Synthesis of carbapenems via metalloimines-ester enolates condensation: a new synthesis of (+)-1β-methyl PS-5

doi:10.1016/S0960-894X(01)80953-7

Bioorganic & Medicinal Chemistry Letters

Volume 3, Issue 11, November 1993, Pages 2347-2350

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Abstract

The synthesis of the new β-lactam antibiotic, namely the (+)-1β-methyl PS-5, is described. The key step involves the ester enolate-metallo imine cycloaddition reaction.

The synthesis of the new β-lactam antibiotic, namely the 1β-methyl PS-5, is described. The key step involves the ester enolate-metallo imine cycloaddition reaction.

References (17)

Perboni, A.; Rossi, T.; Gaviraghi, G.; Ursini A.; Tarzia, G.; P.C.T. Int. Apll. WO 92 03,437 C.A. 117:...
C.M. Cimarusti et al.
Tetrahedron
(1983)
C. Yoshida et al.
J. Antibiot.
(1985)
M.J. Miller et al.
Tetrahedron
(1983)
M.J. Miller
Acc. Chem. Res.
(1986)
R.C. Thomas
D.W. Brooks et al.
Angew. Chem., (Int. Ed. Engl.)
(1979)
G.I. Georg
W.J. Leanza et al.
J. Med. Chem.
(1979)
D.H. Shih et al.
Heterocycles
(1984)
Y. Nagao et al.
J. Org. Chem.
(1992)
C. PalomoT. Ohta et al.
Tetrahedron Lett.
(1988)
C. Bonini et al.
Tetahedron Lett.
(1988)
R.W. Ratcliffe et al.D. Hoppe
Nachr. Chem. Tech. Lab.
(1982)
T. Kametani et al.
Heterocycles
(1982)
M. Shibuya
J. Synth. Org. Chem. Jpn.
(1983)
R. Labia et al.
J. Antibiotiot.
(1984)
T. Nagahara et al.
Heterocycles
(1987)
D.H. Shih et al.
Heterocycles
(1984)
E. Perrone et al.

There are more references available in the full text version of this article.

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Highly efficient chiral ester enolate-imine condensation, giving 3,4-disubstituted β-lactams with excellent trans-syn or trans-anti diastereoselectivity, is reported. The chiral information is included in the electrophilic partner of the condensation, nominally chiral α-, β-silyloxy- or alkoxy-N-trimethylsilyl-imines. The high diastereofacial selectivity is determined by the correct choice of the metal cations present in the reaction medium and the very nature of the hydroxy protecting group. By this procedure a number of azetidinones, intermediates in the synthesis of commercially interesting β-lactam antibiotics have been obtained. Fully assigned ¹H and ¹³C NMR spectra of the so obtained azetidinones are reported.
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Synthesis of carbapenems via metalloimines-ester enolates condensation: a new synthesis of (+)-1β-methyl PS-5

Abstract

Tetrahedron

J. Antibiot.

Tetrahedron

Acc. Chem. Res.

Angew. Chem., (Int. Ed. Engl.)

J. Med. Chem.

Heterocycles

J. Org. Chem.

Tetrahedron Lett.

Tetahedron Lett.

Nachr. Chem. Tech. Lab.

Heterocycles

J. Synth. Org. Chem. Jpn.

J. Antibiotiot.

Heterocycles

Heterocycles