Novel prospects of the acidic thermal rearrangement of spiro[cyclopropane- 1,5′-isoxazolidines] to β-lactams

Article abstract of DOI:10.1002/ejoc.200300595

Monocyclic β-lactams were synthesized by a 1,3-cycloaddition/thermal rearrangement process in the presence of a protic acid, starting from methylenecyclopropane derivatives and acyclic nitrones. Five-membered cyclic nitrones failed to give carbapenam structures under the same conditions, affording exclusively the corresponding N-trifluoroacetyl β-amino acid derivatives in the presence of trifluoroacetic acid. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300595

FULL PAPER
Novel Prospects of the Acidic Thermal Rearrangement of Spiro[cyclopropane-
1,5Ј-isoxazolidines] to β-Lactams
Franca M. Cordero,*[a] Maria Salvati,[a] Federica Pisaneschi,[a] and Alberto Brandi*[a]
Dedicated to Professor Francesco De Sarlo on the occasion of his 65th birthday
Keywords: β-Lactams / β-Homoproline / Cycloaddition / Small ring systems / Spiro compounds
Monocyclic β-lactams were synthesized by a 1,3-cycloaddi-
tion/thermal rearrangement process in the presence of a pro-
tic acid, starting from methylenecyclopropane derivatives
and acyclic nitrones. Five-membered cyclic nitrones failed to
give carbapenam structures under the same conditions, af-
fording exclusively the corresponding N-trifluoroacetyl β-
amino acid derivatives in the presence of trifluoroacetic acid.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
arrangement of the same spiro-[cyclopropane-1,5Ј-isoxazol-
idines] to tetrahydropyridin-4-ones.[3]
The search for new versatile syntheses of β-lactam deriva-
tives represents an important field of research because of
the unique biological activity of these molecules. They are
also increasingly being used as valuable intermediates in or-
ganic synthesis.[1]
We have recently disclosed a new distinctive behavior of
3Ј,4Ј-cis ring-fused spiro[cyclopropane-1,5Ј-isoxazolidines]
2, which are smoothly converted into azetidin-2-ones 4 in
the presence of a protic acid at 70Ϫ110 °C. The process is
believed to occur through the formation of a biradical
cationic intermediate 3b, which spontaneously decomposes
to 4 and ethylene (Scheme 1).[2] The formation of azetidin-
2-ones 4 complements the thoroughly studied thermal re-
Isoxazolidines 2 were easily obtained by intramolecular
1,3-dipolar cycloaddition (1,3-DC) of alkylidenecyclopro-
pane nitrones 1,[3,4] and the two-step process — 1,3-dipolar
cycloaddition/acid-mediated thermal rearrangement (1,3-
DC/ATR) — represents a general and useful strategy to
synthesize 3,4-cis-fused bicyclic azetidin-2-ones 4.[2]
To test the general scope of the two-step process towards
different classes of β-lactams we studied the thermal be-
havior, under acidic conditions, of a variety of substituted
spiro[cyclopropane-1,5Ј-isoxazolidines] (5-sCPI), prepared
by intermolecular 1,3-DC reactions. In particular, the for-
mation of monocyclic β-lactams was investigated starting
from acyclic nitrones (Scheme 2).
Scheme 2
Results and Discussion
Scheme 1
C-(2-Chlorophenyl) N-methyl nitrone (5) reacts slowly
with methylenecyclopropane (6) at 50 °C, in a sealed tube,
to afford a 2.2:1 mixture of 4-oxa-5-azaspiro[2.4]heptane (5-
sCPI) 7 and 5-oxa-6-azaspiro[2.4]heptane (4-SpI) 8 in a
non-optimized 34% overall yield, along with 66% of un-
changed nitrone 5 (Scheme 3).
[a]
`
Dipartimento di Chimica Organica ‘‘Ugo Schiff’’, Universita
degli Studi di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: (internat) ϩ 39-055-4573531
E-mail: franca.cordero@unifi.it
Eur. J. Org. Chem. 2004, 2205Ϫ2213
DOI: 10.1002/ejoc.200300595
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. M. Cordero, M. Salvati, F. Pisaneschi, A. Brandi
FULL PAPER
The regioisomeric ratio of the reaction of the chiral
nitrone 13[7,8] with 6 was again 2.6:1 in favor of 5-sCPI 14.
The adducts 14 and 15 were obtained as a mixture of two
diastereomers in a 1:1 and 3.6:1 ratio, respectively. The low
diastereoselectivity in the cycloaddition of acyclic C-alkoxy-
carbonyl nitrones with a chiral moiety bonded at the nitro-
gen atom has been observed previously.[9] Unfortunately,
the two isoxazolidines 14 were not easily separable and only
small amounts of the pure diastereomer 14a was obtained
after repeated chromatographic separations on silica gel.
The equimolar mixture of the two diastereomers 14 af-
forded an inseparable 1:1 mixture of monobactams 17 (61%
yield) by treatment with p-TsOH in CH3CN at 50 °C for
1 h. Under the same reaction conditions, the sole dia-
stereomer 14a was converted into the single β-lactam 17a
in 50% yield. The absolute configuration of 14a and 17a
has not been determined, but the formation of a single dia-
stereomer from the rearrangement demonstrates that the
conversion occurs without racemization of the ring carbon
stereocenters. Although the formation of the simple β-lac-
tams 17 has only limited synthetic value, it was useful to
establish the applicability of the 1,3-DC/ATR approach to
optically active azetidin-2-ones starting from chiral nitro-
nes.
The use of methylenecyclopropane (6) as dipolarophile
provides azetidin-2-one moieties unsubstituted at C-3, but
1-substituted methylenecyclopropane should give 3-substi-
tuted derivatives directly. To this end, the alkoxycarbonyl
function was particularly appealing because it can be easily
converted into other functional group and, at the same
time, induces a complete regiocontrol in favor of the 5-sCPI
in the 1,3-DC with nitrones.[3] Accordingly, we examined
the β-lactam synthesis starting from [(alkoxycarbonyl)me-
thylene]cyclopropanes 19 and the model nitrones 18
(Scheme 5).
Scheme 3
The 5-sCPI 7 was transformed into 4-arylazetidinone 9
by heating in toluene in the presence of 1 equiv. of p-TsOH.
The rearrangement is almost instantaneous at 90 °C, as the
starting material 7 was completely converted after 2 min,
and 9 was recovered in 56% yield after purification by chro-
matography on silica gel. Compound 9 was also obtained
in the presence of TFA (2 equiv.) in 50% yield. The struc-
ture of 9 was assigned on the basis of its spectroscopic
properties such as the IR absorption at 1747 cmϪ1, attri-
buted to the β-lactam carbonyl group, and the 13C NMR
resonance of C-2 at δ ϭ 167.5 ppm.
The cycloaddition of C-ethoxycarbonyl N-benzyl nitrone
(10)[5] with 6 afforded a 2.6:1 mixture of the regioisomers
11 and 12 in 68% overall yield. The 5-sCPI 11 was easily
converted into the N-benzyl monobactam 16 (νCO(β-lac-
ϭ 1763 cmϪ1; δC-2 ϭ 165.6 ppm) in high yield (91%)
tam)
(Scheme 4). The successful formation of 16 proved that the
N-benzyl and alkoxycarbonyl moieties are compatible with
the rearrangement of 5-sCPI under acidic conditions. The
presence of the benzylic protecting group on the nitrogen
atom is particularly significant as it lays the basis for the
synthesis of N-unsubstituted monobactams and for the in-
troduction of chiral auxiliaries to produce optically active
β-lactams, for instance starting from nitrones derived from
(R)- or (S)-N-(1-phenyl-ethyl)hydroxylamine.[6]
The cycloaddition was carried out at 100 °C and afforded
a mixture of cis- and trans-5-sCPI (cis-20) (3-H,4-H: J ϭ
8.4Ϫ8.5 Hz) and trans-21 (3-H,4-H: J ϭ 7.3Ϫ7.7 Hz). As
expected, the cycloaddition regioselectivity was complete
and in favor of the 5-sCPI adduct, although the diastereo-
selectivity was poor.
The separated isoxazolidines cis-20a and trans-21a
yielded the corresponding monobactams cis-22 (3-H,4-H:
J ϭ 5.8 Hz) and trans-23 (3-H,4-H: J ϭ 2.2 Hz),[10] albeit
in poor yield (cis-22: 30%; trans-23: 29%), upon heating at
80 °C in the presence of 1 equiv. of p-TsOH. The cis and
trans relative orientations of the substituents in 5-sCPI 20
and 21 are completely retained in the corresponding azetidi-
nones 22 and 23, which indirectly confirmed the assigned
structures of cycloadducts 20 and 21. Similar results were
obtained starting from N-benzylisoxazolidines cis-20b and
trans-21b.
The poor yields of the oxoazetidinecarboxylates 22, 23
can be attributed to the low stability of these monobactams
under these reaction conditions. The stability of the prod-
ucts can be improved by reducing the alkoxycarbonyl
group. Thus, treatment of isoxazolidines cis-20b and trans-
21b with DIBAL resulted in the selective reduction of the
Scheme 4
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Rearrangement of Spiro[cyclopropane-1,5Ј-isoxazolidines] to β-Lactams
FULL PAPER
acid 33. The structure of compound 33 was confirmed on
the basis of its spectroscopic data. In particular, the 13C
NMR resonances at δ ϭ 175.1 and 155.6 ppm, ascribed to
the CϭO moieties of the carboxylic acid and amide, respec-
tively, and the presence of a four-bond coupling constant
of 3.8 Hz between the fluorine atoms and C-5, confirm a
covalent bond to the trifluoroacetyl moiety.
