Novel antibacterial macrolides: synthesis of 15-membered diolides.
Novel 15-membered macrolides possessing the dilactone skeleton, diolides 13a and 13b, have been synthesized in our research program aimed at finding new antibacterial macrolides. Key strategic elements of the approach include the ring-expanding reaction of 13-membered dilactones, prepared from erythromycin A (Ery-A), to 15-membered dilactones via intramolecular translactonization. The absolute configuration at the regenerated C-8 position of the new diolides was determined by chemical transformation, leading to the corresponding lactam analogues, whose stereochemistry is known in the literature. For further confirmation, X-ray analysis was performed. The X-ray structure determination of 13a revealed a backbone conformation similar to that of Ery-A. Novel 15-membered diolide 13a and the 11,12-diol 18 exhibited antibacterial activities comparable to that of Ery-A.
Ohara
Takafumi
T
Discovery Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan.
Kume
Masaharu
M
Narukawa
Yukitoshi
Y
Motokawa
Kiyoshi
K
Uotani
Kouichi
K
Nakai
Hiroshi
H
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004917:Erythromycin / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004917:Erythromycin