Acronycine reaction with

Lewis and his co-workers have reported three interrelated syntheses of acronycine 208 (81T209). In one synthesis, 2,6-dimethoxy-4-hydroxy-2 -nitrobenzophenone 250, obtained as a minor product from Friedel-Crafts acylation of 3,5-dimethoxyphenol with 2-nitrobenzoylchloride, was treated with 3-chloro-3-methylbut-l-yne under basic conditions. The resultant nitro compound 251 was reduced to the amine 252 with zinc. Upon reaction with sodium hydride in DMSO, this amine provided a mixture of de-N-methylisoacronycine 253 and de-N-methylacronycine 210. T>e-N-methylacronycine 210 was converted to acronycine 208 by methylation with methyl iodide (Scheme 42). 

The great chemical instability of acronycine epoxide, for instance its fast reaction with water to yield the corresponding diols (72), exclude its possible use as an anticancer agent. This is the reason why we synthesized a series of ci s-l,2-dihydroxy-l,2-dihydroacronycine and c/s-l,2-dihydroxy-... 

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. 

A mixture of linear and angular chromenes (70) and (71) resulted from the reaction of 1,3 -dihydroxyacridone with the hydroxyacetal. Methylation of the angular isomer gave acronycine, which shows broad-spectrum antitumour activity. 

Hydroxynoracronycine (40) is a constituent of Atalantia ceylonica and a metabolite of the antitumour compound acronycine its synthesis has been reported (Scheme 6).31 The reaction of l,3-dihydroxy-5-methoxy-9-acridone (36) with 3-chloro-3-methylbut-l-yne and cyclization in situ of the products furnished the chromenes (38) and (39) the formation of the intermediate (37) involves C-alkylation with the chlorobutyne, a reaction encountered previously during the synthesis of flindersine.32 Chromene (39) was converted into 11-hydroxy-noracronycine by successive methylation and demethylation. 

A one-step synthesis of ( )-rutacridone (37) was achieved by the reaction of acridone (32 R = H) with isoprene dibromide isorutacridone (36), the isomer with linear annelation, was a minor product of the reaction (Scheme 5).19 A full account of the synthesis of acronycine from o-aminobenzophenones has now appeared (c/. Vol. 7, p. 90) and a modified route has been described (Scheme 6).20 Cyclization of the benzophenone derivative (38 R = Me) gave acronycine (39) (38%) and isoacronycine (40) (38%) a similar ring-closure of compound (38 R = H) furnished des-iV-methylacronycine. 

Watanabe et al. (84CPB1264) have reported a one-step synthesis of acronycine 208. Lithium methyl(2-methoxycarbonyl)phenyl amide 258 generated from methyl Al-methylanthranilate 257 in situ in the presence of excess lithium cyclohexylamide (LCA), was reacted with 6-bromo-2, 2-dimethyl-7-methoxychromene 259 to produce acronycine 208. A benzyne intermediate 260 is believed to be involved in this reaction (Scheme 44). 

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