The application of the two-step process to an enantiopure
nitrone, such as the pyrroline N-oxide 34 derived from
(2S,3S)-tartaric acid,[12] was also investigated. The cycload-
dition of 34 with 6 was highly regio- and diastereoselective
and afforded the three isomeric adducts 35, 36 and 37 in a
16:2:1 ratio after separation (76% overall yield)
(Scheme 7).[13] Both the 5-sCPIs 35 and 36 gave the frag-
mentation process leading to N-trifluoroacetylated β-amino
4
acids 40 (δCOOH ϭ 177.0 and δCON ϭ 156.4 ppm; JF,C-5
ϭ
6.5 Hz) and 41 (δCOOH ϭ 176.8 and δCON ϭ 153.6 ppm;
4JF,C-5 ϭ 3.2 Hz), respectively, upon heating in the presence
of 1.5 equiv. of TFA at 110 °C for 2 min in toluene. It is
worth noting that the acidic conditions for the rearrange-
ment are sufficiently mild to maintain the tert-butyl protect-
ing groups.
Scheme 5
ester moiety without affecting the isoxazolidine NϪO bond
(Scheme 5). The 3-(hydroxymethyl)azetidinones cis-26 and
trans-27 could be obtained by the usual acidic treatment,
from cis-24 and trans-25, respectively, with much better
yields (67Ϫ78%) than the oxidized analogues 22 and 23.
When the 1,3-DC/ATR sequence was applied to five-
membered cyclic nitrones, the expected N-bridgehead bicyc-
lic β-lactams failed to form. The cycloaddition of the pyrro-
line N-oxide 28,[11] derived from methyl proline, with 6 was
highly regioselective (10:1 regioisomeric ratio) and afforded
the 2-spirofused pyrrolo[1,2-b]isoxazole 29 in 61% yield
(Scheme 6).
Scheme 7
As products 40 and 41 were obtained as single dia-
stereomeric compounds, and with NMR spectroscopic data
confirming the relative configuration of the parent isoxazol-
Scheme 6
The tricyclic adduct 29 was selectively converted into in- idines, this is further proof that the rearrangement of the
dolizidinone 31 by heating at 130 °C under neutral con- isoxazoline ring followed by fragmentation occurs, as pre-
ditions.[3] Treatment of 29 with p-TsOH at lower tempera- viously proposed,[2] without affecting the stereogenic
ture (50Ϫ110 °C) afforded a complex mixture of non-β-lac- centres present in the molecule.
tam products. Rearrangement at 110 °C in the presence of
The formation of β-homoprolines 33, 40 and 41 probably
1 equiv. of TFA led to the N-trifluoroacetylated β-amino occurs through the intermediate formation of carbapen-
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F. M. Cordero, M. Salvati, F. Pisaneschi, A. Brandi
FULL PAPER
3 H, NMe), 3.00 (dd, J ϭ 12.1, 8.4 Hz, 1 H, 7-Hb), 4.46 (pseudo-
t, J ϭ 7.6 Hz, 1 H, 6-H), 7.19Ϫ7.41 (m, 3 H, Ar), 7.78 (dd, J ϭ
7.7, 1.9 Hz, 1 H, Ar) ppm. 13C NMR (50 MHz): δ ϭ 10.5 (t, cyclo-
propane), 11.0 (t; cyclopropane), 43.6 (t, C-7), 44.8 (q, NMe), 62.1
(s, C-3), 69.4 (d, C-6), 127.2 (d, Ar), 128.2 (d, Ar), 128.3 (d, Ar),
ames 32, 38 and 39, respectively, which are unstable under
the ATR reaction conditions and immediately undergo
opening of the β-lactam ring followed by acylation of the
nitrogen atom. An analogous reaction has previously been
observed by Stoodley et al. for β-lactams fused to a five-
membered ring in the presence of TFA at room tempera-
ture.[14] Despite the failure to form β-lactams in these cases,
the β-amino acidic (β-homoproline type) structure in com-
pounds 33, 40 and 41 is nicely and conveniently achieved,
and can be easily restored by hydrolysis of the trifluoroacet-
amide moiety and utilized for further synthetic purposes.
129.2 (d, Ar), 133.0 (s, Ar), 138.7 (s, Ar) ppm. IR: ν˜ ϭ 2961 cmϪ1
,
2878, 1473, 1439, 1349. MS (EI): m/z (%) ϭ 223 (19) [Mϩ], 194
(37), 180 (14), 166 (23), 154 (39), 152 (83), 140 (24), 138 (86), 132
(58), 112 (15), 103 (54), 84 (100). C12H14ClNO (223.7): calcd. C
64.43, H 6.31, N 6.26; found C 64.37, H 6.63, N 6.29.
7-(2-Chlorophenyl)-6-methyl-5-oxa-6-azaspiro[2.4]heptane (8): Yel-
low oil; 31% yield (calculated with respect to 34% conversion of 5);
Rf
ϭ
0.26 (ethyl acetate/petroleum ether, 1:30). 1H NMR
(200 MHz): δ ϭ 0.28Ϫ0.31 (m, 1 H, cyclopropane), 0.36Ϫ0.52 (m,
1 H, cyclopropane), 0.81Ϫ1.00 (m, 2 H, cyclopropane), 2.80 (s, 3
H, NMe), 3.98 (d, J ϭ 7.7 Hz, 1 H, 4-Ha), 4.13 (d, J ϭ 7.7 Hz, 1
H, 4-Hb), 4.36 (s, 1 H, 7-H), 7.21Ϫ7.38 (m, 3 H, Ar), 7.68 (dd,
J ϭ 7.7, 1.8 Hz, 1 H, Ar) ppm. 13C NMR (50 MHz): δ ϭ 8.5 (t,
cyclopropane), 11.5 (t, cyclopropane), 31.7 (s, C-3), 44.3 (q, NMe),
72.7 (d, C-7), 74.4 (t, C-4), 127.0 (d, Ar), 128.5 (d, Ar), 129.1 (d,
Ar), 130.4 (d, Ar), 133.9 (s, Ar), 135.9 (s, Ar) ppm. IR: ν˜ ϭ 2962
cmϪ1, 2929, 1663, 1609, 1363, 1264, 1036. MS (EI): m/z (%) ϭ 223
(15) [Mϩ], 194 (15), 188 (8), 152 (25), 142 (100), 128 (41), 115 (33),
112 (16). C12H14ClNO (223.7): calcd. C 64.43, H 6.31, N 6.26;
found C 64.62, H 5.95, N 5.93.
Conclusion
New prospects for the two-step 1,3-DC/ATR process in
the synthesis of monocyclic β-lactams or β-homoprolines
have been described. Appealing features of the approach
include the ready availability of the starting materials
(nitrones and methylenecyclopropanes) and the wide range
of accessible products selectively substituted with various
functionalities. The complete control of the stereogenic
centres of the isoxazolidine precursors allows the appli-
cation of this new strategy to the synthesis of more complex
β-lactams or β-amino acids of biological interest.
Ethyl 5-(Phenylmethyl)-4-oxa-5-azaspiro[2.4]heptane-6-carboxylate
(11): Yellow oil; 49% yield; Rf ϭ 0.29 (ethyl acetate/petroleum ether,
1:15). 1H NMR (200 MHz): δ ϭ 0.69Ϫ0.70 (m, 2 H, cyclopropane),
0.99Ϫ1.00 (m, 2 H, cyclopropane), 1.24 (t, J ϭ 7.1 Hz, 3 H,
OCH2CH3), 2.61 (A part of an ABX system, J ϭ 12.6, 6.2 Hz, 1
H, 7-Ha), 2.63 (B part of an ABX system, J ϭ 12.2, 6.2 Hz, 1 H,
7-Hb), 3.83 (dd, X part of an ABX system, J ϭ 8.6, 6.0 Hz, 1 H,
6-H), 4.13 (A part of an AB system, J ϭ 12.1 Hz, 1 H, NCHH),
4.16 (q, J ϭ 7.1 Hz, 2 H, OCH2CH3), 4.22 (B part of an AB system,
J ϭ 13.2 Hz, 1 H, NCHH), 7.26Ϫ7.43 (m, 5 H, Ph) ppm. 13C NMR
(50 MHz): δ ϭ 9.6 (t, cyclopropane), 11.1 (t, cyclopropane), 14.1
(q, OCH2CH3), 38.0 (t, C-7), 61.2 (t, NCH2), 62.4 (t, OCH2), 62.4
(s, C-3), 67.5 (d, C-6), 127.5 (d, Ph), 128.3 (d, 2C, Ph), 129.2 (d,
Experimental Section
General Remarks: All the reactions requiring anhydrous conditions
were carried out under nitrogen and the solvents were dried appro-
priately before use. Rf values refer to TLC on 0.25 mm silica gel
plates (Merck F254). Melting points (m.p.) were determined with
an RCH Kofler apparatus. Polarimetric measures were performed
with a JASCO DIP-370 or a PerkinϪElmer 343 polarimeter. NMR
spectra were recorded with Varian Gemini (1H, 200 MHz), Bruker
AVANCE 400 (1H, 400 MHz), or Bruker DRX-500 (1H, 500 MHz)
instrument with CDCl3 as solvent, unless otherwise specified. The
NMR spectroscopic data are reported in δ (ppm) from TMS at
25 °C. IR spectra were recorded with a PerkinϪElmer 881 or a
PerkinϪElmer Spectrum BX FT-IR System spectrophotometer in
CDCl3 solution. Mass spectra were recorded with a QMD 1000
Carlo Erba instrument by GC or direct inlet; relative percentages
are shown in parentheses. Elemental analyses were performed with
a PerkinϪElmer 2400 analyzer. Accurate mass spectra were re-
corded with a MAT 95S.
2C, Ph), 136.6 (s, Ph), 171.0 (s, CO) ppm. IR: ν˜ ϭ 3670 cmϪ1
,
3454, 3032, 2985, 2875, 1740, 1496, 1454, 1375, 1346, 1273, 1201,
1037, 1014. MS (EI): m/z (%) ϭ 261 (2) [Mϩ], 232 (1), 217 (1), 188
(35), 170 (2), 132 (15), 126 (2), 91 (100), 67 (5), 65 (37), 57 (25).
