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°C gave a 3"-O-propionyl derivative in 96Y.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 ill vitro and higher serum levels than its mother antibiotic.The biological properties of 7 also were compared with those of josamycin and midecamycin**. LeucomycinA5 (1) (Fig. 1) is one of the components of a 16-membered macrolide antibiotic complex, leucomycin, produced by Streptomyces kitasatoensisl).It shows strong antibacterial activit2), and can be successfully obtained as single component by controlling the culture conditions3).Leucomycin A5 (1) has secondary hydroxyl groups at the C-3, C-9, and C-2' positions and a tertiary hydroxyl group at the C-3" position in the molecule.Acylation of the hydroxyl groups at the C-3, C-9, and C-2' positions has been performed by many workers.However, in most cases the antibacterial activity of the acyl derivatives was lower than that of the mother antibiotics4).Acylation of the hydroxyl group at the C-3" position has rarely been performed, since it is a tertiary hydroxyl group and less reactive than the secondary ones at C-3, C-9, and C-2' positions.OMOTO et al.5' reported the synthesis of 9,3 "-di-O-acetylmidecamycin from midecamycin, but no one has described the acylation of the hydroxyl group at the C-3" position alone.The authors have succeeded in selective acylation of the hydroxyl group at the C-3" position in leucomycin A, by treatment with an acyl chloride with heating in the presence of tribenzylamine after protection by trimethylsilylation of the hydroxyl groups at the C-3 and C-9 positions and acetylation of the hydroxyl group at the C-2' position.This paper describes the synthesis of 3 "-O-propionylleucomycin A5i which among 3 "-O-acylleucomycin derivatives possesses the most potent antimicrobial activity and a high serum level.The succeeding paper will report the comparison of the biological properties of 3"-O-acylleucomycins including the 3"-O-propionyl derivative and midecamycin6).** Josamycin and midecamycin were purchased from Yamanouchi Pharmaceutical Co .Ltd. and Meiji Seika Kaisha Ltd., respectively, and their potencies were corrected with the standard samples from National Institute of Health of Japan.