New synthesis of β-lactams by ethylene extrusion from spirocyclopropane isoxazolidines [3]

Full text of DOI:10.1021/ja000108e

J. Am. Chem. Soc. 2000, 122, 8075-8076
8075
Scheme 1
New Synthesis of â-Lactams by Ethylene Extrusion
from Spirocyclopropane Isoxazolidines
Franca M. Cordero,*,† Federica Pisaneschi,† Andrea Goti,†
Jean Ollivier,‡ Jacques Salau¨n,‡ and Alberto Brandi†
Dipartimento di Chimica Organica “Ugo Schiff”
Centro di Studio sulla Chimica e la Struttura
dei Composti Eterociclici e loro Applicazioni-CNR
UniVersita` degli Studi di Firenze
Scheme 2
Via G. Capponi 9, I-50121 Firenze, Italy
Laboratoire des Carbocycles (Associe´ au CNRS)
Institut de Chimie Mole´culaire d’Orsay, Baˆt. 420
UniVersite´ de Paris-Sud, 91405 Orsay, France
ReceiVed January 10, 2000
ReVised Manuscript ReceiVed March 21, 2000
Scheme 3a
Recently we have reported a new and general process that
provides easy access to the pyrrolo[3,4-b]pyridine ring system.1
The synthetic protocol consists of the preparation of alkylidenecy-
clopropanes 1 by palladium(0) catalyzed substitution of 1-tosyl-
oxy-1-vinylcyclopropane using R-amino acid derivatives as nucle-
ophiles, followed by simple conversion of the alkoxycarbonyl
moiety into a nitrone. Alkylidenecyclopropanes 1 spontaneously
undergo intramolecular cycloaddition to spirocyclopropane isox-
azolidines 2 that rearrange to octahydropyrrolo[3,4-b]pyridin-4-
ones 3 upon heating in xylenes at 136-140 °C (Scheme 1).1
In this contribution we report a completely different and novel
behavior of the same isoxazolidines 2, which afford valuable
â-lactam compounds when treated with strong acids.
a a: i. NaH, THF; ii. 1-tosyloxy-1-vinylcyclopropane, Pd(dba)2 (6 mol
%), dppe (7.2 mol %), THF; b: i. DIBAL (3 equiv), CH2Cl2; ii. DMSO,
(COCl)2, CH2Cl2, TEA; c: MeNHOH‚HCl, TEA, toluene, reflux tem-
perature, 2 h.
Scheme 4
To explore the extension of the thermal rearrangement of
5-spirocylopropane isoxazolidines to the synthesis of pyrido[3,4-
b]pyridones 4 starting from â-amino acid derivatives (Scheme
2), we considered utilizing the readily available and inexpensive
anthranilic acid as starting material.
Tosyl (Ts) as well as nosyl (2-nitrobenzenesulfonyl, Ns) groups
were used to protect the amino acid nitrogen atom in 7. The
synthetic sequence occurred with total regio- and diastereoselec-
tivity affording the cis-fused tetracyclic isoxazolidines 9 in
excellent yields (Scheme 3).
loss of ethylene (Scheme 4). The structures of 11a (Z ) Ts) and
11b (Z ) Ns) were unambiguously established by spectroscopic
means. Especially diagnostic were νCO (1752 and 1750 cm-1 for
11a and for 11b, respectively), 13C NMR resonances δCO (166.9
and 166.2 ppm for 11a and for 11b, respectively), and 1H NMR
resonances of H8b (δ ) 4.29 ppm, d, J ) 5.1 Hz for 11a and δ
) 4.45 ppm, d, J ) 5.1 Hz for 11b).
The â-lactams 11a,b could be similarly obtained from 9a,b in
toluene in the presence of p-toluenesulfonic acid and in refluxing
ethanol with HCl, or directly from the aldehydes 8 with MeNH-
OH‚HCl in refluxing toluene or ethanol in absence of triethyl-
amine. In any case, when the reaction conditions were not com-
pletely anhydrous, the ethylketone 12 was also obtained in 1:2
molecular ratio with 11.