C15H19NO3 (261.3): calcd. C 68.94, H 7.33, N 5.36; found C 69.02,
H 7.28, N 5.30.
Ethyl 6-(Phenylmethyl)-5-oxa-6-azaspiro[2.4]heptane-7-carboxylate
(12): Colorless oil; 19% yield; Rf ϭ 0.16 (ethyl acetate/petroleum
1
ether, 1:15). H NMR (200 MHz): δ ϭ 0.64Ϫ0.72 (m, 1 H, cyclo-
propane), 0.76Ϫ0.88 (m, 3 H, cyclopropane), 1.20 (t, J ϭ 7.1 Hz,
3 H, OCH2CH3), 3.41 (s, 1 H, 7-H), 3.81 (A part of an AB system,
J ϭ 7.3 Hz, 1 H, 4-Ha), 4.05 (B part of an AB system, J ϭ 7.3 Hz,
1 H, 4-Hb), 4.06 (A part of an AB system, J ϭ 11.8 Hz, 1 H,
NCHH), 4.10 (q, J ϭ 7.1 Hz, 2 H, OCH2), 4.22 (B part of an AB
system, J ϭ 12.6 Hz, 1 H, NCHH), 7.25Ϫ7.41 (m, 5 H, Ph) ppm.
13C NMR (50 MHz): δ ϭ 6.7 (t, cyclopropane), 13.3 (t, cyclopro-
pane), 14.2 (q, OCH2CH3), 28.4 (s, C-3), 60.9 (t, NCH2), 61.8 (t,
OCH2), 72.0 (d, C-7), 73.5 (t, C-4), 127.6 (d, Ph), 128.2 (d, Ph),
128.3 (d, Ph), 129.1 (d, Ph), 129.3 (d, Ph), 136.2 (s, Ph), 169.7 (s,
CO) ppm. IR: ν˜ ϭ 3067 cmϪ1, 3032, 2938, 2872, 1742, 1497, 1455,
1372, 1340, 1275, 1184, 1030. MS (EI): m/z (%) ϭ 261 (7) [Mϩ],
188 (100), 170 (12), 104 (23), 91 (100), 89 (44), 77 (32), 65 (100),
53 (25), 51 (37). C15H19NO3 (261.3): calcd. C 68.94, H 7.33, N 5.36;
found C 68.73, H 7.42, N 5.29.
Intermolecular Cycloaddition of the Nitrones 5, 10, 28, and 34 with
Methylenecyclopropane (6). General Procedure: Methylenecyclopro-
pane (6) (9.0 mmol for 5, 28, 34; 2.9 mmol for 10) was added to a
solution of the nitrone (5, 28, 34: 3.0 mmol; 10: 1.2 mmol) in tolu-
ene (4 mL; 1 mL for 10) and the mixture was heated in a sealed
vial at 42Ϫ60 °C for 5Ϫ10 d (see Schemes 3, 4, 6 and 7). The
solvent was then removed under reduced pressure and the crude
products were purified by chromatography on silica gel to give the
pure regioisomer adducts 7؊8, 11؊12, 29؊30, and 35؊37.
6-(2-Chlorophenyl)-5-methyl-4-oxa-5-azaspiro[2.4]heptane (7): Pale-
yellow oil; 69% yield (calculated with respect to 34% conversion
of 5); Rf ϭ 0.40 (ethyl acetate/petroleum ether, 1:30). 1H NMR
(200 MHz): δ ϭ 0.59Ϫ0.82 (m, 2 H, cyclopropane), 0.99Ϫ1.09 (m,
2 H, cyclopropane), 2.27 (dd, J ϭ 12.1, 7.0 Hz, 1 H, 7-Ha), 2.81 (s,
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Rearrangement of Spiro[cyclopropane-1,5Ј-isoxazolidines] to β-Lactams
FULL PAPER
Methyl Dihydro-3ЈH-spiro[cyclopropane-1,2Ј-pyrrolo[1,2-b]isoxazole]-
3aЈ(4ЈH)-carboxylate (29): Yellow oil; 61% yield; Rf ϭ 0.15 (ethyl
acetate/petroleum ether, 1:2). 1H NMR (500 MHz): δ ϭ 0.60Ϫ0.67
(m, 1 H, cyclopropane), 0.71Ϫ0.77 (m, 1 H, cyclopropane),
0.91Ϫ0.98 (m, 1 H, cyclopropane), 1.00Ϫ1.08 (m, 1 H, cyclopro-
pane), 1.86Ϫ1.94 (m, 1 H, 5Ј-Ha), 2.03Ϫ2.18 (m, 2 H, 4Ј-Ha, 5Ј-
Hb), 2.26 (A part of an AB system, J ϭ 15.0 Hz, 1 H, 3Ј-Ha),
2.32Ϫ2.39 (m, 1 H, 4Ј-Hb), 2.94 (B part of an AB system, J ϭ
15.0 Hz, 1 H, 3Ј-Hb), 3.26 (ddd, J ϭ 12.5, 8.5, 6.5 Hz, 1 H, 6Ј-Ha),
3.39 (ddd, J ϭ 12.0, 5.5, 1.0 Hz, 1 H, 6Ј-Hb), 3.77 (s, 3 H, CO2Me)
ppm. 13C NMR (50 MHz): δ ϭ 9.1 (t, cyclopropane), 9.7 (t, cyclo-
propane), 24.5, 36.3, 45.6 (t, C-3Ј, C-4Ј, C-5Ј), 52.6 (q, CO2Me),
57.4 (t, C-6Ј), 62.3 (s, C-3aЈ), 78.2 (s, C-2Ј), 174.3 (s, CO2Me) ppm.
IR: ν˜ ϭ 3081 cmϪ1, 2978, 1728, 1437, 1287, 1262, 1193, 1109. MS
(EI): m/z (%) ϭ 197 (4) [Mϩ], 182 (1), 138 (32), 126 (10), 110 (44),
96 (31), 82 (100). C10H15NO3 (197.2): calcd. C 60.90, H 7.67, N
7.10; found C 60.47, H 7.75, N 6.80.
57 (100). C16H29NO3 (283.4): calcd. C 67.81, H 10.31, N 4.94;
found C 67.79, H 10.72, N 5.00.
(3aЈR,4ЈR,5ЈR)-4Ј,5Ј-Di-tert-butoxytetrahydrospiro[cyclo-
propane-1,3Ј-pyrrolo[1,2-b]isoxazole] (37): Colorless oil; 4% yield;
1
Rf ϭ 0.22 (diethyl ether/pentane, 2:1). H NMR (200 MHz): δ ϭ
0.63Ϫ0.88 (m, 3 H, cyclopropane), 0.98Ϫ1.04 (m, 1 H, cyclopro-
pane), 1.15 (s, 9 H, CMe3), 1.18 (s, 9 H, CMe3), 3.03 (dd, J ϭ 12.1,
5.5 Hz, 1 H, 6Ј-Ha), 3.25 (d, J ϭ 2.6 Hz, 1 H, 3aЈ-H), 3.51 (A part
of an AB system, J ϭ 7.3 Hz, 1 H, 2Ј-Ha), 3.56 (dd, J ϭ 11.7,
5.5 Hz, 1 H, 6Ј-Hb), 3.78 (t, J ϭ 2.7 Hz, 1 H, 4Ј-H), 3.87 (dt, J ϭ
5.5, 2.9 Hz, 1 H, 5Ј-H), 4.17 (B part of an AB system, J ϭ 7.3 Hz,
1 H, 2Ј-Hb) ppm. 13C NMR (50 MHz): δ ϭ 7.4 (t, cyclopropane),
13.3 (t, cyclopropane), 15.3 (s, C-3Ј), 28.6 (q, 3C, CMe3), 28.7 (q,
3C, CMe3), 61.8 (t; C-6Ј), 65.8 (d, C-3aЈ), 73.3 (t, C-2Ј), 73.7 (s,
CMe3), 74.2 (s, CMe3), 75.8, 80.7 (d, C-4Ј, C-5Ј) ppm. IR: ν˜ ϭ
2979 cmϪ1, 1392, 1369, 1253, 1189, 1105. MS (EI): m/z (%) ϭ 283
(1) [Mϩ], 228 (25), 172 (80), 170 (71), 154 (62), 142 (33), 57 (88), 56
(100). C16H29NO3 (283.4): calcd. C 67.81, H 10.31, N 4.94; found C
67.56, H 10.30, N 5.38.
Methyl
Dihydrospiro[cyclopropane-1,3Ј-pyrrolo[1,2-b]isoxazole]-
3aЈ(4ЈH)-carboxylate (30): Colorless oil; 6% yield; Rf ϭ 0.33 (di-
1
ethyl ether/pentane, 3:1). H NMR (200 MHz): δ ϭ 0.55Ϫ0.90 (m,
Intermolecular Cycloaddition of the Nitrone 13 with Methylenecyclo-
propane (6): According to the General Procedure, compounds 14
and 15 were obtained from nitrone 13 (129 mg, 0.58 mmol) and an
excess of 6. The two 5-sCPIs 14a and 14b were obtained in 40%
yield as a 1:1 mixture of diastereoisomers and the two 4-SpIs 15a
and 15b in 15% yield as a 3.6:1 mixture of diastereoisomers. The
two 5-sCPIs were further separated by HPLC (15a: Rt ϭ 24; 15b:
Rt ϭ 37; CH2Cl2/hexane, 5% Ǟ30% CH2Cl2 in 25 min) whereas
the 4-SpIs were characterized as a mixture.
