Abstract
A novel strategy was developed for the synthesis of isopenams in high yields. The strategy involves use of the intramolecular counterattack process in the conversions of (±)-5→(±)-11, (±)-6→(±)-12, and (±)-19→(±)-11. Catalytic hydrogenation of (±)-11 afforded isopenam (±)-13, which possessed notable antimicrobial activities. Oxidation of (±)-13 with KMnO 4 gave sulfone (±)-15, which functioned as a potent inhibitor of various bacterial β-lactamases. Sulfone (±)-15 exerted a great synergistic effect on antimicrobial agent (±)-13. Results from the CVFF calculations of the C-2 β-epimer of isopenam 13 (i.e., 23) and the corresponding sulfone derivative 24 indicate the existence of a severe electronic repulsion between the β-lactam carbonyl and the C-2 carboxyl groups. Steric interaction also exists between the C-6 amide side chain and the C-2 carboxylic acid moiety in 23 and 24. These interactions, however, do not exist in the corresponding α-epimers 13 and 15.