Reverse-Cope elimination versus 1,3-dipolar cycloaddition in the reaction of enantiopure 2-azetidinone-tethered alkynylaldehydes with N- methylhydroxylamine

Article abstract of DOI:10.1016/S0040-4039(00)00006-X

Enantiopure 2-azetidinone-tethered alkynylaldehydes 1 react stereoselectively under mild conditions with N-methylhydroxylamine to yield products derived from either intramolecular reverse-Cope elimination or 1,3- dipolar cycloaddition, depending on both t

Full text of DOI:10.1016/S0040-4039(00)00006-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1647–1651
Reverse-Cope elimination versus 1,3-dipolar cycloaddition in the
reaction of enantiopure 2-azetidinone-tethered alkynylaldehydes
with N-methylhydroxylamine
Benito Alcaide ∗ and Elena Sáez
Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
Received 29 October 1999; accepted 21 December 1999
Abstract
Enantiopure 2-azetidinone-tethered alkynylaldehydes 1 react stereoselectively under mild conditions with N-
methylhydroxylamine to yield products derived from either intramolecular reverse-Cope elimination or 1,3-dipolar
cycloaddition, depending on both the length of the tether and the experimental conditions. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: reverse-Cope elimination; cycloadditions; azetidinones; alkynylaldehydes.
Cycloaddition reactions are among the most powerful methods for the construction of rings.1 In
particular, intramolecular cycloadditions with high regio- and stereocontrol are important tools for the
efficient assembly of complex molecular structures. We have recently initiated a study of various types
of intramolecular cycloadditions of appropriately substituted 2-azetidinones.2 Our aim is to develop
efficient routes for the stereocontrolled construction of fused polycyclic β-lactams with different ring
connectivities.3 The development of new approaches to the stereocontrolled synthesis of β-lactam
systems is a subject of interest in the context of their possible use as biologically active compounds
or as versatile chiral building blocks.4,5
The intramolecular nitrone–alkene cycloaddition (INAC) reaction has experienced impressive gro-
wth and found broad application in organic synthesis.6 In contrast to the extensive studies involving
intramolecular reactions of alkenylnitrones, very little attention has been paid to related reactions
with alkynylnitrones. This fact may be due to the known instability of the produced isoxazolines and
the variety of their decomposition pathways which depend mainly on the substitution pattern of the
alkyne.7 The only previous report was by LeBel which described the reaction of 6-octyn-2-one with N-
methylhydroxylamine in ethanol.8 Presumably, the initial strained bridgehead C–C double bond of the
resulting 2,3-dihydroisoxazole reacted with ethanol under the reaction conditions to give two isomeric
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00006-X
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bicyclic isoxazolidines as the final products (Scheme 1). We wish to disclose that the reaction of several
2-azetidinone-tethered alkynylaldehydes 1 with N-methylhydroxylamine result in the regio- and stereo-
selective formation of different novel polycyclic β-lactams (types 3–5) derived from two competitive
processes, namely reverse-Cope elimination and 1,3-dipolar cycloaddition.
Scheme 1.
The starting substrates, enantiopure alkynylaldehydes 1a–c, were conveniently synthesised from
readily available cis-2-azetidinones 2a–c following simple transformations3a,b (Fig. 1). Compounds
2 were easily prepared as single cis-enantiomers from imines of (R)-2,3-O-isopropylidenepropanal,
through Staudinger reactions with the corresponding acid chlorides in the presence of Et3N.9
Fig. 1.
The outcome of the reactions of compounds 1 with N-methylhydroxylamine is determined by the
length of the linking chain to the β-lactam nucleus and the experimental conditions. First, we studied
reactions of enantiopure (3R,4R)-1-propargyl-4-formyl-2-azetidinone 1a with N-methylhydroxylamine
(1.5 equiv.) under different reaction conditions (Table 1). We were pleased to find that depending on the
solvent and the temperature, different nitrones 3a, 6a and 7a were obtained selectively. Thus, bicyclic
nitrone 3a was isolated in 53% yield after column chromatography, when the reaction was performed in
refluxing benzene for 30 min. Keto-nitrone 6a was the major product from the reaction both in toluene
at room temperature and upon heating in chloroform (45% isolated yield), while nitrone 7a was the only
product (65% isolated yield) when the reaction was carried out in methanol at room temperature. The
structure of the bicyclic nitrone 3a was deduced on the basis of spectral data as well as by its facile
transformation to 3-oxocarbacephem 8a, previously prepared by us through a different route (Scheme
2).2b This synthesis of 8a represents a more direct and convenient access to this interesting β-lactam
system.
Scheme 2.
The formation of compounds 3a and 6a is the result of a formal reverse-Cope elimination reaction of
the intermediate α-hydroxy-hydroxylamine as shown in Scheme 3.10,11 Thus, retro-Cope cyclization of
the initially formed carbinolamine 9 gives bicyclic N-oxide 10 which ring opens to N-hydroxyenamine
aldehyde 11, the key intermediate in the process.12 Reacting as a C-nucleophile, compound 11 pro-

