Of aklavinone

The phenolic oxygen on 2-allyl-4-bromophenol (7) readily underwent oxypalladation using a catalytic amount of PdCl2 and three equivalents of Cu(OAc)2, to give the corresponding benzofuran 8. This process, akin to the Wacker oxidation, was catalytic in terms of palladium, and Cu(OAc)2 served as oxidant [17]. Benzofuran 10, a key intermediate in Kishi s total synthesis of aklavinone [18], was synthesized via the oxidative cyclization of phenol 9 using stoichiometric amounts of a Pd(II) salt. 

This reaction was used for an asymmetric synthesis of aklavinone (8), an aglycone of the anthracycline antibiotics. The key step was the reaction of the acetal 6 with 2,... 

Cleavage of alkyl ary ethers (4, 305). The most difficult step in a recent synthesis of aklavinone (3) is demethylation of 1 to 2. Lewis acid reagents (BBr3) were useless because of preferential attack of the allylic hydroxyl nucleophilic demethylation (LiSCH3) results in concomitant aromatization of ring A. Demethylation "with Lil buffered with benzoic acid in pyridine-collidine at 145° was successful and proceeded in 92% yield.4, Aklavinone is the aglycone of an antitumor anthracycline that is less toxic than adriamycin. 

Kishi s synthesis of aklavinone (625) (Section 4.1.8.4) exploits the regiodirecting bias of a bromide substituent in dienophile (94) (which parallels that of the phenylthio group in 90) (Scheme 26). The initially formed cycloadduct underwent spontaneous elimination of HBr (neutralized by SrCOa) and oxidation (air, Pt 2NEt) to give the anthraquinone product (97) as the exclusive regioisomer. 

In contrast, this reaction, when run at room temperature under a pressure of IS kbar (18 h), afforded bicyclic dienedione (226 R = H) in 64% yield. Similarly, the Diels-Alder reaction of p-benzoquinone (224) with dienyl ester (225 R = Et) was significantly improved by high pressure (IS kbar, r.t, 3 h), providing product (226 R = Et) in 60% yield dione (226 R = Et) served as a key intermediate for a synthesis of ( )-aklavinone (625). ... 

Thermal cycloaddition of 346 (Scheme 66) with 1,1-dimethoxyethylene gives the bicyclic lactone 347 (87JOC1889). The reaction is applicable to the synthesis of aklavinone 348. 

Several examples exist wherein the chirality of the substrate serves to influence the degree of diastereoselectivity obtained on oxidation with racemic and nonracemic oxaziridines. These examples are different from those above, since an auxiliary whose sole purpose is to direct the stereoselectivity is not present. The majority of these examples rely on cyclic stereocontrol to direct the facial selectivity. For example, in Meyers synthesis of the AB-ring of aklavinone, oxidation of the thermodynamic enolate derived from 33 resulted in the production of tertiary a-hydroxy ketone 34 as a single diastereomer in modest yield.23 The stereoselectivity is rationalized by invoking a transition state wherein pseudo axial addition to... 

The first hybrid anthracyclines were produced by introducing parts of the rhodomycin biosynthetic gene cluster from S. purpurascens into S. galilaeus [49,53]. The transgenic strain produced glycosides of aklavinone, P-rhodomycinone, s-rhodomycinone, 10-decarbomethoxyaklavinone and, as novel products, glycosides of 11-deoxy-b-rhodomycinone (Struct. 6). 

Scheme 10 Late tailoring steps proposed for the conversion of aklavinone to doxorubicin...

Tsukamoto N, Fuji 1, Ebizuka Y, Sankawa U. Cloning of aklavinone biosynthesis genes from Streptomyces gaiiloeus. J Ancibiot 1992 45 1236-1294. 

An approach to an anthracycline, 8,10-dideoxycarminomycinone (204), which does not involve a Diels-Alder reaction, is by base-induced addition of the nitro-acetal (202) to the anthraquinone (201) resulting in the regioselective formation of (203), which is then converted to (204) using relatively standard methodology. Also of considerable interest in this area are several different total syntheses of aklavinone (205). 

---