4 H, cyclopropane), 1.60Ϫ2.10 (m, 3 H, 4Ј-Ha, 5Ј-H), 2.10Ϫ2.35
(m, 1 H, 4Ј-Hb), 3.27 (m, 2 H, 6Ј-H), 3.75 (s, 3 H, CO2Me), 3.84
(part A of an AB system, J ϭ 8.4 Hz, 1 H, 2Ј-Ha), 3.90 (part B of
an AB system, J ϭ 8.0 Hz, 1 H, 2Ј-Hb) ppm. 13C NMR (50 MHz):
δ ϭ 9.1 (t, cyclopropane), 9.7 (t, cyclopropane), 23.9, 32.6 (t, C-4Ј,
C-5Ј), 34.1 (s, C-3Ј), 52.4 (q, CO2Me), 56.7 (t, C-6Ј), 74.0 (t, C-2Ј),
79.2 (s, C-3aЈ), 173.2 (s,CO2Me) ppm. IR: ν˜ ϭ 3081 cmϪ1, 2956,
1725, 1431, 1270, 1165, 1113. MS (EI): m/z (%) ϭ 197 (0.2) [Mϩ],
138 (100), 96 (4), 84 (70), 82 (8).
Ethyl
5-[(1R)-1-Phenylethyl]-4-oxa-5-azaspiro[2.4]heptane-6-car-
(3aЈR,4ЈR,5ЈR)-4Ј,5Ј-Di-tert-butoxytetrahydro-3ЈH-spiro[cyclo-
propane-1,2Ј-pyrrolo[1,2-b]isoxazole] (35): White solid; 64% yield;
Rf ϭ 0.52 (ethyl acetate/petroleum ether, 1:2); m.p. 45Ϫ47 °C.
[α]2D2 ϭ Ϫ19.8 (c ϭ 0.8, CHCl3). 1H NMR (200 MHz): δ ϭ
0.50Ϫ0.63 (m, 1 H, cyclopropane), 0.67Ϫ0.95 (m, 2 H, cyclopro-
pane), 0.96Ϫ1.08 (m, 1 H, cyclopropane), 1.17 (s, 18 H, CMe3),
2.21 (dd, J ϭ 12.1, 6.0 Hz, 1 H, 3Ј-Ha), 2.58 (dd, J ϭ 12.1, 9.2 Hz,
1 H, 3Ј-Hb), 3.11 (t, J ϭ 9.5 Hz, 1 H, 6Ј-Ha), 3.40 (dd, J ϭ 9.5,
5.9 Hz, 1 H, 6Ј-Hb), 3.58Ϫ3.65 (m, 1 H, 3aЈ-H), 3.80Ϫ3.90 (m, 1
H, 4Ј-H), 3.96 (dt, J ϭ 9.5, 6.2 Hz, 1 H, 5Ј-H) ppm. 13C NMR
(50 MHz): δ ϭ 6.6 (t, cyclopropane), 12.6 (t, cyclopropane), 28.5
(q, 3C; CMe3), 28.8 (q, 3C, CMe3), 40.3 (t, C-3Ј), 58.7 (t, C-6Ј),
61.8 (s, C-2Ј), 70.3 (d, C-3aЈ), 73.7 (s, CMe3), 73.8 (s, CMe3), 75.8,
81.5 (d, C-4Ј, C-5Ј) ppm. IR: ν˜ ϭ 3081 cmϪ1, 2979, 1599, 1451,
1389, 1187, 1083. MS (EI): m/z (%) ϭ 283 (1) [Mϩ], 226 (15), 200
(3), 170 (14), 154 (3), 142 (10), 112 (14), 84 (36), 57 (100).
C16H29NO3 (283.4): calcd. C 67.81, H 10.31, N 4.94; found C
67.99, H 10.44, N 5.02.
boxylate (14). 14a: Colorless oil; 8% yield; Rf ϭ 0.43 (ethyl acetate/
petroleum ether, 1:4). [α]2D0 ϭ ϩ34.4 (c ϭ 0.4 CHCl3). 1H NMR
(200 MHz): δ ϭ 0.86 (m, 2 H, cyclopropane), 0.60 (m, 2 H, cyclo-
propane), 1.30 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.42 (d, J ϭ 6.6 Hz,
3 H, NCHCH3), 2.42 (dd, J ϭ 11.9, 9.0 Hz, 1 H, 7-Ha), 2.60 (dd,
J ϭ 11.9, 6.0 Hz, 1 H, 7-Hb), 3.91 (dd, J ϭ 9.0, 5.7 Hz, 1 H, 6-H),
4.15 (q, J ϭ 6.8 Hz, 1 H, NCHCH3), 4.22 (q, J ϭ 6.8 Hz, 2 H,
OCH2CH3), 7.23Ϫ7.39 (m, 5 H, Ph) ppm. 13C NMR (50 MHz):
δ
ϭ 9.2 (t, cyclopropane), 10.4 (t, cyclopropane), 13.9 (q,
OCH2CH3), 21.0 (q, NCHCH3), 38.5 (t, C-7), 60.9 (t, OCH2CH3),
61.7 (s, C-3), 65.0, 65.1 (d, C-6, NCHCH3), 126.6 (d, Ph), 126.8 (d,
Ph), 127.5 (d, Ph), 127.8 (d, Ph), 128.3 (d, Ph), 142.0 (s, Ph), 171.2
(s, CO) ppm. GC-MS: m/z (%) ϭ 275 (3) [Mϩ], 246 (2), 202 (35),
105 (100), 98 (18), 79 (15), 77 (18). 14b: Colorless oil; 8% yield;
Rf ϭ 0.52 (ethyl acetate/petroleum ether, 1:4). [α]2D0 ϭ ϩ41.9 (c ϭ
1
0.3, CHCl3). H NMR (200 MHz): δ ϭ 0.69Ϫ0.73 (m, 2 H, cyclo-
propane), 1.04Ϫ1.05 (m, 2 H, cyclopropane), 1.16 (t, J ϭ 7.1 Hz,
3 H, OCH2CH3), 1.47 (d, J ϭ 6.6 Hz, 3 H, NCHCH3), 2.47 (dd,
J ϭ 12.3, 8.6 Hz, 1 H, 7-Ha), 2.66 (dd, J ϭ 12.5, 4.4 Hz, 1 H, 7-
Hb), 3.78 (dd, J ϭ 8.6, 4.4 Hz, 1 H, 6-H), 3.98Ϫ4.11 (m, 3 H,
NCHCH3, OCH2CH3), 7.31Ϫ7.37 (m, 5 H, Ph) ppm. 13C NMR
(50 MHz): δ ϭ 7.4 (t, cyclopropane), 12.0 (t, cyclopropane), 13.7
(q, OCH2CH3), 21.9 (q, NCHCH3), 37.4 (t, C-7), 60.7 (t,
OCH2CH3), 62.2 (s, C-3), 65.8, 66.1 (d, C-6, NCHCH3), 127.0 (d,
Ph), 127.4 (d, Ph), 127.7 (d, Ph), 127.9 (d, Ph), 128.1 (d, Ph), 142.0
(s, Ph), 171.3 (s, CO) ppm. GC-MS: m/z (%) ϭ 275 (1) [Mϩ], 202
(24), 105 (100), 98 (22), 77 (100).
