1-Hydroxy-10-methylacridone

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). 

A further study of the root alkaloids of Ruta graveolens has resulted in the identification of a new chlorine-containing acridone (31), named iso-gravacridonchlorine.29 The same source yielded an inseparable mixture of alkaloids, shown by n.m.r. spectroscopy to consist of the new compound furacridone (32) and the known compound l-hydroxy-3-methoxy-N-methylacridone (29 R = H) in a ratio of 4 1. 

Pharmazie, 1975, 30, 753). Two new acridones, l-hydroxy-3,4-dimethoxy-lO-methylacridone (25) and l-hydroxy-3-geranyloxy-4-methoxy-lO-methylacridone (26) occur in extracts of the plant Sarcomelicope leiocarpa indigenous to New Caledonia together with eight other known structures (G. Baudouin et al., J.nat. Prod., 1985, 48, 260). 

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

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. ... 

A preliminary study of the acridone alkaloids of the roots of Boenninghausenia albiflora resulted in the identification of 1-hydroxy-N-methylacridone (41 R = Me) now the Ruta alkaloid rutacridone (42) (c/. Vol. 8, p. 84) and noracrony-cine (43) have been isolated from this species. Of two new alkaloids obtained from B. albiflora, one was shown to be 1-hydroxyacridone (41 R = H) by methylation to (41 R = Me). The n.m.r. spectrum of the other new alkaloid suggested that it was a dihydroxy-N-methyl-acridone in which ring B contained a 1-hydroxy-group and three adjacent aromatic hydrogen atoms structure (44) was proposed. 

Trihydroxy-4-methoxy-10-methyl-2,8-bw(3-methylbut-2-enyl) acridin-9( 10/7)-one, 1,5 -dihydroxy-2,3 -dimethoxy-10-methyl-9-acridone, 2,3-dihydro-4,9-dihydroxy-2-(2-hydroxy-propan-2-yl)-l 1-methoxy-10-methylfuro[3,2-b]acridin-5(1077)-one, 3,4-Dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2/7-pyrano[2,3-a]acridin-12(7/7)-one, 3,4-Dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2/7-pyrano[2,3-a]acridin-12(7/7)-one, l-hydroxy-3-methoxy-10-methyl-9-acridone, 1 -hydroxy-2,3 -dimethoxy-10-methyl-9-acridone, 1 -hydroxy-A-methylacridone, l-methyl-2-[(Z)-pentadec-9-enyl]quinolin-4(l/7)-one,... 

Anti-HIV activity 1 -Hydroxy-W-methylacridone, 2-(pent-1 -enyl)quinoline, 2-(pent-2-en) quinolin, 2-acetyl-4(3H)-quinazolinone, 2- -pentylquinoline, 3-prenyl-4-prenyloxyquinolin-2-one, 4-methoxy-l-methylquinolin-2-one, )V-methyl-3,3-diprenylquinoline-2,4-dione, buchapine, y-fagarine, haplopine, (-1-)-platydesmine, uranidine [28, 30, 34, 38,40,41],... 

Alkaloids considered in this section derive biogenetically from 1,3-dihydroxy-lO-methylacridone (19) and 1,3-dihydroxyacridone (22) by simple deoxygenation and/or oxidation of the acridone aromatic skeleton. Subsequent O-alkylation very often takes place, and most natural acridones bear methoxy or methylenedioxy substituents. A few, exemplified by vebilocine (27) (94), evoprenine (28) (95), and 3-graanyloxy-l-hydroxy-4-methoxy-10-methylacridone (29) (96), are also substituted by prenyloxy or geranyloxy groups. 

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). 

Selective etherification of the 3-hydroxy group of 1,3-dihydroxy-lO-methyl-acridone (19) with excess bromoacetaldehyde diethylacetal in dry dimethylformamide, either by use of sodium hydride at 120"C in a bomb, or in the presence of potassium carbonate at 100°C under nitrogen, afforded 3-(2,2-diethoxyethoxy)- -hydroxy-10-methylacridone (314). Cyclodehydration of 314 by refluxing in a mixture of dioxane and dilute aqueous sulfuric acid, followed by alkalization by addition of sodium hydroxide and heating, gave the desired furacridone (26), accompanied by smaller amounts of the linear isomer, isofuracridone (315) 330). 

More recently, when studying the biomimetic condensation of 1,3-dihydroxy-lO-methylacridone (19) with one equivalent of l-bromo-3-methyl-2-butene (281) in the presence of alumina, Grundon and Reisch obtained glycocitrine-II (25). Oxidative cyclization of 25 with 3-chloroperbenzoic acid gave 2-hydroxy-1,2-dihydronoracronycine (331), accompanied by its dihydrofuran isomer 120. Dehydration of 331, by concentrated sulfuric acid afforded noracronycine (138) 326). Moreover compound 332 was obtained during the oxidative cyclization of 25 (337)... 

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