Studies related to penicillins. Part 28. β-Elimination reactions of sulphones derived from penicillins leading to cis-3-acylamino-4-oxoazetidine-2-sulphinic acids

Abstract

The reactions of the 3-acetyl and 3-formyl derivatives of (3S,5R,6R)-2,2-dimethyl-6-phenoxyacetamidopenam 1,1-dioxide, i.e. compounds (5e,f), and of p-nitrophenyl (3S,5R,6R)benzylpenicillinate 1,1-dioxide (1f) with 1,5-diazabicyclo[5.3.0]non-5-ene (DBN) followed by iodomethane have been studied. In the case of penam dioxide (5e), epimerisation at position 6 competes with the β-elimination at position 3 and a mixture of the trans- and cis-azetidinones (11a) and (12a) is isolated. No epimerisation is observed with compounds (5f) and (1f), which react to give the corresponding cis-azetidinones (12b,c). It is possible to avoid the epimerisation of the penam dioxide (5e), and to isolate the cis-azetidinesulphinate salt (13), by using potassium t-butoxide in place of DBN. The cis-azetidinesulphinic acid (8c) is also isolable from the reaction of the penicillinate dioxide (1f) with DBN followed by acidic work-up. It undergoes O-methylation of the sulphinic acid group in the presence of diazomethane to give the methyl sulphinate (19), as a mixture of diastereoisomers. Saponification of the p-nitrophenyl ester of the cis-azetidinesulphinic acid (8c) is effected by sodium hydroxide to give the disodium salt (18b), which undergoes methylation in the presence of iodomethane to afford the dimethyl derivative (12d).