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Strategies for the Stereocontrolled Formation of Oxygen Analogues of Penicillins and Cephalosporins

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The synthesis of oxacephalotin and oxacephamandol, which are more active than natural, sulfurcontaining congeners, and the isolation of clavulanic acid, a potent inhibitor of β-lactamase enzymes, directed attention of many academic and industrial laboratories the synthesis of oxygen analogues of penicillins and cephalosporins.

The present review focuses attention on the problem of stereocontrol in the formation of a desired configuration of the bridgehead carbon atom in the title compounds. Five feasible synthetic methods leading to the basic skeletons of clavams and 5-oxacephams are discussed. Three of them involve the nucleophilic substitution at C-4 of the azetidin2-ones performed as inter- or intramolecular process and the remaining two involve cycloaddition reactions between ketenes and iminoethers, or between vinyl ethers and isocyanates. Owing to the general application, stereospecificity and high asymmetric induction, the last method seems to be most advantageous. The weak point of the nucleophilic substitution methodology is that a nucleophile approaches the 3-substituted azetidin-2-one ring preferentially anti to the existing substituent and in the case where there is no substituent at C-3, that the stereoselectivity of formation of the new chirality center at C-4 is low. All discussed methods are illustrated by the examples taken from the literature.

Keywords: 5-oxacephams; Stereocontrolled; azetidin-2-one ring; isocyanates; nucleophilic; stereospecificity

Document Type: Review Article


Affiliations: Institute of Organic Chemistry of the Polish Academy of Sciences; Kasprzaka 44 / 52; 01-224 Warsaw, Poland

Publication date: 2004-07-01

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