Novel semisynthetic oxo and alkyl macrolide antibacterials and related derivatives

Abstract

An efficient method of protecting the 10,11-double bond in dienone and epoxy enone 16-membered macrolides has been developed. This involves Michael addition of thioacetic S-acid to the 10,11-ene to give exclusively the 11 -acetylthio derivatives, which can be smoothly deprotected by treatment with fluoride ion. The protected intermediates have been used to prepare a novel class of macrolide antibacterials in which the aldehyde group has been converted into an alkyl ketone by reaction with the appropriate diazoalkane. Thus 20-oxo analogues of rosaramicin, 12,13-de-epoxy-12,13-dehydrorosaramicin, tylosin, and desmycosin have been prepared. The reaction of diazomethane with unprotected macrolides has also been studied including the synthesis of 18-C-methyl-3″-O-propionyll-eucomycin A₅. Derivatives in which the 20-formyl group has been replaced by methyl and by halogeno groups, as well as derivatives having a 2,3-ene are described. A number of base-catalyzed rearrangement products including desmycosin 8β,20α-aldol and desmycoin 8α,20β-aldol are also described.