Concept of counterattack reagents: Intramolecular counterattack strategy in the synthesis of biologically active isopenams

A novel strategy was developed for the synthesis of isopenams in high yield s. 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 wit h KMnO4 gave sulfone (+/-)-15, which functioned as a potent inhibitor of va rious bacterial beta-lactamases. Sulfone (+/-)-15 exerted a great synergist ic effect on antimicrobial agent (+/-)-13. Results from the CVFF calculatio ns of the C-isopenam 13 (i.e., 23) and the corresponding sulfone derivative 24 indicate the existence of a severe electronic repulsion between the bet a-lactam carbonyl and the C-2 carboxyl groups. Steric interaction also exis ts between the C-6 amide side chain and the C-2 carboxylic acid moiety in 2 3 and 24, These interactions, however, do not exist in the corresponding al pha-epimers 13 and 15.