 44.9 (d), 41.5 (t), 34.2 (s), 30.3 (d), 25.4
(q), 24.0 (q); MS (70 eV) m/z 258 (1, M+), 174 (16), 167 (8), 139
(15), 124 (81), 120 (35), 91 (100), 69 (30); IR (CDCl3) ν 2975,
2931, 1754, 1663, 1420, 1189 cm-1; HRMS found 281.16295,
39: Rf ) 0.35; 1H NMR (500 MHz) δ 7.38-7.20 (m, 5H), 3.81
(d, J ) 4.0 Hz, 1H), 3.63 (A part of an AB system, J ) 13.1
Hz, 1H), 3.57 (B part of an AB system, J ) 13.1 Hz, 1H), 2.88
(s, 3H), 2.84 (AB syst, J ) 13.1 Hz, 1H), 2.56 (dd, J ) 12.9,
3.2, Hz, 1H), 2.28 (d, J ) 13.2 Hz, 1H), 2.15 (AB syst, J )
13.1 Hz, 1H), 2.10 (s, 1H), 1.22-1.09 (m, 1H), 1.06 (s, 3H),
0.89 (s, 3H), 0.67-0.63 (m, 3H); 13C NMR (50 MHz) δ 140.1
(s), 128.9 (d, 2C), 128.0 (d, 2C), 126.8 (d), 84.7 (d), 79.3 (d),
64.5 (t), 61.9 (t), 59.0 (t), 47.9 (q), 39.0 (s), 26.8 (s), 26.4 (q),
25.6 (q), 16.2 (t), 2.0 (t); GC-MS m/z 174 (3), 133 (5), 120 (5),
112 (6), 98 (5), 91 (100), 77 (5); IR (CDCl3) ν 3737, 3034, 2985,
2955, 2812, 1599, 1451, 1359, 1177, 1134, 1100 cm-1. Anal.
Calcd for C18H26N2O (286.41): C, 75.48; H, 9.15; N, 9.78.
Found: C, 74.93; H, 9.19; N, 10.00.
C
16H22N2NaO required 281.16298.
(4a R*,8a R*)-Octa h yd r o-3,8,8-tr im eth yl-6-(m eth ylp h en -
yl)[1,6]n a p h th yr id in -4(1H)-on e (47). TFA (18 µL, 0.24
mmol) was added to a solution of 38b (33 mg, 0.12 mmol) in
toluene (3 mL) at rt and under nitrogen atmosphere The
mixture was refluxed for 2 h 45 min. Evaporation of the solvent
and purification by chromatography on silica gel (MeOH + 1%
NH3) gave the 1,6-naphthyridine 47‚TF A (18 mg, 58%) as TFA
salt. After treatment with Ambersep 900 OH ion-exchange
resin and purification by chromatography on silica gel (petro-
leum ether/ethyl acetate + 1% TEA 1:1), the ketone 47 (13
mg, 40%) was obtained as a colorless oil.
(3′a R*,7′a S*)-Octa h yd r o-7′,7′-d im eth yl-1′-(m eth yl-d 3)-
5′-(p h en ylm eth yl)-sp ir o[cyclop r op a n e-1,3′-isoxa zolo[4,3-
c]p yr id in e] (38b-d 3). The same procedure was followed for
the synthesis of the deuterated derivative 38b-d 3, starting
from 37 and N-(methyl-d3)-hydroxylamine acetate.
47‚TF A: 1H NMR (400 MHz, CD3CN) δ 7.54-7.47 (m, 5H),
4.81 (d, J ) 12.0 Hz, 1H), 4.37 (A part of an AB system, J )
12.8 Hz, 1H), 4.16 (B part of an AB system, J ) 12.8 Hz, 1H),
3.86 (dm, J ) 9.3 Hz, 1H), 3.75 (tm, J ) 10.5 Hz, 1H), 3.17 (br
t, J ) 112.2 Hz, 1H), 3.07 (br s, 2H), 3.02-2.95 (m, 2H), 1.51
(s, 3H), 1.21 (s, 3H), 0.95 (s, 3H).
38b-d 3: Rf ) 0.11 (petroleum ether/AcOEt 6:1); 1H NMR (200
MHz) δ 7.37-7.24 (m, 5H), 3.59 (A part of an AB system, J )
13.6 Hz, 1H), 3.51 (B part of an AB system, J ) 13.5 Hz, 1H),
2.94 (td, J ) 11.2, 3.7 Hz, 1H), 2.66 (ddd, J ) 9.9, 3.7, 1.5 Hz,
1H) 2.46 (dd,, J ) 11.5, 1.4 Hz, 1H) 2.24 (d, J ) 11.4 Hz, 1H),
1.78 (t, J ) 10.6 Hz, 1H), 1.77 (d, J ) 11.4 Hz, 1H), 1.16 (s,
3H), 0.93 (s, 3H), 0.95-0.83 (m, 1H), 0.64-0.45 (m, 3H).
(4a R*,8a R*)-Octa h yd r o-1,8,8-tr im eth yl-6-(m eth ylp h en -
yl)[1,6]n a p h th yr id in -4(1H)-on e (45). A solution of cycload-
duct 38a (69 mg, 0.24 mmol) in xylenes (4 mL) was refluxed
for 5 h. After the solution was cooled to rt, the solvent was
eliminated by filtration on silica gel eluting in turn with
petroleum ether and with ethyl acetate. Purification by chro-
matography on silica gel (petroleum ether/AcOEt 1:1) afforded
the ketone 45 (25 mg, 40%) as a colorless oil.