(3aЈS,4ЈR,5ЈR)-4Ј,5Ј-Di-tert-butoxytetrahydro-3ЈH-spiro[cyclo-
propane-1,2Ј-pyrrolo[1,2-b]isoxazole] (36): Colorless oil; 8% yield;
Rf ϭ 0.38 (diethyl ether/pentane, 2:1). [α]2D3 ϭ Ϫ71.1 (c ϭ 1.6,
EtOH). 1H NMR (200 MHz): δ ϭ 0.54Ϫ0.63 (m, 1 H, cyclopro-
pane), 0.70Ϫ0.80 (m, 1 H, cyclopropane), 0.84Ϫ1.05 (m, 2 H,
cyclopropane), 1.18 (s, 18 H, CMe3), 2.13 (m, 1 H, 3Ј-Ha), 2.62
(dm, J ϭ 12.1 Hz, 1 H, 3Ј-Hb), 2.92 (dd, J ϭ 13.9, 9.5 Hz, 1 H, 6Ј-
Ha), 3.45 (dd, J ϭ 13.9, 7.0 Hz, 1 H, 6Ј-Hb), 3.86Ϫ3.98 (m, 2 H,
3aЈ-H, 4Ј-H), 4.06Ϫ4.24 (m, 1 H, 5Ј-H) ppm. 13C NMR (50 MHz):
δ ϭ 9.6 (t, cyclopropane), 10.1 (t, cyclopropane), 28.5 (q, 6C, Ethyl
6-[(1R)-1-Phenylethyl]-5-oxa-6-azaspiro[2.4]heptane-7-car-
CMe3), 36.0 (t, C-3Ј), 59.5 (t, C-6Ј), 62.9 (s, C-2Ј), 66.5 (d, C-3aЈ), boxylate (15a and 15b): Colorless oil; 15% yield (major dia-
73.5 (s, CMe3), 73.8 (s, CMe3), 74.2, 76.7 (d, C-4Ј, C-5Ј) ppm. IR: stereoisomer/minor diastereoisomer ϭ 3.6:1); Rf ϭ 0.56 (ethyl acet-
ν˜ ϭ 2977 cmϪ1, 1390, 1365, 1192, 1117, 1011. MS (EI): m/z (%) ϭ
ate/petroleum ether, 1:4). 1H NMR (200 MHz): δ ϭ 0.66Ϫ0.80 (m,
283 (2) [Mϩ], 226 (4), 170 (8), 142 (18), 126 (16), 112 (54), 83 (23), 4 H major ϩ 4 H minor, cyclopropane), 1.14 (t, J ϭ 7.1 Hz, 3 H
Eur. J. Org. Chem. 2004, 2205Ϫ2213
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2209

F. M. Cordero, M. Salvati, F. Pisaneschi, A. Brandi
FULL PAPER
major, OCH2CH3), 1.14 (t, J ϭ 7.1 Hz, 3 H minor, OCH2CH3), δ ϭ 13.7 (q, OCH2CH3), 19.3 (q, NCHCH3), 40.8 (t, C-3), 49.5 (d,
1.43 (d, J ϭ 7.0 Hz, 3 H minor, NCHCH3), 1.56 (d, J ϭ 6.2 Hz, 3 C-2), 54.6 (d, NCHCH3), 61.1 (t, OCH2CH3), 126.6 (d, 2C, Ph),
H major, NCHCH3), 3.29 (s, 1 H major, 7-H), 3.44 (s, 1 H minor, 127.5 (d, Ph), 128.3 (d, 2C, Ph), 140.0 (s, Ph), 165.4 (s, C-4), 170.2
7-H), 3.63 (d, J ϭ 7.7 Hz, 1 H minor, 4-Ha), 3.83 (d, J ϭ 7.3 Hz, (s, COCH2CH3) ppm. MS (EI): m/z (%) ϭ 232 (12) [Mϩ Ϫ Me],
1 H major; 4-Ha), 3.94Ϫ4.24 (m, 5 H major ϩ 5 H minor; 4-Hb, 174 (33), 159 (1), 146 (32), 142 (4), 120 (79), 105 (100), 77 (71), 73
1
OCH2CH3, NCH2CH3), 7.23Ϫ7.34 (m, 5 H major ϩ 5 H minor; (31). 17b: Colorless oil, 61% yield. H NMR (200 MHz, selection
1
Ph) ppm. 13C NMR (50 MHz, major adduct): δ ϭ 6.0 (t, cyclopro-
pane), 13.9 (t, cyclopropane), 14.1 (q, OCH2CH3), 21.8 (q,
of signals of the H NMR spectrum of the 17a and 17b mixture):
δ ϭ 1.25 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.59 (d, J ϭ 7.0 Hz, 3
NCHCH3), 28.5 (t, C-3), 60.7 (t, OCH2CH3), 66.2, 71.5 (d, C-7, H, NCHCH3), 2.93 (dd, J ϭ 14.3, 2.7 Hz, 1 H, 3-Ha), 3.06 (dd,
NCHCH3), 73.2 (t, C-4), 127.7 (d, Ph), 127.8 (d, Ph), 127.9 (d, Ph), J ϭ 14.3, 5.5 Hz, 1 H, 3-Hb), 3.82 (dd, J ϭ 5.3, 2.7 Hz, 1 H, 2-H),
128.3 (d, Ph), 128.6 (d, Ph), 142.2 (s, Ph), 170.4 (s, CO) ppm. IR: 4.13 (A part of an ABX3 system, J ϭ 7.1 Hz, 1 H, OCHHCH3),
ν˜ ϭ 3066 cmϪ1, 2982, 2936, 2872, 1740, 1602, 1493, 1373, 1281, 4.15 (B part of an ABX3 system, J ϭ 7.0 Hz, 1 H, OCHHCH3),
1182, 1028. GC-MS: m/z (%) ϭ 275 (3) [Mϩ], 202 (100), 149 (36),
105 (100), 103 (50), 98 (100), 77 (80). C16H21NO3 (275.3): calcd. C
69.79, H 7.69, N 5.09; found C 69.49, H 7.64, N 5.19.
4.96 (q, J ϭ 7.2 Hz, 1 H, NCHCH3), 7.26Ϫ7.42 (m, 5 H, Ph) ppm.
Methyl (6R*,7R*)-5-Methyl-6-phenyl-4-oxa-5-azaspiro[2.4]heptane-
7-carboxylate (cis-20a) and Methyl (6R*,7S*)-5-Methyl-6-phenyl-4-
oxa-5-azaspiro[2.4]heptane-7-carboxylate (trans-21a): In a Sovirel
vial, the nitrone 18a (405 mg, 3.00 mmol) was added to a solution
of the ester 19a (251 mg, 2.24 mmol) in toluene (0.50 mL) and the
reaction mixture was heated in an oven at 100 °C for 21 h. Evapor-
ation of the solvent under reduced pressure and purification of the
crude product by chromatography on silica gel (ethyl acetate/petro-
leum ether, 1:7) afforded the two adducts cis-20a (237 mg, 43%)
and trans-21a (210 mg, 38%). cis-20a: Yellow oil; Rf ϭ 0.17. 1H
NMR (200 MHz): δ ϭ 0.68Ϫ0.82 (m, 1 H, cyclopropane),
0.84Ϫ1.00 (m, 1 H, cyclopropane), 1.01Ϫ1.22 (m, 2 H, cyclopro-
pane), 2.75 (s, 3 H, NMe), 3.28 (s, 3 H, OMe), 3.69 (d, J ϭ 8.5 Hz,
1 H, 7-H), 4.29 (d, J ϭ 8.5 Hz, 1 H, 6-H), 7.25Ϫ7.43 (m, 5 H,
Ph) ppm. 13C NMR (50 MHz): δ ϭ 10.2 (t, cyclopropane), 11.3 (t,
cyclopropane), 44.5 (q, NMe), 51.3 (q, OMe), 58.9 (d, C-7), 63.8
(s, C-3), 76.2 (d, C-6), 127.8 (d, 2C, Ph), 128.0 (d, Ph), 128.2 (d,
2C, Ph), 136.0 (s, Ph), 170.3 (s, CO) ppm. trans-21a: Pale yellow
oil; Rf ϭ 0.21. 1H NMR (200 MHz): δ ϭ 0.79Ϫ0.83 (m, 2 H, cyclo-
propane), 1.17Ϫ1.28 (m, 2 H, cyclopropane), 2.68 (s, 3 H, NMe),
3.36 (d, J ϭ 7.7 Hz, 1 H, 7-H), 3.70 (s, 3 H, OMe), 4.22 (d, J ϭ
7.7 Hz, 1 H, 6-H), 7.30Ϫ7.50 (m, 5 H, Ph) ppm. 13C NMR
(50 MHz): δ ϭ 7.2 (t, cyclopropane), 14.1 (t, cyclopropane), 43.3
(q, NMe), 51.8 (q, OMe), 61.2 (d, C-7), 64.4 (s, C-3), 77.2 (d, C-
6), 127.8 (d, 2C,Ph), 128.2 (d, Ph), 128.6 (d, 2C, Ph), 138.0 (s, Ph),
171.5 (s, CO) ppm. IR: ν˜ ϭ 3034 cmϪ1, 3003, 2955, 2879, 2780,
1737, 1604, 1494, 1455, 1437, 1346, 1330, 1285, 1248, 1192, 1172,
1021. MS (EI): m/z (%) ϭ 247 (1) [Mϩ], 216 (5), 188 (5), 168 (34),
111 (6), 106 (35), 92 (100), 78 (79). C14H17NO3 (247.3) calcd. C
68.00, H 6.93, N 5.66; found C 68.40, H 6.96, N 5.53.
Synthesis of β-Lactams 9, 16, 17. General Procedure: p-Toluensul-
fonic acid (1 equiv.) was added to a 0.04  solution of the cycload-
ducts 7, 11 or 14 (1:1 mixture of the two diastereoisomers or pure
14a) (0.02Ϫ0.25 mmol) in CH3CN and the mixture was heated at
50Ϫ90 °C for between 2 min and 1 h (cf. Schemes 3 and 4). The
solvent was then removed under reduced pressure. Purification of
the crude products by chromatography on silica gel afforded pure
β-lactams 9, 16 and 17 (1:1 mixture of the two diastereoisomers or
pure 17a).
4-(2-Chlorophenyl)-1-methylazetidin-2-one (9): Pale yellow oil; 56%
yield; Rf ϭ 0.28 (ethyl acetate/petroleum ether, 1:2). 1H NMR
(200 MHz): δ ϭ 2.76 (dd, J ϭ 14.4, 2.4 Hz, 1 H, 3-Ha), 2.87 (s, 3
H, NMe), 3.47 (dd, J ϭ 14.4, 5.3 Hz, 1 H, 3-Hb), 4.97 (dd, J ϭ
5.3, 2.4 Hz, 1 H, 4-H), 7.31Ϫ7.43 (m, 4 H, Ar) ppm. 13C NMR
(50 MHz): δ ϭ 27.8 (q, NMe), 46.3 (t, C-3), 52.5 (d, C-4), 125.8
(d, Ar), 127.3 (d, Ar), 129.1 (d, Ar), 129.9 (d, Ar), 133.0 (s, Ar),
136.0 (s, Ar), 167.5 (s, C-2) ppm. IR: ν˜ ϭ 2961 cmϪ1, 1747, 1446,
1386, 1053. MS (EI): m/z (%) ϭ 195 (1) [Mϩ], 152 (22), 140 (31),
138 (100), 103 (54), 84 (61), 57 (35). C10H10ClNO (195.6): calcd. C
61.39, H 5.15, N 7.16; found C 61.13, H 5.13, N 7.52.
Ethyl 4-Oxo-1-(phenylmethyl)-2-azetidinecarboxylate (16): Color-
less oil; 91% yield; Rf ϭ 0.30 (ethyl acetate/pentane, 1:4). 1H NMR
(200 MHz): δ ϭ 1.23 (t, J ϭ 7.2 Hz, 3 H, och2ch3), 3.01 (dm, J ϭ
14.6 Hz, 1 H, 3-Ha), 3.20 (dd, J ϭ 14.6, 5.5 Hz, 1 H, 3-Hb),
3.89Ϫ3.93 (m, 1 H, 2-H), 4.14 (q, J ϭ 7.2 Hz, 2 H, och2ch3), 4.17
(A part of an AB system, J ϭ 15.0 Hz, 1 H, NCHH), 4.74 (B part
of an AB system, J ϭ 15.0 Hz, 1 H, NCHH), 7.21Ϫ7.34 (m, 5 H,
Ph) ppm. 13C NMR (50 MHz): δ ϭ 14.0 (q, och2ch3), 41.9 (t, C-
3), 45.6 (d, C-2), 50.1 (t, NCH2), 61.5 (t, och2ch3), 127.8 (d, Ph),
128.4 (d, 2C, Ph), 128.7 (d, 2C, Ph), 134.8 (s, Ph), 165.6 (s, C-4),
170.1 (s, COCH2) ppm. MS (EI): m/z (%) ϭ 234 (1) [MHϩ], 205
(90), 160 (100), 132 (100), 128 (7), 117 (16), 106 (52), 101 (31), 91
(100), 77 (29), 65 (99), 55 (46). IR: ν˜ ϭ 3671 cmϪ1, 3488, 3034,
2962, 1755 br, 1496, 1441, 1392, 1353, 1294, 1218, 1087, 1049, 1029.