1649
Table 1
Reaction between alkynylaldehyde 1a and N-methylhydroxylaminea
vides bicyclic hydroxynitrone 12 and, finally, the α,β-unsaturated nitrone 3a by dehydration. On the
other hand, compound 11 may produce enamine-nitrone 1312 by reaction with a new molecule of N-
methylhydroxylamine. Further hydrolysis of the enamine moiety in 13 yields keto-nitrone 6a. Compound
6a could be alternatively formed by transamination of compound 11.
Scheme 3.
Next, we studied reactions of the homologous 1,4-tethered alkenylaldehydes 1b and 1c, respectively,
which behaved differently when heated in toluene under reflux. Thus, while compound 1b afforded the
corresponding aziridine carbaldehyde 4b as the sole product (55% pure, isolated yield), compound 1c
gave a (1:3) mixture of cycloadduct 5c and nitrone 7c, the former being obtained in 15% yield as pure
product (Scheme 4). Clearly, the 4-isoxazoline (type 5) is the intermediate, and aziridine carbaldehyde

1650
4b may arise by thermal sigmatropic rearrangement according to Baldwin et al.13 In contrast, nitrone
7a on heating in toluene under similar conditions gave a complex mixture of unidentified products. The
ring size and the stereochemistry (by vicinal proton couplings and NOE experiments) of compounds 3–5
were established by NMR including two-dimensional techniques.14
Scheme 4.
The above results demonstrate the utility of the reported methodology for the elaboration of highly
functionalised enantiopure bicyclic and tricyclic β-lactam systems relevant to the synthesis of antibiotics.
Furthermore, as far as we know, these are the first examples of intramolecular reverse-Cope eliminations
in the reactions of alkynylaldehydes with monosubstituted hydroxylamines. Other aspects of this chem-
istry will be reported in due course.
Acknowledgements
We would like to thank the DGES (MEC-Spain, grant PB96-0565) for financial support. E. Sáez thanks
the DGES (MEC, Spain) for a predoctoral-FPI fellowship. We thank Dr. M. F. Aly for fruitful discussions.
References
1. For reviews on cycloaddition reactions, see: (a) Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Paquette, L.
A., Eds.; Pergamon: Oxford, 1991; Vol. 5, Chapters 1–9. (b) Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press:
Greenwich, 1994; Vols. 1–3.
2. (a) Alcaide, B.; Almendros, P. Tetrahedron Lett. 1999, 40, 1015. (b) Alcaide, B.; Alonso, J. M.; Aly, M. A.; Sáez, E.;
Martínez-Alcázar, M. P.; Hernández-Cano, F. Tetrahedron Lett. 1999, 40, 5391.
3. For other related cyclization methods recently developed in our group see, for example: (a) Alcaide, B.; Rodríguez-Campos,
I. M.; Rodríguez-López, J.; Rodríguez-Vicente, A. J. Org. Chem. 1999, 64, 5377. (b) Alcaide, B.; Polanco, C.; Sierra, M. A.
J. Org. Chem. 1998, 63, 6786.
4. β-Lactam antibiotics continue to play a pre-eminent role in antibacterial therapy with the invention of new chemical entities
being driven by the emergence of resistant strains of bacteria. See, for instance: (a) Hook, V. Chemistry in Britain, 1997, 33,
34. (b) Niccolai, D.; Tarsi, L.; Thomas, R. J. Chem. Commun. 1997, 2333. (c) Spratt, B. G. Science 1994, 264, 388.
5. See, for example: Symposia-in-Print Number 8, Recent Advances in the Chemistry and Biology of β-Lactams and β-Lactam
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1997, 53, 403. (d) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.

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7. Freeman, J. P. Chem. Rev. 1983, 83, 241, and references cited therein.
8. LeBel, N. A.; Banucci, E. J. Am. Chem. Soc. 1970, 92, 5278.
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S.; Bose, A. K. J. Org. Chem. 1988, 53, 4227. (b) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of β-Lactams;
Georg, G. I., Ed.; VCH: Weinheim, 1993; Ch. 3, p. 295.
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E.; Holmes, A. B.; Forbes, I. T.; Thompson, M. Tetrahedron Lett. 1992, 33, 9431. (b) Fox, M. E.; Holmes, A. B.; Forbes, I.
T.; Thompson, M. J. Chem. Soc., Perkin Trans. 1 1994, 3379.
11. For related reverse-Cope cyclizations involving unsaturated hydroxylamines see, for example: Knight, D. W.; Salter, R.
Tetrahedron Lett. 1999, 40, 5915, and references cited therein.
12. To rule out the alternative route involving direct addition of the amine to the alkyne functional group, we studied the reaction
of 4-furyl-3-phenoxy-1-propargyl-2-azetidinone with N-methylhydroxylamine in similar experimental conditions to those
used for 1a. The starting 2-azetidinone was recovered unaltered even after prolonged reation times in refluxing benzene or
toluene.
13. Baldwin, J. E.; Pudussery, E. G.; Qureshi, A. K.; Sklarz, B. J. Am. Chem. Soc. 1968, 90, 5325.
14. All new compounds gave satisfactory analytical and spectral data.