Daunomycinone, synthesis

Similar results are obtained with the /htetralone derivatives 12, which are useful building blocks in the synthesis of anthracycline antibiotics. Furthermore, the usefulness of the diastereoselec-tive addition to ot-oxo acetals was impressively demonstrated in the synthesis of (-)-7-deoxy-daunomycinone, which uses the completely stereoselective addition of (trimethylsi-lylethynyl)magnesium chloride to the /i-tetraione acetal 12 (R =OMOM R2 = Br) as the key reaction31. 

Antkracyclinones. A key step in a stereocontrolled synthesis of 4-demethoxy-daunomycinone (4) involves cycloaddition of the epoxide 1 with this diene (2). Later steps follow known transformations. 

This methodology provides a regiocontrolled synthesis of anthracyclinones such as daunomycinone (2) as outlined in Scheme (I).3... 

For a review of synthetic strategies towards daunomycinone, see P. J. Harrington, Transition Metals in Total Synthesis, Wiley, New York, 1990, pp. 346-399. 

Oxidative decyanation (6,430). Two laboratories have reported regiospedfic syntheses of anthracyclines based on conjugate addition of the enolate of a nitrile to an O, /3-unsaturated ester. For the synthesis of daunomycinone (7), the reaction involved addition of the enolate of 1 to 2 to give 3 in 94% yield. The ester group of 3 was hydrolyzed and the resulting acid was cyclized to 4. Oxygenation of the enolate of 4 by the procedure of Watt results in the quinone 5, which is oxidatively demethylated deketalization of the product led to 6, which had been converted previously into 7. 

In connection with a synthesis of 11-deoxydaunomycinone [35] we did not observe the expected linear cyclization of the bromide 21, but rather the exclusive angular cyclization to the benzo[u]anthraquinone (22) [36]. This reaction was later exploited in the synthesis of a daunomycinone-rabelomycin hybrid 24 which incorporated structural elements of both antibiotics [37]. The required bromide 21 was prepared by alkylation of a bromomethylanthraquinone... 

Scheme 7. Electrophilic cyclization of 21 to 22 followed by the introduction of an oxygen atom in the synthesis of a daunomycinone-rabelomycin hybrid 24 [37]...

Diels-Alder reactions have played an eminent role (c/. Schemes 25, 26, 45, 53, 107, 109 and 124) in the synthesis of analogs of daunomycinone (624) and aldavinone (625), two representative aglycones of the tumor-inhibiting anthracyclines (Scheme 140). ... 

The annulations of alkenyl complexes of the type (233 Scheme 34) have been examined mainly with alkyl substituents and in a few cases with oxygen - ° and silicon - substituents in a variety of cyclic and noncyclic systems. It is notable that the benzannulations of the parent vinyl complex of (233) (42a Scheme 7) fail, which is apparently due to competing polymerization of (42a). ° Annulations of complexes of the type (233) are successful if at least one of the three substituents is nonhydrogen. Benzannulations of alkenyl complexes have been employed in the synthesis of 7-ethoxyprecocene, ° vitamin E - and daunomycinone. " ... 

In a total synthesis of daunomycinone (b, the aglyconc of an antitumor antibiotic). Ho et effected selective ether cleavage of (6, daunomycinone trimethyl ether) to (7, 4-0-demethyl-7-0-methyldaunomycinone) by treatment with aluminum chloride at room temperature. 

Substituted quinone ketals serve nicely in annelation strategies. The methodology has been skillfully applied to the total synthesis of several natural products, including (+)-4-demethoxydaunomycinone (237) and (-i-)-daunomycinone (238) [57-59]. One annelation strategy calls for a Michael addition of 234 to quinone ketal 233 followed by capture of the intermediate enolate, and leads to annelated product 235 when R = H, and to 236 when R = OMe. These materials were converted to the natural products 237 and 238 in the manner shown in Scheme 19 [59]. 

Like Gaul, the synthesis of the anthracyclines is divided into three parts construction of the aglycones (e.g.,adrlamycinone, lb, daunomycinone, 2b, or carminomyclnone, 3b), synthesis of the sugar residue and coupling of the two. 

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