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Pure Appl. Chem., 2010, Vol. 82, No. 9, pp. 1749-1759

Published online 2010-06-04

Use of functionalized β-lactams as building blocks in heterocyclic chemistry

Matthias D’hooghe, Stijn Dekeukeleire, Erika Leemans and Norbert De Kimpe

Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium

Abstract: β-Lactams represent flexible building blocks suitable for the preparation of a large variety of nitrogen-containing target compounds. In the present study, the formerly neglected synthetic potential of 4-haloalkyl-β-lactams has been elaborated in detail with a focus on the preparation of different mono- and bicyclic heterocycles. A first approach involved ring transformations of these halogenated building blocks toward stereodefined aziridines, azetidines, pyrrolidines, and piperidines via intermediate aziridinium or azetidinium ions. In a second part, novel and stereoselective entries into 1,4- and 3,4-fused bicyclic β-lactams were developed through either a radical or an ionic cyclization protocol. Furthermore, the ring enlargement of halogenated β-lactams into functionalized mono- and bicyclic pyrrolidin-2-ones was established as the aza-analog of the cyclobutylmethylcarbenium ion to cyclopentylcarbenium ion rearrangement. Finally, chiral versions toward azetidin-2-ones and ring transformation products were elaborated, involving the synthesis of 3(S)-alkoxy-4(S)-[1(S)‑chloroethyl]azetidin-2-ones and the preparation of bicyclic β-lactams annelated to piperazines, morpholines, and diazepanes.