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2004
Antibiotics
U 1200
52- 193
Synthesis and Antibacterial Activity of C-6 Carbamate Ketolides, a Novel Series
of Orally Active Ketolide Antibiotics. — A ten-step synthesis yields the target compounds such as (VI) starting from erythomycin A. The synthesis involves the concurrent carbamoylation of the C-6 and C-12 hydroxyls by treatment of the sugar-protected
and C-11 hydroxyl-activated erythromycin A (I) with trichloroacetylisocyanate (II).
Hydrolysis, followed by equilibration of the epimeric C-10 mixture afford the more stable C-10 epimer (III). Reinstalling of the C-2' acetate and cleavage of the cladinose sugar furnish (V). After oxidation of the C-3 hydroxyl and methanolysis of the C-2' acetate
the side chain is selectively attached to the C-6 carbamate by reductive alkylation of
the intermediate ketolide with aldehydes. Interestingly, partial epimerization at C-2,
unobserved in previously reported ketolides, occurs. Ketolides (VIa) and (VIb) display
in vitro and in vivo antibacterial activity comparable to that of telithromycin. —
(HENNINGER*, T. C.; XU, X.; ABBANAT, D.; BAUM, E. Z.; FOLENO, B. D.;
HILLIARD, J. J.; BUSH, K.; HLASTA, D. J.; MACIELAG, M. J.; Bioorg. Med.
Chem. Lett. 14 (2004) 17, 4495-4499; Johnson and Johnson Pharm. Res. Dev.,
Raritan, NJ 08869, USA; Eng.) — H. Hoennerscheid
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