A trans-stereoselective synthesis of 3-halo-4-alkyl(aryl)-NH-azetidin-2-ones

Article abstract of DOI:10.1021/ol005633x

Conrotatory ring closure of 1-halo-3-aza-4-alkyl-1,3-dienes in refluxing toluene gives rise to 3-halo-4-aryl-2-azetidinones in satisfactory yields. Dehalogenation of the resulting β-lactams by tris(trimethylsilyl)silane furnished 3-unsubstituted azetidino

Full text of DOI:10.1021/ol005633x

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1077-1079
A Trans-Stereoselective Synthesis of
3-Halo-4-alkyl(aryl)-NH-azetidin-2-ones
,†
Elisa Bandini, Gianfranco Favi, Giorgio Martelli, Mauro Panunzio,* and
Giovanni Piersanti
ICoCEA-CNR Via Gobetti 101, 40129 Bologna, Italy
panunzio@ciam.unibo.it
Received February 7, 2000
ABSTRACT
Conrotatory ring closure of 1-halo-3-aza-4-alkyl-1,3-dienes in refluxing toluene gives rise to 3-halo-4-aryl-2-azetidinones in satisfactory yields.
Dehalogenation of the resulting â-lactams by tris(trimethylsilyl)silane furnished 3-unsubstituted azetidinones, valuable intermediates in the
synthesis of biologically active compounds.
The utilization of 2-aza-1,3-dienes for preparation of the
â-lactam ring was explored by our group.1 In this paper we
report a trans-stereoselective synthesis of 3-halo-4-arylaze-
tidin-2-ones and 3-halo-4-[1-(triialkylsilyloxy)alkyl]azetidin-
2-ones.
R-Halo-â-lactams are versatile synthons in constructing a
wide variety of functionalized lactams.2 Major transforma-
tions directed at the CR-halogen center include reduction,
metalation, alkylation, and replacement by azide. Notable
routes to R-halo-â-lactams are cycloaddition of haloketenes
to imine3 and thermal decomposition of [N-(dihaloacetyl)-
piperidinyl]phenyl mercury.4 More recently, a nickel-
promoted cyclization route,5 a catalytic Hunsdiecker,6 and a
synthesis of 3-halo-â-lactams from R,â-unsaturated N-
sulfonamides7 have been reported. New procedures for the
synthesis of 3-halo-4-substituted-â-lactams are welcomed
since these compounds allow a faster and easier synthesis
of substituted â-lactams, which are known to be useful
compounds with potential applications as â-lactamases or
inhibitors of 3-hydroxy-3-methyl glutarate coenzyme A
synthase, human leukocyte elastase, poliovirus, and human
rhinovirus C3-proteinase.8
Following our published general protocol on the synthesis
of the â-lactam ring using a two-step Staudinger reaction,9
we synthesized azadiene 4 starting from N-(trimethylsilyl)-
arylmethanimine 210,11 and R-haloacetyl chloride 3 in the
presence of TEA as base.12 Identification of 4 and the relative
1
stereochemical assignments were obtained by H NMR
† Present address: CSFM-CNR Via Selmi; 2 I 40126 Bologna, Italy.
(1) (a) Bacchi, S.; Bongini, A.; Panunzio, M.; Villa, M. Synlett 1998,
843. (b) Panunzio, M.; Bacchi, S.; Fiume, L.; Vicennati, P. Tetrahedron
Lett. 1999, 40, 8495. (c) Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.;
Panunzio, M. Tetrahedron Lett. 1996, 37, 4409. (d) Bandini, E.; Martelli,
G.; Spunta, G.; Panunzio, M. Synlett 1996, 1017. (e) Martelli, G.; Spunta,
G.; Panunzio, M. Tetrahedron Lett. 1998, 39, 6257.
(2) (a) Ogliaruso, M. A.; Wolfe, J. F. Synthesis of Lactones and Lactams;
John Wiley & Sons: Chichester, New York, 1993. (b) Southgate, R.
Contemp. Org. Synth. 1998, 417.
(3) (a) Bose, A. K.; Spiegelman, G.; Manhas, M. S. Tetrahedron Lett.
1971, 3167. (b) Duran, F.; Ghosez, L. Tetrahedron Lett. 1970, 245.
(4) (a) Akermark, B.; Bystrom, S.; Florin, I.; Johansson, N.; Lagerland,
I. Acta Chem. Scand. Ser. B 1974, 28, 375. (b) Seyferth, D.; Burlitch, J.
M.; Dertouzos, H., Jr.; Simmons, H. D. J. Organomet. Chem. 1967, 7, 405.
(5) Quiclet-Sire, B.; Saunier, J. B.; Zard, S. Z. Tetrahedron Lett. 1996,
37, 1397.
(7) Homsi, F.; Rousseau, G. J. Org. Chem. 1999, 64, 81.
(8) (a) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B. M.;
Dahlgreen, M. E. Tetrahedron 1990, 46, 2255. (b) Skiles, J. W.; McNeil,
D. Tetrahedron Lett. 1990, 31, 7277. (c) Thompson, K. L.; Chang, M. N.;
Chang, Y. C. P.; Yang, S. S.; Chabala, J. C.; Ariston, B. H.; Greenspan,
M. D.; Hanf, D. P.; Yudkovitz, J.; Singh, R.; Cooper, R. D. G. Tetrahedron
1994, 50, 12049. (d) Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Federici,
M. E.; Seiler, S. M.; Meanwell, N. H. Bioorg. Med. Chem. 1995, 3, 1123.
(9) For an up-to-date review on [2 + 2] cycloadditions of imines and
ketenes, see: Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur.
J. Org. Chem. 1999, 3223. See also: Georg, G. I.; Ravikumar, V. T. In
The Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; pp 295-368.
(10) For the synthesis and chemistry of N-silyl imines see: Panunzio,
M.; Zarantonello, P. Org. Process Res. DeV. 1998, 2, 49
(11) For [2 + 2] cycloaddition of N-silyl imines and ketenes, see also:
Bennet, D. M.; Okamoto, I.; Danheiser. R. L. Org. Lett. 1999, 1, 641.
(6) Naskar, D.; Roy, S. J. Chem. Soc., Perkin Trans. 1 1999, 2435.
10.1021/ol005633x CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

