The total synthesis of dl-6-demethyl-6-deoxytetracycline

A practical, convergent route to the key precursor to the tetracycline antibiotics

“…23 Nose-worthy, 24 and later Woodward in collaboration with Pfizer scientists, showed that under somewhat different conditions (CaCl 2 , water-butanol containing ethanolamine, pH 8.5, reflux, 3.5 h) a mixture of C4-epimers of sancycline is isomerized to afford predominately the natural (4 S )-stereoisomer. 20 These examples are somewhat distantly removed from the substrate of present interest, the (4 R )-C12a hydroxylation product 14 . In the event, when a solution of the latter was heated at 52 °C for 15 h in a mixed solvent containing tetrahydrofuran (2 parts), methanol (2 parts), and 2 M aqueous sodium dihydrogen phosphate solution (3 parts) almost complete isomerization to the desired 4 S -epimeric product ( 15 ) occurred.…”

“…In the first fully synthetic route to any tetracycline antibiotic, ( d , l -6-demethyl-6-deoxytetracycline, sancycline, 17 ), Woodward and co-workers reported that d , l -6-demethyl-6,12-dideoxytetracycline ( 16 ) was hydroxylated in the presence of dioxygen and cerous chloride in buffered methanol-DMF to provide synthetic sancycline in 6.5% yield (Scheme 8). 20 In their synthesis of d , l -terramycin, the Muxfeldt laboratory described a more efficient C12a-hydroxylation reaction ( 18 → 19 , 52% yield) using a different protocol, also employing dioxygen as the stoichiometric oxidant. 21 A later publication from the Stork laboratories reported that conditions could not be found to achieve late-stage C12a hydroxylation of 12a-deoxytetracycline to produce tetra-cycline itself ( 20 → 21 ).…”

Chemical Modification of the Tetracyclines

“…No explanation has as yet been found for these contradictory results. Under alkaline conditions 4-epitetracyclines are converted almost completely back to the bioactive oe-isomer in the presence of chelating metals (KORST et al 1968). …”

“…The totally synthetic route of W oodward and the Pfizer Company is much more circuitous than the totally synthetic pathway of Muxfeldt and coworkers and gives considerably inferior yields (CONOVER et al 1962;KORST et al 1968;MUXFELDT and ROGALSKI 1965;MUXFELDT et al 1979). It is only logical, therefore, that attempts at finding new tetracyclines not producible by semisyn- w. ROGALSKI thetic means have generally followed the synthetic pathway of Muxfeldt, which is distinguished by a particularly elegant structuring of rings A and B.…”

Fortschritte in der Chemie und Biologie natürlicher Antibiotika

“…Es überrascht daher nicht, dass der hohe Grad molekularer Komplexität in einem trügerisch einfach erscheinenden Kohlenstoffgerüst angesichts der wichtigen antibakteriellen Breitbandwirkung der Tetracycline die Aufmerksamkeit vieler Synthesechemiker auf sich gelenkt hat. Wegweisende Arbeiten mit Blick auf die Totalsynthese von Tetracyclinen wurden unter anderem in den Laboratorien von R. B. Woodward, [23] H. Muxfeldt [24] und G. Stork durchgeführt. [25] Ebenso ist eine Semisynthese von Tetracyclinen durch H. H. Wasserman et al von Bedeutung.…”