Table 1.
Synthesis of 6-substituted tetracyclines by Michael—Claisen cyclization using D-ring precursors with anion-stabilizing substituents in the benzylic position and a stepwise protocol for addition of the base and enone 1, followed by deprotection [(i) HF (aq), CH3CN; (ii) H2, Pd/C (or Pd black), CH3OH-dioxane].
| D-ring Precursor | Cyclization Conditions | Cyclization Product | Cyclization Yield | Tetracycline | Deprotection Yield |
|---|---|---|---|---|---|
 |
LDA; 1 −78 → −10 °C |
 |
84% |  |
71% |
 |
LDA; 1 −78 → −5 °C |
 |
57% |  |
70% |
 |
LDA; 1 −78 → −10 °C |
 |
79% |  |
72% |
 |
LDA; 1 −78 → −10 °C |
 |
79% |  |
83% |
 |
LDA, DMPU; 1 −78 → −10 °C |
 |
81% |  |
72% |
 |
LDA, DMPU; 1 −78 → −10 °C |
 |
37% |  |
59% |
 |
LDA, DMPU; 1 −78 → −10 °C |
 |
78% |  |
79% |
 |
LDA; 1 −78 → −5 °C |
 |
74% |  |
64% |
 |
LHMDS, HMPA; 1 −78 → −10 °C |
 |
49% |  |
79% |