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Paper | Regular issue | Vol 36, No. 8, 1993, pp.1747-1762
Published online, 1st January, 1970
DOI: 10.3987/COM-92-6327
Functionalization of the Dihydrothiazine Ring of Cephem Sulfones

Marco Alpegiani, Pierluigi Bissolino, Daniela Borghi, Pietro Sbraletta, Roberto Tonani, and Ettore Perrone*

*Pharmacia Farmitalia Carlo Erba R&D, 20014 Nerviano, Milano, Italy

Abstract

Functionalization of the dihydrothiazine ring of cephem esters and 4-ketones was studied at the sulfone oxidation level. On the esters, alkylation and Michael addition gave 4β- and 2α,4β-substituted products. On the ketones, electrophilic insertion of carbon, halo, oxygen and sulfur substituents was achieved with acceptable selectivity at 2α. Nucleophilic sulfenylation and acyloxylation was successful on 2-bromocephem ketones, themselves electrophilic bromination products. Noticeable events included shift of the 3-cephem double bond and epimerization at C-2. Configurations and ring conformation were evinced by nmr studies. Several compounds were potent inhibitors of human leukocyte elastase.