The ring-fused structure of cycloadducts 9 could readily be
1
assigned on the basis of H and 13C NMR data. Diagnostic res-
onances of C3a′-H (δH ) 2.54 ppm, δC ) 43.7 ppm), C9b′-H
(δH ) 3.52 ppm, δC ) 66.5 ppm) and C3′ (δC ) 64.2 ppm)
characteristic of 5-spirocyclopropane isoxazolidines2 have been
reported for compound 9a as an example. Compound 9b shows
analogous values. The value of the vicinal coupling constant
between the two bridged hydrogens of 6.5 Hz for 9a and 9b
suggests a cis relationship between the two atoms.
When subjected to the same thermal conditions used to induce
the rearrangement of 2, the adducts 9a,b failed to give pyridones
10a,b (Scheme 4), but they were stable up to 120 °C and
decomposed at higher temperatures. Whether the starting materials
9a,b or the pyridones 10a,b decomposed at this temperature was
the object of an investigation; however, an unequivocal conclusion
could not be reached. We found that a clean reaction occurred
when compounds 9a,b were heated in toluene in the presence of
a small excess of trifluoroacetic acid (TFA) (Scheme 4).
Under these conditions the unexpected â-lactams 11a,b were
obtained in good yield (72%) by ring contraction followed by
To establish the exact structure of the C2 fragment eliminated
in the acid-induced reorganization of isoxazolidine 9, a solution
of 9a (Z ) Ts) and TFA in CD3CN was heated in a screw cap
NMR tube in an oven at 70 °C. After 1 h the 1H NMR spectrum
of the mixture revealed the complete disappearance of 9a and
the formation of 11a and showed an intense singlet at 5.41 ppm,
which indicated the formation of ethylene.
To our knowledge, only a few examples of non-reductive ring-
contraction of isoxazolidines to â-lactams have been reported.
The examples refer to 5-nitroisoxazolidines,3 5-cyanoisoxazo-
lidines,4 and 5-phenylthioisoxazolidines.5 In all of these cases,
† Universita` degli Studi di Firenze.
‡ Universite´ de Paris-Sud.
(1) (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.
(2) (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.
10.1021/ja000108e CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

8076 J. Am. Chem. Soc., Vol. 122, No. 33, 2000
Communications to the Editor
Scheme 5
Scheme 7
Scheme 6
Scheme 8
strong basic conditions and an electron-withdrawing group at the
five-position of the isoxazolidine ring were required for the rear-
rangement to occur. The analogy with the present case, therefore,
is only minimal.
The double bond fission of the cyclopropane ring in 9 to give
ethylene is reminescent of the enzymatic conversion of 1-ami-
nocyclopropane carboxylic acid (ACC) into ethylene during the
plant growth regulation and the maturation of fruits.6 The bio-
synthesis of the phytohormone ethylene from ACC is believed
to occur through a stepwise oxidative process.7 ACC and other
aminocyclopropyl derivatives have been degradated to ethylene
also by chemical oxidation under different conditions.8
The rationalization of the formation of 11 and ethylene from
9 in the presence of non-oxidative acidic conditions is puzzling.
Pyridones 10 as intermediates for the formation of 11 could be
excluded, as model compounds tested under the same reaction
conditions proved to be stable. The key role of the acid must in-
volve the protonation of the isoxazolidine nitrogen atom, resulting
in an easier cleavage of the N-O bond that can occur thermally
either in hetero- or homolytic manner. In the first hypothesis, the
increasing electron deficiency on the cyclopropyloxy moiety can
induce a concomitant rearrangement to 14, by analogy with the
cyclopropylcarbinyl cation9 behavior (Scheme 5). The transient
oxetane cation 14 can be intramolecularly trapped by nitrogen to
form the spiro oxetane 15 that can evolve to â-lactam 11 and
ethylene by a formal retro-Paterno-Bu¨chi reaction.10
In the case that an N-O bond homolysis occurs, by analogy
with the Hofmann-Lo¨ffler-Freytag reaction11,12 of the related
protonated N-haloamines, the diradical cation 16 would be formed
(Scheme 6). The oxoethyl diradical cation 17, originating from
16 in a manner similar to the rearrangement of the parent neutral
species, does not undergo the usual intramolecular diradical
coupling13 or 1,5-hydrogen shift13 because of the presence of a
strong intramolecular hydrogen bond. This might stabilize the
intermediate conformation with the radical carbon atom far away
from the nitrogen atom, settling the carbonyl moiety in the proper
position to form a new N-C bond to give the diradical 18. The
product 11 and ethylene derive, then, from 18 through a radical
fragmentation and proton loss.
