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Muxfeldt’s Synthetic Tetracycline Antibiotics
Tetracyclines. 9. Total Synthesis of dl-Terramycin.
J. Am. Chem. Soc. 1979;
Key wordsoxytetracycline - terramycin - antibiotics - Diels–Alder reaction - thiazolone condensation
Tetracyclines are broad-spectrum antibiotics with potent activities against Gram-positive and Gram-negative pathogens. Since their discovery in the 1940s several members of this natural product family as well as semi-synthetic derivatives thereof have been used clinically. While the group of R. B. Woodward accomplished the total synthesis of simplified analogues earlier (J. Am. Chem. Soc. 1968, 90, 439), it was Hans Muxfeldt and his co-workers who first finished the racemic total synthesis of the structurally more challenging natural product terramycin (oxytetracyclin).
The opening step of their total synthesis was an endo-selective Diels–Alder reaction. Further transformations afforded the key thiazolone building block A. A subsequent elegant condensation with the 1,3-acetone dicarboxylate B then afforded the functionalized A/B-ring system in just a single step. While further diastereomers formed, the desired tetracyclic product readily crystallized from the mixture. Unfortunately, oxidative conditions mostly afforded the undesired C11a- over the desired C12a-hydroxylation product. The thioamide could be cleaved by methylation followed by treatment with dilute hydrochloric acid.
20 January 2021 (online)
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