C13H15NO3 (233.3): calcd. C 66.94, H 6.48, N 6.00; found C 66.59,
H 6.55, N 5.73.
Ethyl (6R*,7R*)-6-Phenyl-5-(phenylmethyl)-4-oxa-5-azaspiro[2.4]-
heptane-7-carboxylate (cis-20b) and Ethyl (6R*,7S*)-6-Phenyl-5-
(phenylmethyl)-4-oxa-5-azaspiro[2.4]heptane-7-carboxylate (trans-
21b): According to the same procedure, the two adducts cis-20b
(228 mg, 28%) and trans-21b (316 mg, 40%) were obtained from
the nitrone 18b (500 mg, 2.37 mmol) and the ester 19b (388 mg,
3.08 mmol). cis-20b: Colorless oil; Rf ϭ 0.21 (ethyl acetate/petro-
1
leum ether, 1:20). H NMR (200 MHz): δ ϭ 0.83 (t, J ϭ 7.1 Hz, 3
H, OCH2CH3), 1.03Ϫ1.09 (m, 2 H, cyclopropane), 1.24Ϫ1.34 (m,
2 H, cyclopropane), 3.67 (A part of an ABX3 system, J ϭ 7.0 Hz,
1 H, CHHCH3), 3.68 (A part of an ABX3 system, J ϭ 7.0 Hz, 1
H, CHHCH3), 3.71 (d, J ϭ 8.4 Hz, 1 H, 7-H), 4.01 (B part of an
Ethyl 4-Oxo-1-[(1R)-1-phenylethyl]-2-azetidinecarboxylate (17).
17a: Colorless oil; 50% yield; Rf ϭ 0.21 (ethyl acetate/petroleum
ether, 1:4). 1H NMR (200 MHz): δ ϭ 1.16 (t, J ϭ 7.1 Hz, 3 H,
OCH2CH3), 1.74 (d, J ϭ 7.3 Hz, 3 H, NCHCH3), 2.91 (A part of AB system, J ϭ 14.3 Hz, 1 H, NCHH), 4.15 (B part of an AB
an ABX system, J ϭ 14.3, 2.6 Hz, 1 H, 3-Ha), 3.11 (B part of an system, J ϭ 14.3 Hz, 1 H, NCHH), 4.56 (d, J ϭ 8.4 Hz, 1 H, 6-
ABX system, J ϭ 14.3, 5.5 Hz, 1 H, 3-Hb), 3.90 (dd, X part of an H), 7.19Ϫ7.37 (m, 8 H, Ph), 7.44 (dd, J ϭ 7.5, 1.7 Hz, 2 H, Ph)
ABX system, J ϭ 5.5, 2.6 Hz, 1 H, 2-H), 3.99 (A part of an ABX3
system, J ϭ 7.2 Hz, 1 H, OCHHCH3), 4.01 (B part of an ABX3
ppm. 13C NMR (50 MHz): δ ϭ 9.1 (t, cyclopropane), 11.7 (t, cyclo-
propane), 13.7 (q, OCH2CH3), 57.5 (d, C-7), 60.3, 60.7 (t,
system, J ϭ 6.8 Hz, 1 H, OCHHCH3), 4.70 (q, J ϭ 7.1 Hz, 1 H, OCH2CH3, NCH2), 63.9 (s, C-3), 72.9 (d, C-6), 127.2 (d, Ph), 127.8
NCHCH3), 7.26Ϫ7.38 (m, 5 H, Ph) ppm. 13C NMR (50 MHz): (d, Ph), 128.0 (d, 2C, Ph), 128.1 (d, 2C, Ph), 128.2 (d, 2C, Ph),
2210
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2205Ϫ2213

Rearrangement of Spiro[cyclopropane-1,5Ј-isoxazolidines] to β-Lactams
FULL PAPER
128.8 (d, 2C, Ph), 137.0 (s, Ph), 169.6 (s, CO) ppm. IR: ν˜ ϭ 3631
cmϪ1, 3031, 2855, 1740, 1496, 1455, 1372, 1182, 1030. MS (EI):
m/z (%) ϭ 338 (1) [MHϩ], 195 (7), 132 (27), 116 (6), 104 (13), 92
(100), 78 (15). C21H23NO3 (337.4): calcd. C 74.75, H 6.87, N 4.15;
13C NMR (50 MHz): δ ϭ 6.7 (t, cyclopropane), 10.6 (t, cyclopro-
pane), 51.9 (d, C-7), 61.3 (t, NCH2), 61.4 (t, OCH2), 64.8 (s, C-3),
73.0 (d, C-6), 127.1 (d, Ph), 127.9 (d, Ph), 128.1 (d, 2C, Ph), 128.2
(d, 2C, Ph), 128.4 (d, 2C, Ph), 128.7 (d, 2C, Ph), 137.0 (s, Ph), 137.5
found C 74.30, H 7.08, N 4.60. trans-21b: White solid; Rf ϭ 0.29 (s; Ph) ppm. IR: ν˜ ϭ 3621 cmϪ1, 3066, 3031, 2928, 2890, 1603,
1
(ethyl acetate/petroleum ether, 1:20); m.p. 106Ϫ109 °C. H NMR
1496, 1454, 1029, 1016. MS (EI): m/z (%) ϭ 295 (10) [Mϩ], 236
(200 MHz): δ ϭ 0.74Ϫ0.85 (m, 2 H, cyclopropane), 0.88Ϫ1.14 (m, (19), 194 (21), 135 (14), 119 (35), 104 (79), 92 (100), 77 (45).
2 H, cyclopropane), 1.24 (t, J ϭ 7.1 Hz, 3 H, OCH2CH3), 3.35 (d,
J ϭ 7.3 Hz, 1 H, 7-H), 3.92 (A part of an AB system, J ϭ 14.2 Hz,
1 H, NCHH), 4.04 (B part of an AB system, J ϭ 13.9 Hz, 1 H,
NCHH), 4.13Ϫ4.20 (m, 2 H, OCH2CH3), 4.52 (d, J ϭ 7.3 Hz, 1
H, 6-H), 7.22Ϫ7.35 (m, 8 H, Ph), 7.48Ϫ7.51 (m, 2 H, Ph) ppm.
13C NMR (50 MHz): δ ϭ 7.9 (t, cyclopropane), 13.3 (t, cyclopro-
pane), 14.3 (q, OCH2CH3), 60.1 (t, NCH2), 60.9 (d, C-7), 61.1 (t,
OCH2), 64.8 (s, C-3), 74.6 (d, C-6), 127.0 (d, Ph), 127.9 (d, Ph),
128.0 (d, 2C, Ph), 128.1 (d, 2C, Ph), 128.5 (d, 2C, Ph), 128.8 (d,
2C, Ph), 137.8 (s, Ph), 139.2 (s, Ph), 171.2 (s, CO) ppm. IR: ν˜ ϭ
3690 cmϪ1, 2928, 1731, 1603, 1496, 1455, 1180. MS (EI): m/z (%) ϭ
338 (5) [MHϩ], 309 (1), 265 (6), 195 (22), 147 (16), 131 (66), 107
(37), 92 (100), 78 (34). C21H23NO3 (337.4): calcd. C 74.75, H 6.87,
N 4.15; found C 74.82, H 6.74, N 4.40.
C19H21NO2 (295.4): calcd. C 77.26, H 7.17, N 4.74; found C 77.16,
H 7.00, N 4.69.
(6R*,7S*)-7-(Hydroxymethyl)-6-phenyl-5-(phenylmethyl)-4-oxa-5-
azaspiro[2.4]heptane (trans-25): Under the same conditions, the ad-
duct trans-21b (78 mg, 0.23 mmol) afforded the alcohol trans-25
(58 mg, 78%) as a white solid, which was recrystallized from diiso-
propyl ether. Rf ϭ 0.28 (ethyl acetate/pentane, 1:5); m.p. 94Ϫ96
1
°C. H NMR (200 MHz): δ ϭ 0.57Ϫ0.67 (m, 1 H, cyclopropane),
0.88Ϫ1.15 (m, 3 H, cyclopropane), 1.52 (m, 1 H, OH), 2.59 (dt,
J ϭ 7.3, 5.1 Hz, 1 H, 7-H), 3.64Ϫ3.80 (m, 2 H, CH2O), 3.80 (A
part of an AB system, J ϭ 14.6 Hz, 1 H, NCHH), 3.90 (d, J ϭ
7.3 Hz, 1 H, 6-H), 3.99 (B part of an AB system, J ϭ 14.6 Hz, 1
H, NCHH), 7.19Ϫ7.40 (m, 8 H, Ph), 7.51Ϫ7.55 (m, 2 H, Ph) ppm.
13C NMR (50 MHz): δ ϭ 6.0 (t; cyclopropane), 13.0 (t, cyclopro-
pane), 57.4 (d, C-7), 60.0 (t, NCH2), 62.4 (t, OCH2), 64.2 (s, C-3),
74.8 (d, C-6), 126.9 (d, Ph), 127.9 (d, Ph), 128.0 (d, 2C, Ph), 128.1
(d, 2C, Ph), 128.4 (d, 2C, Ph), 128.7 (d, 2C, Ph), 137.8 (s, Ph), 139.9
(s, Ph) ppm. IR: ν˜ ϭ 3623 cmϪ1, 3031, 2876, 2248, 1603, 1498,
Methyl (3R*,4R*)-1-Methyl-2-oxo-4-phenyl-3-azetidinecarboxylate
(cis-22): p-Toluenesulfonic acid (6 mg, 0.04 mmol) was added to a
solution of the isoxazolidine cis-20a (6 mg, 0.03 mmol) in toluene
(1 mL) and the reaction flask was placed in an oil bath at 80 °C.
