Synthesis of (−)-Tetracycline

We describe a convergent, enantioselective synthesis of (−)-tetracycline (<b>1</b>) from benzoic acid (17 steps, 1.1% yield). Benzoic acid was transformed into the AB precursor <b>2</b> in 10 steps (11% yield), as previously described, and the latter compound was activated toward Diels−Alder cycloaddition by the introduction of an α-phenylthio group (two steps, 66% yield). Heating of the resulting α-(phenylthio)enone (<b>3</b>) with the triethylsilyloxybenzocyclobutene derivative <b>4</b> at 85 °C gave the endo-Diels Alder adduct <b>5</b> in 64% yield. Deprotection and oxidation of the latter intermediate gave the 2-(phenylthio)-1,3-diketone <b>7</b>, which was oxidized with <i>m</i>-chloroperoxybenzoic acid in the presence of trifluoroacetic acid. The sulfoxide intermediate(s) formed eliminated upon warming to 35 °C to give the anyhydrotetracycline derivative <b>8</b>. Intermediate <b>8</b> underwent spontaneous autoxidation at 23 °C to form the hydroperoxide keto-<b>9</b> stereoselectively. Without isolation, hydrogenolysis of <b>9</b> in the presence of palladium black gave (−)-tetracycline (42% yield from <b>7</b>), indistinguishable from an authentic sample.