Acridone alkaloids cyclization

Acridone alkaloids are formed by the addition of three acetate (or malonate) units, followed by cyclization (Figs. 31.9 and 31.10) (Geissman and Grout, 1969 Groger, 1980). More than 100 alkaloids of this type are known (Gray, 1993). 

Synthesis of highly oxygenated acridone alkaloids by cyclization of a carboxylic diphenylamine was first introduced by Hughes, Neill and Ritchie for the... 

The second involves construction of the acridone nucleus in the course of the synthesis. The main approaches used in this latter case are very similar to those which permitted access to the simple acridone alkaloids, e.g. (i) cyclization of a diarylamine intermediate, (ii) cyclization of a benzophenone intermediate, or (iii) construction of the acridone system starting from a quinoline or a quinolinone which bring together the A and B or B and C rings of the acridone skeleton. 

In addition to quinoline alkaloids (see Table 1), Glycosmis mauritiana contains 5-hydroxy-2,3-dimethoxy-A7-methylacridone (arborinine) and a new prenyl-acridone (28).4 The structure of the latter alkaloid was indicated by spectroscopy, by the presence of a peri-hydroxyl group, and by heating it with formic acid to give the cyclization product (29), thus showing that the prenyl group was at C-2, i.e. adjacent to the hydroxyl group, rather than at C-4. An unexpected by-product of the reaction with formic acid was the acridone (22). 

Synthesis.—Reisch, Mester, and co-workers have made important contributions this year by synthesizing the alkaloids furacridone (34) and ( )-rutacridone (37) for the first time. Regioselective etherification of 1,3-dihydroxy-jV-methylacridone (32 R = H) gave the acetal (33), which furnished furacridone (34) as the major product of acid-catalysed cyclization (Scheme 4). Claisen rearrangements of the 3-allyloxy-acridone (32 R = CH2CH=CH2) and the propargyl derivative (32 R = CH2C=CH) were also studied.18... 

Atalaphylline (C23H25O4N mp 246°) and iV-methylatalaphylline (C24H27O4N mp 192°) show UV and IR spectra consonant with 9-acridones. Chemical and other spectral data point to structures 22b, 22c, respectively, for these alkaloids. Atalaphylline on treatment with diazomethane yields a dimethyl ether (mp 145°) which still has a hydroxyl and under forcing conditions with methyl iodide and potassium carbonate generates an 0,0,0-trimethyl-jiV-methyl derivative. Treatment with formic acid resulted in cyclization of both prenyl groups to give 23 (mp 251°) (26). 

The alkaloids melicopicine from Melicope fareana [86], acronycine from Acrony-chia baueri [87, 88], and rutacridone from R. graveolens (Rutaceae) typify some of the structural variety that may then ensue. For instance, radioactivity biosynthetic studies on R. graveolens, using [1- H]DMAPP (dimethylallyl diphosphate), demonstrated that 1,3-dihydroxy-A-methylacridone reacted with DMAPP upon mediation of a monoprenyl aryl transferase. The formed prenylated acridone glycocitrine-H in turn cyclized to give the dihydrofuran portion of rutacridone. Compounds 21 and 22 are hypothetical intermediates (Figure 6.18) [89]. 

Most methods applicable for the synthesis of a greater vari of simple acridones, including alkaloids bearing numerous oxygenated substituents, also rely on the coupling of two aromatic substrates, which bring the preformed A and C rings of the fiiture acridone skeleton. Thus, closure of the central B lii can be obtained either by cyclization of an intermediate diphenylamine or by cyclization of an intermediate benzophenone. 

The introduction of polyphosphoric acid, instead of phosphoryl chloride, as the reagent for the cyclization of carboxylic diphenylamines permitted the direct access to 9-acridanones, avoiding the tedious steps of acid hydrolysis or alkaline methanolysis of the intermediate 9-chloroacridines (304). This modified process appears as the most popular for the synthesis of simple natural acridones and has been applied to the synthesis of 1,3-dimethoxyacridone (49) (305), 1,3-dimethoxy-lO methylacridone (53) (30S), 1,2,3-trimethoxyacridone (223) (306), 1,2,3-trimethoxy-lO-methylacridone (73) (306), l,2,4-trimethoxy-10-me(iiylacridone (72) (202), l-hydroxy-7-methoxyacridone (46) (307), 1,2,3,5,6-pentamethoxyacridone (95) (210), l-hydroxy-2,3,5,6-tetramethoxyacridone (92) (210), glyfoline (96) (308), and severd congeners of this latter alkaloid (309). 

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 first one envisages alkylation of a preformed 1,3-dioxygenated acridone comprising the ABC tricyclic portion of the alkaloid by a C3 unit, and elaboration of the pyran D ring from this unit, by simultaneous or subsequent cyclization. 

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