SYNTHESIS OF 2-METHYLTHIO-SUBSTITUTED,4-METHYLTHIO-SUBSTITUTED, AND 7-METHYLTHIO-SUBSTITUTED CEPHALOSPORINS

Methylthiolation of various 7-substituted cephalosporins in the presence of lithium amide bases proceeded stereospecifically (7-imino ether, 7-[(triphenylmethyl)amino], or 7-pht.halimido) or stereoselectively (7-amido) to give 4β-(methylthio) derivatives. Methylthiolation of 7-imino, 7-imino chloride, or 7-imino ether cephalosporins using KO-f-Bu afforded 7a substitution or 7α and 4β, let substitution depending upon substituents at C-3, C-4, and C-7. Methylthiolation of 7-(tritylamino)- and 7-phthalimidocephalosporins using KO-f-Bu proceeded stereospecifically to give 4/3-(methylthio)cephems, although epimerization at C-7 accompanied thiolation in the case of phthalimido. Methylthiolation of 7-amidocephalosporin S-sulfoxides proceeded regiospecifically to give 2αsubstitution which was sometimes accompanied by 2, 2-disubstitution. These various 2-, 4-, and 7-methylthiolated cephems were converted to corresponding 7-amidocephalosporanic acid derivatives. Attempted removal of ester protecting groups from 4-(methylthio)-Δ2-cephems using CF3COOH gave allylically rearranged products, 2α-(methylthio)cephalosporanic acids. © 1979, American Chemical Society. All rights reserved.