47: Rf ) 0.37 (AcOEt); 1H NMR (500 MHz, CD3OD) δ 7.48-
7.32 (m, 5H), 3.68 (A part of an AB system, J ) 13.2 H, 1H),
3.54 (B part of an AB system, J ) 13.2 Hz, 1H), 3.52 (dd, J )
12.3, 6.3 Hz, 1H), 3.18 (ddd, J ) 12.0, 3.5, 2.3 Hz, 1H), 2.78-
2.46 (m, 2H), 2.59 (t, J ) 12.0 Hz, 1H), 2.58 (dd, J ) 11.4, 2.2
Hz, 1H), 2.35 (d, J ) 11.3 Hz, 1H), 2.13 (t, J ) 11.6 Hz, 1H),
1.86 (d, J ) 11.3 Hz, 1 H), 1.24 (s, 3H), 1.08 (s, 3H) 1.06 (d, J
) 6.7 Hz, 3H); 13C NMR (50 MHz, CD3OD) δ 212.9 (s), 139.8
(s), 129.9 (d, 2C), 129.1 (d, 2C), 128.0 (d), 71.6 (d), 67.3 (t),
63.9 (t), 55.7 (t), 54.1 (t), 52.0 (d), 46.8 (d), 35.9 (s), 26.8 (q),
19.9 (q), 11.4 (q); MS m/z 195 (7), 166 (19), 152 (11), 134 (40),
106 (14), 91 (100), 84 (49); IR (CDCl3) ν 3031, 2953, 2805, 1707,
1452, 1361 cm-1; HRMS found 287.21236, C18H27N2O required
287.21234.
Under the same conditions, adduct 38b (55 mg, 0.19 mmol)
afforded the ketone 45 (21 mg, 38%).
(4aR*,8aR*)-1,2,4a,5,6,7,8,8a-Octah ydr o-3,8,8-tr im eth yl-
6-(m eth ylp h en yl)[1,6]n a p h th yr id in -4-ol-2,2-d 2 Tr iflu or o-
a ceta te (47-d 2‚TF A). The same procedure was followed for
the synthesis of the deuterated derivative 47-d 2‚TF A, starting
from 38b-d 3.
45: Rf ) 0.34; 1H NMR (200 MHz) δ 7.18-7.12 (m, 5H),
3.48-3.32 (m, 1H), 3.55 (A part of an AB system, J ) 13.5
Hz, 1H), 3.20 (B part of an AB system, J ) 13.5 Hz, 1H), 3.18
(ddd, J ) 11.5, 3.5, 2.4 Hz, 1H), 3.00-2.78 (m, 2H), 2.60 (ddd,
J ) 17.6, 9.5, 4.8 Hz, 1H), 2.47 (s, 3H), 2.42 (dd, J ) 11.5, 2.5
Hz, 1H), 2.28 (dt, J ) 17.6, 4.8 Hz, 1H), 1.98 (d, J ) 11.1 Hz,
1H), 1.96 (dd, J ) 11.6, 10.6 Hz, 1H) 1.70 (d, J ) 11.7 Hz,
1H), 1.16 (s, 3H), 0.94 (s, 3H); 13C NMR (50 MHz) δ 211.6 (q),
138.8 (s), 128.6 (d, 2C), 128.1 (d, 2C), 126.8 (d), 72.8 (d), 66.4
(t), 62.6 (t), 53.5 (t), 51.5 (t), 47.0 (q), 44.8 (d), 37.1 (s), 36.6 (t),
27.2 (q), 19.2 (q); GC-MS m/z 286 (3), 174 (12), 162 (11), 120
(19), 91 (100); IR (CDCl3) ν 3031, 2953, 2805, 1707, 1452, 1361
cm-1. Anal. Calcd for C18H26N2O: C, 75.48; H, 9.15; N, 9.78.
Found: C, 75.28; H, 8.77; N, 9.80.
47-d 2‚TF A: 1H NMR (600 MHz, CD3CN) δ 7.54-7.47 (m,
5H), 4.77 (d, J ) 12.1 Hz, 1H), 4.30 (A part of an AB system,
J ) 13.2 Hz, 1H), 4.13 (B part of an AB system, J ) 13.2 Hz,
1H), 3.77 (ddd, J ) 12.0, 4.3, 2.4 Hz, 1H), 3.63 (dt, J ) 12.0,
4.3 Hz, 1H), 3.07 (t, J ) 12.0 Hz, 1H), 3.00 (dd, J ) 12.4, 2.4
Hz, 1H), 2.89 (d, J ) 12.4 Hz, 1H), 1.30 (s, 3H), 1.20 (s, 3H),
0.94 (s, 3H).
Ack n ow led gm en t. Mrs. B. Innocenti and Mr. S.
Papaleo (University of Firenze) are acknowledged for
technical support. This work was financially supported
by the CNR (Italy) and by the CNRS (France) within
an Italian-French Cooperation Program.
(1R*,6R*)-5,5,7-Tr im eth yl-3-(m eth ylp h en yl)-3,7-d ia za -
bicyclo[4.2.0]octa n -8-on e (46). TFA (31 µL, 0.40 mmol) was
added to a solution of the adduct 38a (59 mg, 0.20 mmol) in
toluene (5 mL) at rt. The mixture was refluxed for 2 h.
J O034003G
3280 J . Org. Chem., Vol. 68, No. 8, 2003