1.3.4- Trimethoxy-10-methylacridone

The genus Teclea is another rich source of alkaloids from T. bovincana come the new acridones, 6-methoxytecleanthine (12), 1,3,5-trimethoxy-lO-methylacridone (13) (J. Vaquette et al.. Plant.med.Phytother., 1974, 8, 57) and 1,3,4-trimethoxy-lO-methylacridone (14) (idem., Planta Med., 1978, 33, 78). 

Evoxanthine, melicopidine, l,2,3-trimethoxy-10-methylacridone, kokusaginine, evoprenine, evolatine, 1 -hydroxy-2,3-dimethoxy-10-methylacridone, skimmianine, evoxine... 

Seitdem die Bildung der Acridinbasen (z.B. 1,2,3-Trimethoxy-N-methylacridon (CCLXVI) aus Evodia alata) unter. .zellmoglichen" Be-dingungen (s. Schema 48) gelungen ist (146), muB man annehmen, daB dieser Alkaloidtyp auch in der Pflanze aus Anthranilsaure entsprechend Schema 48 aufgebaut werden kann. 

Five acridone alkaloids were obtained previously from the bark of Teclea boiviniana cf. Vol. 6, p. 108) a recent investigation showed that the constituents of the leaves are similar, and resulted in the isolation of arborinine (37 R = H), tecleanthine (38 R = H, R = OMe), evoxanthine (38 R = R = H), 6-methoxytecleanthine (38 R = R = OMe), and 1,3,4-trimethoxy-iV-methyl-acridone (39 R = Me, R = OMe). The latter compound has not been obtained previously from a natural source. The n.m.r. and mass spectra indicated that the new alkaloid was a trimethoxy-iV-methylacridone and that ring A was unsubstituted. The three possible acridones had been synthesized earlier, and from melting-point data the alkaloid appeared to be the 1,3,4-trimethoxy-derivative this was confirmed by synthesis using a modification of the published procedures. 1,2,3-Trimethoxy-iV-methylacridone (37 R = Me), previously isolated from Evodia alata, has now been obtained from Melicope leratii. The known alkaloids melicopidine (40 R = Me, R = OMe) and xanthovedine (40 R = R = H) were also shown to be constituents of M. leratii. Arborinine (37 R = H) has been obtained from Vepris pilosa and from Ruta chalapensis. Other known acridone alkaloids isolated from a new source include the l-hydroxy-3-methoxy-deriva-tive (39 R = R = H) and its methyl ether (39 R = Me, R = H), from Vepris pilosa. ... 

This versatile methodology was successfiiUy q[>plied, with slight modifications, for the synthesis of a number of other aciidone alkaloids, including l-hydroxy-3-methoxy-lO-methylacridone (48) 301), 1,3-dimethoxy-lO-methylacridone (53) 301, 302), 1,3-dihydroxy-lO-methylacridone (19) 301, 302), 1,2,3-trimethoxy-lO-methylacridone (73) 303), xanthoxoline (58) 30S), and l,5-dihydn)xy-2,3-dimethoxy-lO-methylacridone (S-hydroxyaiborinine) (75) 188). 

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). 

Cyclization of a substituted 1 -aiylanthranilamide was the key step for the synthesis of citrusinine-I (76) described by Kato ei al. (312). The required 2-(2-hydroxyphenylamino)-3,4,6-trimethoxy-Af -dimethylbenzamide (235) was obtained by Ullmann reaction of 2-aminophenol with 2-iodo-3,4,6-trimethoxy-iV -dimethylbenzamide (236), prepared in ee steps from commercially available 2,4,S-trimethoxybenzoic acid (237) via o-lithiation of the corresponding amide and subsequent iodination. Benzylation of 235 to 238 was followed by phosphoryl diloride cyclization and hydrolysis of the intermechate with aqueous hydrochloric acid to give 5 benzyloxy-l,3,4-trimethoxyacridone (239) as the major product. Methylation to 5-be izylo3 -l,3,4-trimethoxy-10-methylacridone (240), followed by simultaneous hydrolysis of the benzyloxy group, and of the methoxy group at C-1, gave citrusinine-I I (64). 

Synthesis of 1,2,3-trimethoxy-10-methylacridone (73) and evoxanthine (13) by the same approach necessitated the preparation of 4,5,6-trimethoxy-iV-methyl-isatoic anhydride (262) and 6-methoxy-4,5-methylenedioxy-7V-methylisatoic anhydride (263). Nitration of 2,3,4-trimethoxybenzoic acid (264) afforded 6-nitro-... 

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