spectra. Refluxing 4 in toluene overnight resulted in the
formation of trans-â-lactam 5 as single stereoisomer (J3-4
) 1.5-2.5 Hz) (Scheme 1 and Table 1). The presence of
Table 2. Synthesis of Azetidinones 5 and d-5
Scheme 1
EWG or EDG in the para-position of the aromatic ring of
the imine substituents does not have any effect on the
stereochemical outcome of the reaction (Table 1, entries
3-6). As a matter of fact no cis-stereoisomer was detected
in the crude reaction mixture.
Application of this protocol to N-trimethylsilyl alkyl imines
2 containing a stereogenic center in the imine moiety once
again results in the formation of the sole trans-azetidinones
5 and d-5 through the azadiene 4. Of the four possible
stereoisomers only the two trans-isomers were obtained
(Scheme 1 and Table 2). The ratio of the isomers were
determined by 1H NMR spectroscopy, and separation of the
products by flash chromatography on silica gel yielded the
pure isomers. The trans-configuration was established by 1H
NMR spectroscopy, and the relative configuration of the
â-lactams was determined by comparison with previously
prepared similar compounds. No particularly appreciable
effect was obtained on the facial stereochemical outcome
when changing the steric requirement of the trialkylsilyl
groups directly linked to the enolic oxygen as well as to the
ethereal oxygen (Table 2, entries 2, 3, 9, and 10).
Table 1. Synthesis of Azetidinones 5
A useful modification of the so-obtained â-lactams has
been achieved with a new dehalogenation procedure by
means of the recently developed tris(trimethylsilyl)silane.13
Treatment of R-haloazetidinone 5 in toluene with com-
mercially available tris(trimethylsilyl)silane 6 (100 °C, 2 h)
in the presence of AIBN furnished the 3-unsubstituted
azetidinones 7 in good yields (Scheme 2 and Table 3).
Scheme 2
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Org. Lett., Vol. 2, No. 8, 2000

antibiotics as well as Monobactams inhibiting the human
cytomegalovirus protease.14 Work in this direction is ongoing.
Table 3. Synthesis of Azetidinones 7
In this paper we have reported a new application of our
two-step protocol for the synthesis of azetidinone ring by [2
+ 2] reaction. Although the final yields are not very high
(the yields in azetidinone reported are based on the starting
aldehydes), they can be considered satisfactory taking into
account the three-step process. The isolation and stereo-
chemical identification of the neutral intermediates 4 and
the elaboration15 of 3-haloazetidinones to 3-unsubstituted
azetidinone by a new dehalogenation procedure confers an
extra interest to this contribution.
Acknowledgment. This work was supported by the
Progetto Strategico “Applicazioni Industriali della Tecnologie
delle Microonde-CNR Rome”. Thanks are due to Biosearch
Italia S.p.A. for financial suppport.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR spectra for
azadienes, and cycloaddition and reduced products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL005633X
(12) Synthesis and applications of azadiene in HDA reaction have been
studied extensively by Ghosez and co-workers. See: (a) Jnoff, E.; Ghosez,
L. J. Am. Chem. Soc. 1999, 121, 2617. (b) Ghosez, L.; Jnoff, E.;
Beaudegnies, R.; Bayard, P.; Sainte, P. Tetrahedron 1999, 55, 3387. (c)
Ntirampebura, D.; Ghosez, L. Tetrahedron Lett. 1999, 40, 7079. (d) Ghosez,
L. Pure Appl. Chem. 1996, 68, 15. (e) Ghosez, L.; Bayard, P.; Nshimyumuki-
za, P.; Gouverneur, V.; Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-
Hesbain, A. M.; Wynants, C. Tetrahedron 1995, 51, 11021 and references
therein cited. See also: (a) Bongini, A.; Panunzio, M.; Bandini, E.; Martelli,
G.; Spunta, G. J. Org. Chem. 1997, 62, 8911. (b) Panunzio, M.; Villa, M.;
Missio, A.; Rossi, T. Seneci, P. Tetrahedron Lett. 1998, 39, 6585. (c)
Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio, M.; Piersanti,
G. Tetrahedron: Asymmetry 1997, 8, 3717. (d) Bandini, E.; Bongini, A.;
Martelli, G.; Panunzio, M.; Piersanti, G.; Spunta, G. Tetrahedron: Asym-
metry 1999, 10, 1445. (e) Bandini, E.; Martelli, G.; Spunta, G.; Bongini,
A.; Panunzio, M. Synlett 1999, 1735.
(13) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(14) Ogilvic, W. W.; Yoachim, C.; Do, F.; Hache, B.; Lagace, L.; Naud,
J.; O’Meara, J. A.; Deziel, R. Bioorg. Med. Chem. 1999, 7, 1521.
(15) The stereochemical assignments were deduced by NOE experiments.
The resulting 3-unsubstituted azetidinones may be used
as useful intermediates for the synthesis of carbapenem
Org. Lett., Vol. 2, No. 8, 2000
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