CLADINOSE ANALOGS OF 16-MEMBERED MACROLIDE ANTIBIOTICS .3. EFFICIENT SYNTHESIS OF 4-O-ALKYL-L-CLADINOSE ANALOGS - IMPROVED ANTIBACTERIAL ACTIVITIES COMPATIBLE WITH PHARMACOKINETICS

The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as a neutral sugar a re described. These potent novel derivatives have been efficiently syn thesized avoiding glycosylations. Two hydroxyl groups in mycarose of t he tri-(tert-butyldimethylsilyl) ether intermediate were successively alkylated. Sequential deprotections of silyl groups afforded 4-O-alkyl -L-cladinose analogues and 3,4-di-O-alkyl-L-mycarose analogues of leuc omycin V. Some 4-O-alkyl-L-cladinose analogues exhibited potent antiba cterial activities. The mast active derivative, 3 ''-O-methyl-4 ''-O-( 3-methylbutyl)leucomycin V, showed improved metabolic stability in rat plasma in vitro an extremely high concentrations in serum after oral administrations in mice and in hamsters.