Dihydroxy acridone

Oxidation of appropriate mono- and di-hydroxyquinolines leads to quinones. This can be achieved by a variety of oxidizing agents including chromic acid and Fremy s salt (dipotassium nitrosodisulfonate, (KS03)2N0-) (67CB2077, 67CB2918). Examples are shown in Scheme 92. 9-Acridonequinones result from analogous oxidations of dihydroxy-9-acridones. 

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. 

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... 

Hydroxynoracronycine (16) occurs in the plant Atalantia coylonica, it is also a metabolite of acronycine in maimnals. A part synthesis from 1,3-dihydroxy-S-nethoxy-9-acridone (15) (outlined in Scheme 1) confirms this structural assignment (J.K. Adams, P.T. Bruce and J.R. Lewis, Lloydia, 1976, 39, 399). ... 

C]Tryptophan gave inactive alkaloids but tritiated 2,4-dihydroxy-quinoline (34) and its N-methyl derivative were incorporated into (47) (0.009 % and 0.020% respectively) an early route had suggested the derivation of what was essentially (34) from tryptophan. Radioisotope dilution showed the presence of both these quinoline precursors together with iV-acetyl- and N-methyl-anthranilic acid in A. baueri. A satisfactory incorporation of N-methylanthranilic acid into (47) was found in Evodia xanthoxyloides, and this, together with its natural occurrence, indicates that early methylation may be important in the biosynthesis of acridone alkaloids. 

Dihydroxy-9( 0H )-acridone, 1,8-dihydroxy- 10-methyl-9( 10W)acridinone, 1,3,8-trihydroxy-10-methyl-9(10W)-acridinone, l-acetoxymethyl-2,3-dimethyl-4-(l//)-quinolinone... 

Reisch et al. (93JHC981) described two different methods for the synthesis of 4-azaacronycine 71. One method involves the fusion of 1,3-dihydroxy-10-methyl-9(10//)-acridone 69 with 3-amino-3-methylbut-l-yne in the presence of CuCb in a closed ampule, followed by methylation (Scheme 13). The second method involves the A-alkylation of 3-amino-l-methoxy-lO-methyl-9(107/)-acridone 70 with 3-chloro-3-methylbut-l-yne, followed by in situ cyclization (Scheme 13). 

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. 

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]. 

Leishmaniasis 1,5-Dihydroxy-2,3-dimethoxy-10-methyl-9-acridone, 2-phenylquinoline,... 

Trihydroxy-4-methoxy-10-metbyl-2,8-f>/i(3-metbylbut-2-enyl) acridin-9(10/f)-one, l,5-dihydroxy-2,3-dimetboxy-10-metbyl-9-acridone, 2,3-Dihydro-4,9-dihydroxy-2-(2-bydroxypropan-2-yl)-I I-methoxy-10-methylfuro[3,2-b]acridin-5(10/7)-one, 3,4-Dibydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2//-pyrano[2,3-a]acridin-12(7/7)-one, 2-(3,4-methylenedioxyphenyletbyl)quinoline, 2-n-nonylquinolin-4(l/f)-one, 2-nonylquinolin-4-ol V-oxide, 2-[(lE)-undec-... 

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. 

A more straightforward access to glycocitrine-II (25) was described by Grundon and Reisch, through direct C-alkylation of 1,3-dihydroxy-lO-methylacridone (19) with one equivalent of the readily available l-bromo-3-methyl-2-butene (281), in tetrahydrofriran at 20°C, in the presenee of alumina in order to prevent O-alkylation (326). The isomeric l,3-dihydroxy-10-methyl-2-(3-methyl-2-butenyl)-acridone (282) and the dialkylated l,3-dihydroxy-10-methyl-2,4-bis(3-methyl-2-butenyl)-acridone (283) were also formed during the reaction. Excess of alkylating agent resulted in the formation of tetracyclic compounds 284 and 285. 

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). 

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