Aklavinone

When allylic compounds are treated with Pd(0) catalyst in the absence of any nucleophile, 1,4-elimination is a sole reaction path, as shown by 492, and conjugated dienes are formed as a mixture of E and Z isomers[329]. From terminal allylic compounds, terminal conjugated dienes are formed. The reaction has been applied to the syntheses of a pheromone, 12-acetoxy-1,3-dode-cadiene (493)[330], ambergris fragrance[331], and aklavinone[332]. Selective elimination of the acetate of the cyanohydrin 494 derived from 2-nonenal is a key reaction for the formation of the 1,3-diene unit in pellitorine (495)[333], Facile aromatization occurs by bis-elimination of the l,4-diacetoxy-2-cyclohex-ene 496[334],... 

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. 

In a clever, convergent and regiospecific route to the aklavinone ring system, it was shown that treatment of the lithio anion of the cyanophthalide 1 with the enone lactone 2 in THF/HMPA gave the tetracyclic quinone 3 directly (25% yield after conversion to the methyl ester and purification). 

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,... 

Hydrolysis of a methyl ether.1 Treatment of either 1 or 2 with BF3 etherate yields exclusively 3 (aklavinone). One explanation for the result is formation of a cyclic borate ester intermediate involving the C7- and C9-hydroxyl groups. Under similar conditions, trifluoroacetic acid converts either 1 or 2 into an 8 1 mixture of 3 and 7-epi-3. BF3 etherate was also used to convert the C,0-epimer of 2 into 3. 

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. 

Other mutants, with rhodinose as component of the oligosaccharide, have been described.261 For example, the aklavinone in the mutant H026 is glycosylated by a trisaccharide containing a terminal rhodinose and two other deoxy sugars. The mutant H026 is deficient in the oxidoreductase which converts Rho into cinerulose A, resulting in aclacinomycin A (aclarubicin) (Scheme 52). 

Bicyclocyclization,1 The key step in a short, stereocontrolled synthesis of the antitumor agent aklavinone (5) is a biomimetic cyclization of the tricarbonylnaphthalene derivative 1 to the tetracyclic product 3. The cyclization involves a Michael addition followed by aldol condensation. The first step to provide 2 can be effected in high yield... 

Although there are remarkable exceptions (see below), it has nonetheless often been shown that glycosyl transfer happens always at the very end of a biosynthetic sequence. For example, the biosynthesis of aclacinomycin A (37), a less cardiotoxic anthracycline than doxorubicin (30), proceeds via aklavinone (38)... 

Scheme 14. The biosynthesis of aclacinomycin A (37 proceeds via aklavinone (38) and the monosaccharide aklavin (39), i. e., the glycosylation steps follow the complete construction of the aglycon. A similar process occurs in the biosynthesis of pradimicin S (38 a) the glycosyl transfer steps occur after complete assembly of the polyketide aglycon moiety...

Nevertheless, a few biosynthetic studies have shown that glycosyl transfer can occur much earlier, sometimes well before construction of the aglycon moiety is complete. In the perhaps best-known example, the biosynthesis of daunomycin (= daunorubicin, 29) and adriamycin (= doxorubicin, 30), glycosyl transfer of daunosamine is postulated to occur either at the aklavinone (38) stage [86], as in the biosynthesis of aclacinomycin A 37 (see above), or after 11-hydroxylation to -rhodomycinone [87], i. e., six to seven biosynthetic steps prior to completion of adriamycin formation (30, Scheme 17) [88]. 

Scheme 35. Microbial conversion of 4-deoxyaklanonic acid (133) to 4,7-deoxy-aklavinone (133) [100]...

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. 

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