Facile conversion of tetracycline antibiotics to 4,11a-bridged derivatives via oxidative mannich cyclization

Abstract

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.

Fungal Biotransformation of Tetracycline Antibiotics

“…These considerations, together with diagnostic 2D NMR correlations (Figure ), supported assignment of structures for seco -cyclines E ( 13 ) and F ( 14 ) as shown, with retention of the C-5a configuration from 4 . Of note, a 2010 report described the Ag 2 CO 3 /EDTA (66% yield) and Hg­(OAc) 2 (88% yield) preparation of 4,11a-bridged derivatives of 4 , which were readily converted to 13 (55% yield) via decarboxylative rearrangement in acidic aqueous phosphate buffer (pH 6.4) at 35 °C …”

“…Of note, a 2010 report described the Ag 2 CO 3 /EDTA (66% yield) and Hg(OAc) 2 (88% yield) preparation of 4,11a-bridged derivatives of 4, which were readily converted to 13 (55% yield) via decarboxylative rearrangement in acidic aqueous phosphate buffer (pH 6.4) at 35 °C. 11 Our commercial sample of 5 was contaminated with three isomers tentatively identified on the basis of HRESI(+)MS as 4-epi-chlortetracycline ( 15 7). 12,13 The acid-mediated epimerization of 5 to 15 likely proceeds as illustrated above for 3:3a (Figure 2) with the ring D Cl substituent further activating the C-11 carbonyl to intramolecular lactonization and cleavage of C-11 to C-11a to yield 16 and 17 (Figure 8).…”