Acid catalyzed ring opening reactions of 6-deoxy-9-deoxo-9a-aza-9a-homo-erythromycin A 6,9-cyclic imino ether

In recent years, there has been growing interest in ring opening reactions of the macrolide antibiotic erythromycin A leading to the synthesis of chimeric 9a- and 8a-azalides which are structurally homologous to their potent prototypes azithromycin and its 8a-isomer in their critical eastern halves of the molecule but are functionally simplified in the left-hand part of the 15-membered macrocyclic ring. As part of our program in this area we have recently reported the synthesis of 6,9-cyclic seco oxime (2) starting from 6,9-cyclic imino ether (1), the key intermediate in the synthesis of azithromycin. Base catalyzed internal acylation of 2 followed by reduction and N-methylation afforded a series of linear C-1 amides in which the C-10 similar to C-15 fragment was inversely bound to the C-1 carbon atom. This paper is concerned with the acid catalyzed hydrolysis of 1 and the synthesis of novel seco macrolides with C-1 amido group, potential intermediates for new macrolide antibiotics.