Optical isomers of 4-ethyl-5 or 6-methyl-2, 3-dioxopiperazine were prepared from (S) or (R)-alanine, respectively, and subjected to synthesis of the penicillin derivatives (R1=CH3 of II, III, IV, V) via the phenylglycine derivatives (XVI). 6-Alkyl-4-ethyl-2, 3-dioxopiperazine derivatives were prepared and these phenylglycine derivatives (XXVI) were separated to diastereomers XXVIa, XXVIb by silica gel column chromatography. Their configurations were determined on the basis of the correlation of thin-layer chromatography (TLC) Rf values and optical rotations. The corresponding penicillin derivatives (II, III) were prepared from XXIVa, XXIVb. These penicillin derivatives showed in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae and Serratia marcescens, the activity being in the order of II, piperacillin IV, V, III. In (S)-6-alkyl derivatives (II), the stability against β-lactamase increased with increasing the number of carbons of the 6-alkyl group.
