key: cord-0034382-wzl8mpaz
authors: Groundwater, Paul W.; Munawar, Munawar Ali
title: Heterocycle-Fused Acridines
date: 2008-04-25
journal: Adv Heterocycl Chem
DOI: 10.1016/s0065-2725(08)60930-7
sha: 576daa6ae48b03616fbc6d804e94af0f946c6a01
doc_id: 34382
cord_uid: wzl8mpaz

nan

This review covers the following groups of heterocycle-fused acridines: pyridoacridines, pyranoacridines, pyrroloacridines, thienoacridines, and furoacridines.

Heterocycle-fused acridines possess a variety of biological activities, including Ca2+ releasing, antiviral (e.g., anti-HIV), antimicrobial (e.g., antiamebic and antiplasmodium) and antitumor properties. They are also enzyme inhibitors (e.g., topoisomerase I1 inhibitors and protein tyrosine kinase inhibitors) and have DNA-intercalation and metal-chelating properties.

Depending on the ring fusion, pyridoacridines can be classified into the following main classes: pyrido [ 

The pyridine ring is fused at bond a of the acridine. Depending on the position of the nitrogen in the fused pyridine ring, four different types of pyrido[a]acridines are possible.

amine 2 with a mixture of POC13 and PCls (Scheme 1). The pyridoacridine 3 was then converted to a potential antimalarial compound 4, but poor activity was observed.

Gordon et al. (90MI1) obtained a triquinobenzene 5 from a two-step reaction between 1,3,5-tribromobenzene and anthranilic acid. The reaction involved three Ullmann-amine couplings followed by intramolecular acylations. 5 Reisch et al. (93JHC1469) obtained quino[a]acridone 6 as the main product from the condensation of phloroglucinol and 6-methylanthranilic acid (Scheme 2). The synthesis of similar quino[a]acridones from phloroglucinol and anthranilic acids has been reported in patents (35FRP771486).

The condensation product 7 of rn-phenylenediamine and 2-formylcyclohexanone, on treatment with polyphosphoric acid (PPA), gave the octahydrobenzophenanthroline 8, which, on dehydrogenation, afforded quino[a]acridine 9 (Scheme 3) (74IJC1230). A rearrangement prior to cyclodehydration is involved. The synthesis of similar compounds from 1,3-diiodobenzene and 2-acylanilines, using the Ullmann-amine coupling reaction followed by cyclization, has been reported by Hellwinkel and Ittemann (85LA1501) .

In an attempted reaction toward a pyrido[2,3,4-kl]acridine, Gellerman et al. (92TL5577) isolated a pyrido[2,3-~]acridine 11 from an acid-catalyzed reaction between l-amino-4-methylacridin-9( 10H)one 10 and acetylacetone (Scheme 4).

12-Chloropyrido[3,2-a]acridines 12 were prepared by the route described in Scheme 1, but with 6-aminoquinolines instead of 7-aminoquinoline (46JCS151; 47JCS678). The chloroderivatives 12 were then converted to potent antimalarial agents with dialkylaminoalkylamines or alkylaminoalkylamines in phenol at 100°C. 

14 R=Me

The double Ullmann-amine coupling of p-phenylenediamine with 2chlorobenzoic acid followed by two acid-catalyzed Friedel-Crafts acylations afforded quino[3,2-a]acridone 13 (52JCS1874). A similar regioselectivity was observed when 1Q-diiodobenzene was coupled with aminoacetophenone and the resultant diketone was treated with H2S04 to give quino[3,2-a]acridine 14 (85LA501). The quino[3,2-~]acridine 15 was obtained after dehydrogenation of the minor product from p-phenylenediamine and 2-formylcyclohexanone (see Section II,B,l on pyrido[2,3-b]acridines) (74IJC1324).

We have prepared pyrido[3,2-~]acridines, 20 and 21 (96TH1), by Lewis acid-catalyzed cyclization of enamines 18, formed by the condensation of 6-aminoquinoline 16 with 2-cyano-17a ( Z = CN) or 2-ethoxycarbonylcyclohexanone 1% ( Z = C02Et), to give the tetrahydropyrid0[2,3-~]acridines 19. Oxidation of these tetrahydro derivatives, with palladium on charcoal, gave the fully aromatic systems 20 (Scheme 5). Oxidation of the amino derivative 19a also resulted in the formation of some of the deaminated product 21.

