Facile conversion of tetracycline antibiotics to 4,11a-bridged derivatives via oxidative mannich cyclization.
Treatment of a variety of tetracyclines (tigecycline, minocycline, tetracycline and doxycycline) with Ag(2)CO(3)/EDTA or Hg(OAc)(2) cleanly gave the 4,11a-bridged derivatives in high yields. The reactions proceeded through a novel, intramolecular Mannich cyclization of an iminium species generated by oxidation of the tertiary dimethylamino group at C(4) by Ag(I) or Hg(II). Tetracyclines without 5-OH-substitution (tigecycline, tetracycline and minocycline) gave the 4-OH-substituted, 4,11a-bridged compound, whereas doxycycline gave the 4-dimethylamino-substituted, 4,11a-bridged product. In the case of tetracycline, the 4,11a-bridged compound can equilibrate further to a 4,6-bridged hemiketal. Some of the bridged compounds underwent a novel decarboxylation--rearrangement sequence under acidic conditions to give tricyclic, open chain 1,4-quinoid compounds.
Gu
Jianxin
J
Vaccine Research & Early Development, Pfizer Biotherapeutics, Pearl River, NY, USA.
Cai
Ping
P
Gong
Yumin
Y
Ruppen
Mark E
ME
Storz
Thomas
T
D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002254:Carbonates / Q000737:chemistry; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008628:Mercury / Q000737:chemistry; D009636:Norbornanes / Q000138:chemical synthesis / Q000737:chemistry; D010084:Oxidation-Reduction; D018030:Silver Compounds / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013754:Tetracyclines / Q000737:chemistry*
D001952:Bridged-Ring Compounds; D002254:Carbonates; D009636:Norbornanes; D018030:Silver Compounds; D013754:Tetracyclines; D008628:Mercury; C029823:mercuric acetate; C033260:silver carbonate