Synthesis of (-)-tetracycline.
We describe a convergent, enantioselective synthesis of (-)-tetracycline (1) from benzoic acid (17 steps, 1.1% yield). Benzoic acid was transformed into the AB precursor 2 in 10 steps (11% yield), as previously described, and the latter compound was activated toward Diels-Alder cycloaddition by the introduction of an alpha-phenylthio group (two steps, 66% yield). Heating of the resulting alpha-(phenylthio)enone (3) with the triethylsilyloxybenzocyclobutene derivative 4 at 85 degrees C gave the endo-Diels Alder adduct 5 in 64% yield. Deprotection and oxidation of the latter intermediate gave the 2-(phenylthio)-1,3-diketone 7, which was oxidized with m-chloroperoxybenzoic acid in the presence of trifluoroacetic acid. The sulfoxide intermediate(s) formed eliminated upon warming to 35 degrees C to give the anyhydrotetracycline derivative 8. Intermediate 8 underwent spontaneous autoxidation at 23 degrees C to form the hydroperoxide keto-9 stereoselectively. Without isolation, hydrogenolysis of 9 in the presence of palladium black gave (-)-tetracycline (42% yield from 7), indistinguishable from an authentic sample.
Charest
Mark G
MG
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Siegel
Dionicio R
DR
Myers
Andrew G
AG
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis; D019817:Benzoic Acid / Q000737:chemistry; D013237:Stereoisomerism; D013752:Tetracycline / Q000138:chemical synthesis*
D000900:Anti-Bacterial Agents; D019817:Benzoic Acid; D013752:Tetracycline