Transformation of penicillins into 3-substituted Δ³-cephems through addition/cyclization of allenecarboxylates

A straightforward synthesis of Δ³-cephems 2 bearing heteroatom substituents directly attached to C(3)-position was performed successfully by a sequential addition/cyclization reaction of allenecarboxylate 4 derived from eithen penicillin 1. Upon treatment of the allenecarboxylate 4 with morpholine, pyrrolidine, sodium azide, and 5-methyl-1,3,4-thiadiazole-2-thiol in DMF in the presence of calcium chloride, the addition/cyclization reaction proceeded smoothly to afford the corresponding 3-substituted Δ³-cephems 2a-e. Reaction of the allenecarboxylate 4 with lithium chloride in NMP (N-methyl-2-pyrrolidone) in the presence of aluminum chloride afforded 3-chloro-Δ³-cephem 2f, while without aluminum chloride, 3-phenylsulfonyl-Δ³-cephem 2e was mainly obtained. The 3-sulfenyl-Δ³-cephems 12 were prepared by a similar addition/cyclization reaction of allenecarboxylates 10 with a catalytic amount of thiolates. The sulfenyl moieties attached at the sulfur atom of the C(4)-substituent of 10 were introduced at the C(3)-position of the cephem framework 2.