Acyl derivatives of 16-membered macrolides. I. Synthesis and biological properties of 3"-O-propionylleucomycin A5 (TMS-19-Q).

Using leucomycin A5 (1), 3"-O-propionylleucomycin A5 (7) was synthesized by the following synthetic route: 2"-O-acetylation, 3,9-di-O-trimethylsilylation, 3"-O-propionylation, 3,9-di-O-detrimethylsilylation and 2'-O-deacetylation. Acylation of the 3"-tertiary hydroxyl group of 2'-O-acetyl-3,9-di-O-trimethylsilylleucomycin A5 with propionyl chloride in the presence of tribenzylamine at 70 degrees C gave a 3"-O-propionyl derivative in 96% yield. The structure of the final compound, 3"-O-propionylleucomycin A5 (7) was confirmed by means of mass, 1H-NMR and 13C-NMR spectrometry and chemical degradations. 3"-O-Propionylleucomycin A5 (7) showed higher antibacterial activity in vitro and higher serum levels than its mother antibiotic. The biological properties of 7 also were compared with those of josamycin and midecamycin.