GENERAL-ROUTE TO ANTHRAQUINONE NATURAL-PRODUCTS VIA DIRECTED METALATION OF N,N-DIETHYLBENZAMIDES

Regiospecific, short, and efficient synthesis of the naturally occurring anthraquinones islandicin (1a), digitopurpone (1b), erythroglaucin (1c), catenarin (1d), cynodontin (1e), and soranjidiol (1f) have been achieved in 20-30% overall yields by using directed metalation of easily accessible methoxylated IV, IV-diethylbenzamides (3 and 10a-d) as the key step. In a representative example (Scheme IV), sequential treatment of IV, IV-diethyl-3, 5-dimethoxybenzamide (3) with sec-BuLi and 2, 5-dimethoxy-4-methylbenzaldehyde (4) gives the hydroxyamide 5 which, without isolation, is subjected to p-toluenesulfonic acid in refluxing toluene to provide the phthalide 6. Hydrogenolysis of 6 affords the benzylbenzoic acid 7 which upon Friedel-Crafts cyclization with trifluoroacetic anhydride yields the anthracenol 8. Compound 8, when exposed to chromium trioxide, undergoes facile oxidation to the anthraquinone 9. Selective demethylation (BBr3) of 9 gives erythroglaucin (1c), while vigorous conditions (pyridine hydrochloride) provide catenarin (Id). Formal syntheses of islandicin (1a) and digitopurpone (1b) and total syntheses of cynodontin (le) and soranjidiol (If) have been effected by analogous six-step sequences starting with the benzamides lOa-d and, in three of the four cases (10a-c), the same ptolualdehyde (4). Methoxy and methyl substituents on the aromatic ring offer no complications in metalation ortho to the CONEt2 function. The condensation of the resulting species with aromatic aldehydes is compatible with acidic methyl hydrogens in the aldehyde component. © 1979, American Chemical Society. All rights reserved.