Takuo Chiba

Studies on amino acid derivatives. Part 7. General method for the synthesis of penam and cepham and their substituted derivatives

Penam (7-oxo-4-thia-1-azabicyclo[3.2.0]heptane), a basic skeleton of penicillin-type β-lactams, has been synthesized as a stable compound from thiazolidinylacetic acid. The key step in this synthesis is the formation of the β-lactam ring by Mukaiyama-Ohnos procedure. Three methods are developed for the synthesis of thiazolidinylacetic acid from cysteamine by reactions with ethyl propiolate, ethyl ethoxycarbonylacetimidate, or t-butyl formylacetate. Using appropriate derivatives of the latter compounds, 5-, 6-, and 5,6-substituted derivatives of penam are also synthesized. The yields of the bicyclic β-lactams are shown to be strongly dependent upon the pattern of substituents on the thiazolidinylacetic acid. The synthesis of cephams using homocysteamine is also described.