Synthesis of γ-lactam analogues of carbapenems with substituted-thio groups at the C-3 position

Abstract

γ-Lactamanalogues of carbapenems{(7S)-7-acylamino-2-carboxy-3-(substituted-thio)-1-azabicyclo[3.3.0]oct-2-en-8-ones}(2) were synthesized starting from L-aspartic acid. Condensation of the oxo ester (4) with 2, 4-dimethoxybenzylamine followed by cyclization gave preferentially the E-γ-lactam (6), which was transformed into the 3, 5-cis-5-carboxymethyl-γ-lactam cis-(9)via stereoselective catalytic reduction. The major product cis-(9) and its trans-isomer were converted into compound (2)via a carbene insertion reaction. The antibacterial activity of the trans-acetamidoethylthio derivative (23) slightly exceeded that of the corresponding cis-derivative (17).