Pyranoacridones

Acronycine was first synthesized in 1967-68 by Beck et al. who published simultaneously three interrelated syntheses of that alkaloid (13, 14). Around ten other total syntheses have been reported up till now (15-26). Most of the synthetic strategies developped are sufficiently versatile to permit access to acronycine structural analogues as far as substitution on the A ring is concerned. Syntheses of analogues modified at B, C and D rings have been comparatively less explored. Most of them rely on chemical modifications performed on a preformed pyranoacridone skeleton, at the latest steps of the synthesis. 

In terms of organization, biosynthetic considerations take precedence. These are followed by a description of the various groiqrs of naturally occurririg acridone alkaloids the simple aoidones, C-prenylacridones, futoacridones, pyranoacridones, and finally the dimeric acridone all oids and related compounds. 

Tables II, HI, IV and V survey the structures, properties and the distribution of naturally occurring C-prenylacridones, furanoacridones, pyranoacridones and dimeric acridone alkaloids, respectively.

Dihydroxyacridone prepared in this way has been used fiequently as a starting material for e synthesis of other acridone alkaloids including simple O-and JV-alkylated derivatives (288) and more complex C-prenylanidones (289), pyranoacridones (290,291), and acridone-coumarin mers (292). 

The key step of the acridone synthesis introduced by Coppola is the condensation of a A methylisatoic anhydride with the lithium enolate of a 2-cyclohexen-l-one. The formed diketo intermediate spontaneously cyclizes into a dihydroacridone, easily aromatized to the corresponding acridone. The versatility of this method, which enables carbon-carbon and carbon-nitrogen bond formation under very mild conditions, is illustrated by the efficient syntheses of the demethoxy analogues of natural fliro and pyranoacridones 319, 320), as well as by those of several naturally occurring alkaloids, including 10-methylacridone (30),... 

The synthesis of natural pyranoacridone alkaloids and analogues has received more attention than that of their flirano counterparts, due to the interesting antitumor properties exhibited by acronycine and some of its derivatives. Two main strategies have been developed for the synthesis of pyrano[2,3-c]acridin-7-one and pyrano[3,2-A]acridin-7-one alkaloids. 

In addition, oxidation reactions performed on pyranoacridones led to several alkaloids modified on the C and D rings, and to acronycine analogues with improved antitumor activity. 

Three different types of reagents have been used for the alkylation of 1,3-dioxyacridones and subsequent construction of the fused dimethylpyran D ring of pyranoacridone alkaloids. l-Halo-3-methyl-2-butenes enable cyclization to a dihydrodimethylpyran ring, and dehydrogenation or oxidation has to take place in the course of the synthesis, in order to obtain the desired pyranoacridone. In contrast, the use of the tertiary alcoholic 3-hydroxyisovaleraldehyde dimethylacetal and of the acetylenic 3-chloro-3-methyl-l-butyne permit direct cyclization to the required dimethylpyran. 

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