A support to the second proposed mechanism might derive from
the result of the rearrangement of isoxazolidine 19 obtained from
2,3,4,5-tetrahydropyridine-1-oxide and 1-methylene-2-phenylcy-
clopropane. In CH2Cl2/TsOH isoxazolidine 19 gave a complex
mixture of the â-lactam 20,14 styrene (21), the enone 22, and the
quinolizidinone 23 as the major product already at room temper-
ature (Scheme 7). The newly discovered process, confirmed by
the formation of â-lactam 20 and extrusion of styrene, is clearly
accelerated by the presence of the phenyl substituent. Formation
of the enone 22 (and of quinolizidinone 23 deriving from 22 by
conjugated intramolecular addition15) derived likely by hydrogen
abstraction, occurred in this case in competition with cyclization
and fragmentation of the proposed diradical intermediates (Scheme
6). Due to the peculiar nature of the phenyl ring, however, no
general conclusion on the mechanism of this new reaction can
be drawn at this level of study.
From the synthetic point of view, this new â-lactam synthesis
proved to be a general process, as other 5-spirocyclopropane iso-
xazolidines underwent identical ring contraction when heated un-
der acidic conditions. For example, the enantiomerically pure ad-
ducts 2a-c,1 obtained from L-alanine, L-valine, and L-tryptophan,
respectively, gave â-lactams 24a-c16 in good yields (57-63%)
(Scheme 8).
The compounds 24a-c are characterized by â-lactam distinc-
tive spectral data such as νCO and δCO (24a: νCO ) 1753 cm-1
,
δCO 165.9 ppm; 24b: νCO ) 1756 cm-1, δCO 165.4 ppm; 24c:
νCO ) 1753 cm-1, δCO 165.8 ppm). Furthermore, the values of
the coupling constants between vicinal C-H are consistent with
the depicted stereochemistry (24a: H1-H5 J ) 4.0 Hz and H4-
H5 J ) 0 Hz; 24b: H1-H5 J ) 3.7 Hz and H4-H5 J ) 0 Hz;
24c: H1-H4a J ) 3.7 Hz and H4-H4a J ) 0 Hz).
In conclusion, a novel chemoselective reaction of 5-spirocyclo-
propane isoxazolidines has been reported. When heated in neutral
conditions these compounds generally undergo ring expansion
to tetrahydropyridones, whereas in the presence of protic acids
they undergo ring contraction to â-lactam derivatives. This last
process, which proceeds with extrusion of ethylene, mimics the
biosynthesis of ethylene from ACC. Further studies are in progress
to establish the wider scope of this new approach to â-lactams
and to verify the mechanistic proposals.
(3) (a) Padwa, A.; Koehler, K. K.; Rodriguez, A. J. Org. Chem. 1984, 49,
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(6) For reviews see: (a) Salau¨n, J. Top. Curr. Chem. 1999, 207, 1-67. (b)
Salau¨n, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511-542.
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Chem. Soc., Chem. Commun. 1985, 206-207. (b) Pirrung, M. C. J. Am. Chem.
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Acknowledgment. The authors thank a CNR (Italy)-CNRS (France)
bilateral research program for financial support of exchange of researchers.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(9) For a review see: Salau¨n, J. The Chemistry of the cyclopropyl group,
Rappaport, 2nd ed.; John Wiley: 1987; pp 809-878.
(10) For a review see: Jones, G., II. Org. Photochem. 1981, 5, 1-22.
(11) For reviews see: (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983,
22, 337-350. (b) Wolff, M. E. Chem. ReV. 1963, 63, 55-64.
(12) We are grateful to a reviewer for suggesting a Hofmann-Lo¨ffler-
Freytag type initiation of the process.
JA000108E
(14) Brunwin, D. M.; Lowe, G.; Parker, J. J. Chem. Soc. (C) 1971, 3756-
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1
(13) Brandi, A.; Cordero, F. M.; Goti, A.; De Sarlo, F.; Guarna, A. Synlett
1993, 1, 1-8.
(16) The enantiomeric purity of 24a-c has been confirmed by H NMR
analysis with Eu(hfc)3.