Biomimetic Syntheses of Pretetramides. 2. A Synthetic Route Based on a Preformed D Ring

Article abstract of DOI:10.1021/ja00226a037

A route to pretetramides has been developed on the basis of tandem condensations of homophthalate esters with the dianion of methyl acetoacetate to give aromatic bis(diketo esters), which cyclize spontaneously to anthracene diesters.A further condensation of one of the ester groups with acetamide synthons gives anthracene ester-keto amides, which can be cyclized to naphthacenecarboxamides.By this technique dimethyl 3-methoxyhomophthalate (2b) was condensed with the dilithium salt of methyl acetoacetate to give anthracene diester (4b).Protection of the hydroxyl groups followed by treatment with the dilithium salt of N-(trimethylsilyl)acetamide gave anthracene ester-keto amide 6, which cyclized to pretetramide (1) on treatment with HBr in acetic acid.The procedure for synthesis of pretetramide was modified to permit separate addition of the ketide chains.By use of the aliphatic mono ester (7b) of 3-methoxyhomophthalic acid, chain extension was brought about at the aliphatic carboxyl group by condensation with the dilithium salt of tert-butyl acetoacetate.This product was cyclized to isocoumarin 9b by treatment with acetic anhydride.Completion of the backbone was achieved in a single condensation by treatment of 9b with trianion 18 of 3,5-dioxohexanenitrile (prepared from the nitrile or indirectly by cleavage of isoxazole 17 with LDA) to give anthrone 32.A variety of other condensations of the trianion 18 was performed with electrophiles to demonstrate the utility of the reagent.The synthesis of pretetramide from anthrone 32 was completed by treatment with HI/phenol.