A synthetic method for the 3-azacephem and 3-azacepham nuclei 15, 17, and 18,structurally novel analogues of cephalosporin (II), has been established starting from penicillin V. The azide 6 was prepared from the thiazoline 1. More conveniently, 6 was constructed from the 4-mercaptoazetidine 7 via the oxamide 10. Reduction, formylation, and dehydration then yielded the 4-mercaptoisonitrile 16, a key intermediate of the synthesis. Removal of the protecting group in 16 resulted in the direct formation of the Δ^2-3-azacephem 15 via a spontaneous cyclization of the intermediate thiol. The isomerization of the Δ^2 double bond in 15 to the Δ^3-position could be achieved in a regiospecific manner. Thus, reduction of 15 to the 3-azacepham 18, followed by conversion into the triflamide 19 and treatment with DBU, afforded the Δ^3-3-azacephem 17. The β-lactam system of this new cephem nucleus 17 was found to be highly reactive, while its Δ^2-isomer 15 is relatively stable. Some of the new cephem and cepham derivatives showed an antimicrobial activity.