After heating for 2 h, the reaction mixture was allowed to reach 1454, 1365, 1089, 1015. MS (EI): m/z ϭ 295 (10) [Mϩ], 264 (3),
room temp. and the solvent was then removed under reduced press-
ure. Purification of the crude product by chromatography on silica
gel (ethyl acetate/petroleum ether, 1:2) gave the pure β-lactam cis-
207 (24), 194 (35), 134 (23), 116 (42), 104 (86), 91 (100), 79 (46).
C19H21NO2 (295.4): calcd. C 77.26, H 7.17, N 4.74; found C 77.76,
H 7.42, N 4.68.
1
22 (2 mg, 30%) as a colorless oil. Rf ϭ 0.07. H NMR (200 MHz):
(3R*,4S*)-3-(Hydroxymethyl)-4-phenyl-1-(phenylmethyl)-2-
azetidinone (cis-26): p-Toluenesulfonic acid (14 mg, 0.08 mmol) was
added to a solution of the isoxazolidine cis-24 (23 mg, 0.08 mmol)
in CH3CN (2 mL) and the reaction flask was placed in an oil bath
δ ϭ 2.89 (s, 3 H, NMe), 3.23 (s, 3 H, OMe), 4.40 (d, J ϭ 5.9 Hz,
1 H, 3-H), 4.86 (d, J ϭ 5.9 Hz, 1 H, 4-H), 7.27Ϫ7.40 (m, 5 H,
Ph) ppm.
Methyl (3R*,4S*)-1-Methyl-2-oxo-4-phenyl-3-azetidinecarboxylate at 47 °C. After heating at 50 °C for 1.5 h, the reaction mixture was
(trans-23): Under the same conditions, the isoxazolidine trans-21a
(14 mg, 0.06 mmol) gave the β-lactam trans-23 (4 mg, 29%) as a
colorless oil. Rf ϭ 0.23 (ethyl acetate/petroleum ether, 1:7). 1H
allowed to reach room temp. and the solvent was evaporated under
reduced pressure. Purification of the crude product by chromatog-
raphy on silica gel (ethyl acetate/petroleum ether, 1:1) gave the isox-
NMR (200 MHz): δ ϭ 2.82 (s, 3 H, NMe), 3.80 (s, 3 H, OMe), azolidines cis-24 (3 mg) and pure β-lactam cis-26 (12 mg, 58%; 67%
3.88 (m, 1 H, 3-H), 4.82 (d, J ϭ 2.2 Hz, 1 H, 4-H), 7.30Ϫ7.43 (m, with respect to 87% of conversion of cis-24) as a colorless oil. Rf ϭ
5 H, Ph) ppm. 13C NMR (50 MHz): δ ϭ 27.2 (q, NMe), 52.4 (d, 0.35. 1H NMR (200 MHz): δ ϭ 3.46Ϫ3.58 (m, 1 H, 3-H),
C-3), 58.6 (d, C-4), 63.4 (q, OMe), 126.1 (d, 2C, Ph), 128.7 (d, Ph),
3.64Ϫ3.75 (m, 2 H, OCH2), 3.93 (d, J ϭ 14.8 Hz, 1 H, NCHH),
4.66 (d, J ϭ 4.8 Hz, 1 H, 4-H), 4.91 (d, J ϭ 14.8 Hz, 1 H, NCHH),
128.8 (d, 2C, Ph), 135.7 (s, Ph), 162.0, 166.9 (s, C-2, CO2Me) ppm.
IR: ν˜ ϭ 3035 cmϪ1, 2956, 1763, 1735, 1457, 1439, 1362, 1333, 1258, 7.14Ϫ7.18 (m, 2 H, Ph), 7.23Ϫ7.35 (m, 5 H, Ph), 7.37Ϫ7.41 (m, 3
1211, 1014. MS (EI): m/z (%) ϭ 219 (1) [Mϩ], 190 (14), 161 (41), H, Ph) ppm. 13C NMR (50 MHz): δ ϭ 44.3 (t, NCH2); 56.5 (d, C-
131 (100), 118 (26), 103 (45), 91 (8), 77 (39), 51 (27).
3), 57.2 (t, OCH2), 57.9 (d, C-4), 126.7 (d, 2C, Ph), 127.5 (d, 2C,
Ph), 128.2 (d, 2C, Ph), 128.5 (d, 2C, Ph), 128.6 (d, 2C, Ph), 134.3
(s, Ph), 134.9 (s, Ph), 167.7 (s, C-2) ppm. IR: ν˜ ϭ 3608 cmϪ1, 3033,
2925, 1742, 1456, 1029. MS (EI): m/z (%) ϭ 267 (0.2) [Mϩ], 194
(10), 134 (89), 105 (47), 91 (100), 78 (53). C17H17NO2 (267.3): calcd.
C 76.38, H 6.41, N 5.24; found C 76.14, H 6.72, N 5.16.
(6R*,7R*)-7-(Hydroxymethyl)-6-phenyl-5-(phenylmethyl)-4-oxa-5-
azaspiro[2.4]heptane (cis-24): A 1.5  solution of DIBAL-H in tolu-
ene (0.4 mmol) was added dropwise under nitrogen to a solution
of the adduct cis-20b (61 mg, 0.18 mmol) in CH2Cl2 (0.60 mL) co-
oled to 0 °C. The reaction mixture was stirred at low temperature
for 2 h and then treated in turn with methanol and a saturated
sodium potassium tartrate solution. The aqueous phase was ex-
tracted twice with CH2Cl2 and the combined organic extracts were
dried with anhydrous Na2SO4. Evaporation of the solvent and puri-
fication by chromatography on silica gel gave the alcohol cis-24
(3R*,4R*)-3-(Hydroxymethyl)-4-phenyl-1-(phenylmethyl)-2-
azetidinone (trans-27): Under the same conditions, the isoxazolidine
trans-25 (10 mg, 0.03 mmol) gave the β-lactam trans-27 (7 mg, 78%)
as a colorless oil. Rf ϭ 0.20 (ethyl acetate/petroleum ether, 1:1). 1H
NMR (200 MHz): δ ϭ 3.25 (m, 1 H, 3-H), 3.82 (d, J ϭ 15.4 Hz, 1
(39.5 mg, 74%) as a colorless oil. Rf ϭ 0.14 (ethyl acetate/petroleum H, NCHH), 3.91 (A part of an ABX system, J ϭ 12.1, 4.0 Hz, 1
1
ether, 1:10). H NMR (200 MHz): δ ϭ 0.64Ϫ0.73 (m, 1 H, cyclo- H, OCHH), 4.06 (B part of an ABX system, J ϭ 12.1, 4.8 Hz, 1
propane), 0.85Ϫ1.00 (m, 3 H, cyclopropane), 1.60 (br. s, 1 H, OH),
2.76 (q, J ϭ 5.9 Hz, 1 H, 7-H), 3.41Ϫ3.50 (m, 2 H, CH2O), 3.96 1 H, NCHH), 7.16Ϫ7.46 (m, 10 H, Ph) ppm. 13C NMR (50 MHz):
(A part of an AB system, J ϭ 14.3 Hz, 1 H, NCHH), 4.11 (B part δ ϭ 44.3 (t, NCH2), 56.7 (d, C-3), 58.5 (t, OCH2), 62.0 (d, C-4),
H, OCHH), 4.46 (d, J ϭ 2.2 Hz, 1 H, 4-H), 4.87 (d, J ϭ 15.0 Hz,
of an AB system, J ϭ 14.7 Hz, 1 H, NCHH), 4.47 (d, J ϭ 7.3 Hz, 126.3 (d, Ph), 127.3 (d, Ph), 127.9 (d, 2C, Ph), 128.1 (d, 2C, Ph),
1 H, 6-H), 7.23Ϫ7.43 (m, 8 H, Ph), 7.49Ϫ7.54 (m, 2 H, Ph) ppm. 128.3 (d, 2C, Ph), 128.6 (d, 2C, Ph), 135.0 (s, Ph), 137.0 (s, Ph),
Eur. J. Org. Chem. 2004, 2205Ϫ2213
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2211

F. M. Cordero, M. Salvati, F. Pisaneschi, A. Brandi
FULL PAPER
168.2 (s, CO) ppm. IR: ν˜ ϭ 3617 cmϪ1, 3444, 3033, 2925, 2879,
1738, 1497, 1456, 1029. MS (EI): m/z (%) ϭ 267 (0.3) [Mϩ], 134
(41), 132 (82), 116 (18), 105 (33), 92 (83), 90 (100), 78 (30), 76 (38).
116.6 (q, JC,F ϭ 286.1 Hz, CF3), 156.4 (q, JC,F ϭ 36.7 Hz, CF3CO),
177.0 (s, CO2H) ppm. IR: ν˜ ϭ 2982 cmϪ1, 1740, 1710, 1680, 1366,
1240, 1149, 1077. GC-MS: m/z (%) ϭ 240 (2), 222 (30), 214 (10),
C17H17NO2 (267.3): calcd. C 76.38, H 6.41, N 5.24; found C 75.89, 196 (4), 156 (3), 102 (9), 57 (100). HRMS (EI): calcd. for
H 6.52, N 5.68.
C16H26F3NO5 [Mϩ] 392.16607; found 392.16605.
