Synthetic Studies of Hydronaphthacenic Antibiotics. I. The Synthesis of 4-Demethoxy-7-O-methyl Daunomycinone

Abstract

Daunomycin is a new and very promising antitumor antibiotic. This communication reports the synthesis of (dl)-4-demethoxy-7-0-methyl daunomycinone as part of a scheme toward the totaI synthesis of daunomycin.La daunomycine est un antibiotique nouveau et prometteur contre les tumeurs. Cette communication relate la synthese du dl demethoxy-4 0-methyl-7 daunomycinone en tant qu'etape en vue de la synthese totale de Ia daunomycine.

Syntheses of linear tetracyclic antibiotics—tetracyclines and anthracyclines

“…Deketalization of (33) using sulfuric acid gave the ketone (34) which was treated with acetic anhydride and p-toluenesulfonic acid at 1450 C. The crude enol acetates were transformed into the epoxide with m-chloroperbenzoic acid. This epoxy acetate was treated successively with sodium hydroxide and acetic acid, to ensure complete hydrolysis and rearrangement, to give 7-deoxydaunomycinone (35) in 50% overall yield from (34). As methods for the introduction of hydroxyl functions at C-7819 and C-148, 9 are already known, this route constitutes a formal total synthesis of adriamycinone (36).…”

“…35 Treatment of the 2-acetyl-2-hydroxytetralin (111) with an isomeric mixture of methyl 3-acetoxyphthalate in boiling trifluoroacetic anhydride, followed by hydrolysis and Friedel-Crafts cyclization using hydrofluoric acid at room temperature affords a mixture of the linear tetracyclic compound (112) and the regiochemical isomer in 19% overall yield. Without separation, the compounds were quantitatively methylated with dimethyl sulfate in the presence of potassium carbonate to give the nonphenolic compounds (113).…”

“…The hydroxy ketone (145), prepared from 5,8-dimethoxy-I-or &tetralone by a new route, was treated with 3-acetoxyphthalic acid half ester, and the product obtained in 38% yield was converted in two steps to a mixture of the dimethyl ethers (146) and (147). Demethylation of (146) gave the quinone (148) which on selective methylation of the C,-hydroxy group by treatment with diazomethane afforded 7-deoxydaunomycinone (35), which had already been converted into daunomycinone (54) by Kende.8 A slightly different approach to the general scheme DBA * DCBA for the synthesis of linear tetracyclic compounds has been reported independently by Sih42,43 and Kende. 44 The method, which involves a Fries rearrangement, shows high regioselectivity in the ring formation stage.…”

“…Cyclization of (108) using sulfuric acid afforded the tetracyclic compound (109), which was converted into 9-deacetyl-4-demethoxy-9-deoxydaunomycinone (1 10) by the sequence of demethylation, bromination, acyloxylations, and hydrolysis.z7 Similar approaches, involving stepwise Friedel-Crafts reactions, have been reported by many g r o~p s .~~-~~ A good example is provided by W~n g ' s~~ total synthesis of daunomycinone (54, achieved in 1973 after he had carried out a model synthesis of demethoxydaunomycinone (71). 35 Treatment of the 2-acetyl-2-hydroxytetralin (111) with an isomeric mixture of methyl 3-acetoxyphthalate in boiling trifluoroacetic anhydride, followed by hydrolysis and Friedel-Crafts cyclization using hydrofluoric acid at room temperature affords a mixture of the linear tetracyclic compound (112) and the regiochemical isomer in 19% overall yield. Without separation, the compounds were quantitatively methylated with dimethyl sulfate in the presence of potassium carbonate to give the nonphenolic compounds (113).…”

The Total Synthesis of Daunomycinone

“…We wish to report a total synthesis of 1 fashioned in the CD + ABCD annelation sequence which has been successfully put to test in a model study (3). The synthesis of the antibiotic aglycone itself utilized also the bicyclic ketol 2, obtained from 2,5-dimethoxybenzaldehyde in seven steps (3) or, preferably, 2 may be prepared as shown in Scheme 1.…”