Aklavinone synthesis

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. 

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... 

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 same type of chiral oxidizing reagent was used in the synthesis of Y-rhodomydnone, a-citromycinone [69] and aklavinone [70]. Enantio-selective oxidation was applied in the synthesis of the known hydroxyketone 58 (Scheme 12), which was used previously as a key enantiopure intermediate in the synthesis of (-)-y-rhodomycinone [71]. In this case the required sense of chirality was induced using the dextrorotatory oxaziridine (lS)-(+)-52, and the highest enantiomeric excess was obtained using (lS)-(+)-52c (Fig. 7). The latter was prepared from the imine 55 [72] (Fig. 8) by refluxing with trimethyl orthoformate and subsequent oxidation with 3-chloroperbenzoic add in 91% yield [73]. 

Benzo-annelated nitrogen heterocycles (indoles, quinolines, isoquinolines, etc.) are often found to be a part of biologically active compounds of both natural and synthetic origin. In a considerable body of data on the syntheses of these compounds, which have so far been documented in the literature, the crucial step is vicarious nucleophilic substitution of hydrogen in nitroarenes. Good examples are presented by the synthesis of nordehydrobufotenine [49], eupolauramine [50, 51], damirone [52], and aklavinone [53]. 

Aklavinone (70), which is the aglycone of aclacinomycin A, remains a popular synthetic target, and Kishi et al have now outlined an asymmetric synthesis of the molecule which is based on a slight modification of their earlier route. The synthesis starts with the acetal (67), which is first converted into the keto-ester (68). Treatment of (68) with potassium carbonate in methanol resulted then in smooth asymmetric crossed-aldol condensation, leading to (69), which was easily transformed into optically pure aklavinone. An alternative route to aklavinone is based on a key Diels-Alder reaction between (71) and (72). ... 

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