Sulfur-free Penicillin Derivatives. I. Functionalization at C-5

Abstract

Direct chlorination of an anhydropenicillin produces a sulfur-free dichloride in which the two C—S bonds are replaced by two C—Cl bonds. The reaction is general for anhydropenicillins and proceeds with predominant retention of configuration at C-5 except in the case of anhydro-6-phthalimidopenicillin, which gives variable stereochemical results.Hydrolysis of the COCl function to COOH, conversion of the acids or acid chlorides to methyl, t-butyl, and benzhydryl esters, and regeneration of the acids from the latter two esters are described.Nucleophilic substitution at C-5 of these compounds proceeds smoothly and with inversion of configuration. The rate of the reaction depends on the C-6 substituent in the direction H2N > acylamino > phthalimido.