[(2S,3R,4R)-3,4-Di-tert-Butoxy-1-(trifluoroacetyl)pyrrolidinyl]acetic
Acid (41): Pale yellow oil; 35% yield; Rf ϭ 0.27 (diethyl ether/pen-
tane, 1:1). H NMR (500 MHz): δ ϭ 1.18 (s, 9 H, CMe3), 1.20 (s,
Methyl 7-Oxohexahydro-8a(1H)-indolizidinecarboxylate (31): The
cycloadduct 29 (59 mg, 0.30 mmol) was dissolved in o-xylene
(15 mL) and the solution was heated at 130 °C for 2 h. After cool-
ing the reaction mixture to room temp., the solvent was removed
by filtration through a short pad of silica gel, eluting in turn with
petroleum ether and ethyl acetate. Purification of the crude product
by chromatography on silica gel (ethyl acetate/petroleum ether, 1:3)
afforded the ketone 31 (38 mg, 64%) as a yellow oil. Rf ϭ 0.35
(ethyl acetate/petroleum ether, 1:1). 1H NMR (500 MHz): δ ϭ 1.74
(ddd, J ϭ 12.7, 9.6, 8.2 Hz, 1 H, 1-Ha), 1.91Ϫ2.09 (m, 2 H, 1-Hb,
2-Ha), 2.26Ϫ2.37 (m, 3 H, 2-Hb, 6-Ha, 8-Ha), 2.50 (ddd, J ϭ 16.0,
9.9, 7.4 Hz, 1 H, 6-Hb), 2.79 (dd, J ϭ 14.8, 1.7 Hz, 1 H, 8-Hb),
2.85Ϫ3.93 (m, 2 H, 3-Ha, 5-Ha), 3.07 (dt, J ϭ 8.6, 5.3 Hz, 1 H, 3-
Hb), 3.18 (ddd, J ϭ 12.2, 7.3, 2.7 Hz, 1 H, 5-Hb), 3.68 (s, 3 H,
OMe) ppm. 13C NMR (50 MHz): δ ϭ 22.4, 36.3, 38.2, 44.8 (t, C-
1, C-2, C-6, C-8), 48.1, 50.9 (t, C-3, C-5), 51.8 (q, OMe), 69.3 (s,
1
9 H, CMe3), 2.82Ϫ2.87 (m, 2 H, CH2CO2H), 3.48 (dm, J ϭ
12.9 Hz, 1 H, 5Ha), 3.75 (dd, J ϭ 11.9, 4.8 Hz, 1 H, 5-Hb), 3.94 (q,
J ϭ 4.1 Hz, 1 H, 4-H), 3.93 (dd, J ϭ 6.1, 4.0 Hz, 1 H, 3-H), 4.49
(q, J ϭ 6.5 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz): δ ϭ 28.2 (q,
3C, CMe3), 28.3 (q, 3C, CMe3), 31.6 (t, CH2CO2H), 51.7 (qt,
JC,F ϭ 3.2 Hz, C-5), 57.3 (d, C-2), 73.5 (s, CMe3), 74.3 (s, CMe3),
74.6, 74.9 (d, C-3, C-4), 116.0 (q, JC,F ϭ 287.5 Hz, CF3), 156.3 (q,
J
C,F ϭ 36.6 Hz, CF3CO), 176.8 (s, CO2H) ppm. IR: ν˜ ϭ 3514 cmϪ1
,
2979, 1745, 1711, 1688, 1366, 1235, 1189, 1152, 1085. GC-MS:
m/z (%) ϭ 369 (1) [Mϩ], 255 (25), 240 (29), 213 (55), 195 (47), 178
(14), 100 (54), 83 (82), 56 (100). C16H26F3NO5 (369.4): calcd. C
52.03, H 7.09, N 3.79; found C 52.48, H 7.13, N 4.04.
C-8a), 173.0 (s, CO2Me), 207.2 (s, C-7) ppm. IR: ν˜ ϭ 2954 cmϪ1
,
Acknowledgments
2836, 1725, 1435, 1339, 1218, 1196. MS (EI): m/z (%) ϭ 138 (100),
136 (4), 96 (89), 84 (10).
The authors thank the Ministry of Instruction, University and
Research (MIUR, Italy, project FIRB 2001 RBNE017F8N) for fin-
ancial support. Mrs. B. Innocenti and Mr. M. Passaponti (Univer-
sity of Firenze) are acknowledged for technical support.
Synthesis of β-Amino Acids 33, 40 and 41. General Procedure: TFA
(1 equiv. for 29, 1.5 equiv. for 35 and 36) was added to a 0.04 
solution of the cycloadduct 29, 35 or 36 (0.51Ϫ0.70 mmol) in tolu-
ene and the mixture was heated at 110 °C for between 2 min and
1.5 h (cf. Schemes 6 and 7). The reaction mixture was filtered
through a short pad of silica gel eluting initially with petroleum
ether to remove the high-boiling solvent, then with ethyl acetate to
recover the product. Purification of the crude products by chroma-
tography on silica gel afforded pure β-amino acids 33, 40 and 41.
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For some reviews see:
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B. Alcaide, P. Almendros, Chem. Soc. Rev.
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F. M. Cordero, F. Pisaneschi, M. Salvati, V. Paschetta, J.
[2-(Methoxycarbonyl)-1-(trifluoroacetyl)-2-pyrrolidinyl]acetic Acid
(33): Colorless oil; 72% yield; Rf ϭ 0.61 (ethyl acetate/petroleum
ether, 3:1). 1H NMR (500 MHz): δ ϭ 1.98Ϫ2.18 (m, 2 H, 4-H),
2.23 (ddd, J ϭ 13.3, 7.1, 4.3 Hz, 1 H, 3-Ha), 2.47 (ddd, J ϭ 13.5,
9.6, 7.5 Hz, 1 H, 3-Hb), 3.19 (A part of an AB system, J ϭ 16.3 Hz,
1 H, CHHCO2H), 3.38 (B part of an AB system, J ϭ 16.3 Hz, 1
H, CHHCO2H), 3.75 (s, 3 H, OMe), 3.70Ϫ3.89 (m, 1 H, 5-Ha),
3.91Ϫ4.00 (m, 1 H, 5-Hb) ppm. 13C NMR (50 MHz): δ ϭ 23.8 (t,
C-4), 34.9 (t, C-3), 36.4 (t, CH2CO2H), 48.4 (tq, JC,F ϭ 3.8 Hz, C-
5), 53.0 (q, OMe), 67.8 (s, C-2), 115.8 (q, JC,F ϭ 285.3 Hz, CF3),
155.6 (q, JC,F ϭ 37.9 Hz, CF3CO), 171.5 (s, CO2Me), 175.1 (s,
CO2H) ppm. IR: ν˜ ϭ 3683 cmϪ1, 3509, 2958, 1745, 1716, 1693,
Ollivier, J. Salaün, A. Brandi, J. Org. Chem. 2003, 68,
[2b]
3271Ϫ3280.
V. Paschetta, F. Cordero, R. Paugam, J. Olliv-
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For a recent review see: A. Brandi, S. Cicchi, F. M. Cordero,
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897Ϫ909.
M. Ferrara, F. M. Cordero, A. Goti, A. Brandi,
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K. Estieu, R. Paugam, J. Ollivier, J. Sa-
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1453, 1267, 1234, 1215, 1155. MS (EI): m/z (%) ϭ 224 (35) [Mϩ
Ϫ
62, 8276Ϫ8277.
CO2Me], 223 (19), 206 (88), 178 (100), 83 (53), 69 (16), 59 (2).
C10H12F3NO5 (283.2): calcd. C 42.41, H 4.27, N 4.95; found C
42.72, H 4.16, N 4.17.
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Y. Inouye, Y. Watanabe, S. Takahashi, H. Kakisawa, Bull.
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[6]
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[(2R,3R,4R)-3,4-Di-tert-Butoxy-1-(trifluoroacetyl)pyrrolidinyl]-
acetic Acid (40): Colorless oil; 68% yield; Rf ϭ 0.52 (ethyl acetate/
petroleum ether, 1:1). [α]2D3 ϭ Ϫ8.1 (c ϭ 0.7, EtOH). 1H NMR
(400 MHz, CD3OD): δ ϭ 1.25 (s, 9 H, CMe3), 1.27 (s, 9 H, CMe3),
2.87 (A part of an ABX system, J ϭ 16.2, 4.4 Hz, 1 H,
CHHCO2H), 2.96 (B part of an ABX system, J ϭ 16.2, 10.4 Hz, 1
H, CHHCO2H), 3.61 (d, J ϭ 11.3 Hz, 1 H, 5-Ha), 3.95 (dd, J ϭ
11.3, 4.4 Hz, 1 H, 5-Hb), 4.05 (s, 1 H, 3-H), 4.08Ϫ4.12 (m, 1 H, 4-
H), 4.26 (X part of an ABX system, dd, J ϭ 10.4, 4.4 Hz, 1 H, 2-
H) ppm. 13C NMR (125 MHz): δ ϭ 28.6 (q, 3C, CMe3), 28.8 (q,
3C, CMe3), 34.4 (t, CH2CO), 54.1 (tq, JC,F ϭ 6.5 Hz, C-5), 63.9
(d, C-2), 75.2 (s, CMe3), 75.4 (s, CMe3), 76.7, 77.2 (d, C-3, C-4),
F. Machetti, F. M. Cordero, F. De Sarlo, A. Brandi, Tetra-
hedron 2001, 57, 4995Ϫ4998.
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For the C-methoxycarbonyl nitrone see:
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F. Machetti, F. M. Cordero, F. De Sarlo, A.
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Helv. Chim. Acta 1977, 60, 1273Ϫ1295.
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2212
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 2205Ϫ2213

Rearrangement of Spiro[cyclopropane-1,5Ј-isoxazolidines] to β-Lactams
FULL PAPER
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A. Padwa, K. F. Koehler, A. Rodriguez, J. Org. Chem. 1984,
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Received September 24, 2003
Eur. J. Org. Chem. 2004, 2205Ϫ2213
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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