1.8- Dihydroxy-10-methylacridone

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... 

Synthesized 1,3-dihydroxy-N-methylacridone is readily incorporated into rutacridone by cell-free extracts of Ruta graveolens (Maier et al, 1993). It has been hypothesized that the final step in the biosynthesis of these alkaloids... 

Baumert, A., Porzel, A., Schmidt, J. and Groger, D. (1992) Formation of 1,3-dihydroxy-N-methylacridone from N-methylanthranoyl-GoA and malonyl-CoA by cell cultures of Ruta graveolens. Z. Naturforsch., 47c, 365-8. 

Maier, W., Baumert, A., Schumarm, B., Furukawa, H. and Groger, D. (1993) Synthesis of 1,3-dihydroxy-N-methylacridone and its conversion to rutacridone by cell-free extracts of Ruta graveolens cell cultures. Phytochemistry, 32, 691-8. 

Structure (85) for a new alkaloid of Atalantia monophylla was based on the n.m.r. spectrum.An alkaloid obtained from Boenninghausenia albiflora, formerly regarded as 1,7-dihydroxy-N-methylacridone, has now been shown from the n.m.r. spectrum to... 

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]. 

Figure 6.18 Hypothetical reaction sequence for the conversion of 1,3-dihydroxy-A -methylacridone into rutacridone.

Biogenetic Conversion Route of 1,3-Dihydroxy-N-methylacridone into Rutacridone in the Microsomes of Ftuta... 

In the biosynthesis of rutacridone, it is proposed that 1,3-dihydroxyacri-done is first formed from anthranilic acid and three C2 units, then the N-10 nitrogen is methylated to form 1,3-dihydroxy-N-methylacridone. Next, a C5 unit, IPP or DMAPP, is attached to 1,3-dihydroxy-N-methylacridone to fc>rm glycocitrine II, which is probably oxidized to produce an as-yet-uniden-tified epoxide. The epoxide is cyclized and dehydrated to give rutacridone [4]. Though rutacridone is a small molecule, as in the case of the quinoline alkaloids, three main biosynthetic precursors are involved in the biosynthesis of this alkaloid. Namely, the shikimic acid, the polyketide, and probably the iso-prenoid pathways all provide precursors for the biosynthesis of rutacridone. 

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,... 

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. 

Dihydroxy-2-methoxy-l 0-methylacridone C15H13NO4 MW 271 spectral data. 144 source 144... 

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). 

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). 

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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