[Sec. 1I.B

This ring system can be seen in the pentacyclic alkaloids: ascididemin 28, 2-bromoleptoclinidone 29, 11-hydroxyascididemin -+mx- ' 0 34 The organic pigments, the linear-trans-quinacridones, such as 36, also possess this ring system. These quinacridones can be used in printing ink and as a colorant for plastics (67CRVl). They also exhibit photovoltaic and photoconductive properties (84CL1305; 87CL609). A large number of quinacridones have been synthesized. The synthetic methods have been reviewed by Labana and Labana (67CRV1) . The most useful method involves the dehydrogenation of dihydroquinones, such as 35, prepared from diethyl 2,5-dioxo-1,4-cyclohexanedicarboxylate and anilines (Scheme 7).

Some soluble quinacridones 37 have been prepared by applying this strategy (92JHC167). The introduction of long alkylthio groups into the 4 and 11 positions weakened the intermolecular hydrogen bonding and increased the solubility in different solvents. Diethyl 2,5-dioxo-1,4-cyclohexanedicarboxylate, on acid-catalyzed condensation with 2aminobenzophenone followed by dehydrogenation with chloranil, afforded quinacridine 38 (88JHC1063). The synthesis of isoquino [3,4-b] acridine 40 from the interaction of pphenylenediamine with 2-formylcyclohexanone, followed by ring closure (after in situ rearrangement) and then dehydrogenation of 39, has been reported by Berde et al. (72IJC332) . Further examination of the cyclodehydration reaction also gave octahydroquino[3,2-a]acridine 41 as the minor product, which was then dehydrogenated to provide quino[3,2-a]acridine 15 (Scheme 8) (74IJC1324).

The auxiliary pyridine is fused at bond c of the acridine nucleus. Depending upon the position of the nitrogen in the auxiliary pyridine ring, four different types of pyrido[c]acridine are possible.

[Sec. 1I.C

Among the pyridoacridine alkaloids, meridine 50 and cystodamine 51 exhibit this ring skeleton (see Section II,D,l on pyrido[2,3,4-kl]acridines). This ring pattern can also be observed in quino[a]acridines 6 and 9 and triquinobenzene 5 (see Section II,A,l on pyrido[2,3-a]acridines). 50 The coupling reaction between 5-aminoquinoline 54 and 2-chlorobenzoic acid gave a very poor yield (5%) of quinolylanthranilic acid 56. With diphenyliodonium-2-carboxylate 55, the yield increased to 80%. Quinolylanthranilic acid 56 was then converted to the sulfonamide 57 after cyclization with P0Cl3 (Scheme 10) (87MI1). The sulfonamide 57 showed negligible activity against L1210 leukemia cells in culture, against P388 leukemia in vivo, and against the Lewis lung solid tumor.

Wardani and Lhomme (93TL6411) reported two routes for the synthesis of 10-aminobenzo[b][ 1,7]phenanthroline 64 from 3,6-diaminoacridine (proflavine) 58. In first route the proflavine 58 was monoacylated to give 59. Activation of the free amino group was achieved by tosylation. Alkylation of the monoacetyl monotosyl proflavine 60 with 3-bromopropionaldehyde ethylene acetal gave the intermediate 61. A large number of l-hydroxy-2-ethoxycarbonylbenzo[b][l,7]phenanthrolines 68 have been synthesized from 3-aminoacridines 67 by using the route shown in Scheme 12, and potent antimicrobial activities and low toxicities have been claimed (78USP4060.527).

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

We prepared a range of pyrido [2,3-c] acridines 74 by the base-or acid-catalyzed cyclization of the corresponding enamines 72, followed by -R l q N oxidation of the dihydro derivatives 73 (Scheme 14) (96TH1). The aminopyrido[2,3-~]acridine 74a was tested for the inhibition of the spontaneous proliferation of a human gastric carcinoma cell line, MKN 45, and had an IC5@ < 1 pmol dm-3, but was noncytotoxic (95BRP9425409, 95MIP1). 

Eilatin 33 and eudistone A 48 and B 49 are pyridoacridine alkaloids that possess this ring skeleton. This ring system is also found in a synthetic isomer, isoascidemin 77, of ascididemin 28 (see pyrido [b] acridines and pyrido[2,3,4-kl]acridines). Three other alkaloids, the plakinidines (A-C) 78-80 from Plukortis sponge, also share this ring system (90JA1,90TL3271). The synthesis of a number of 7-(mono and dialkylaminoalkylamino) derivatives 81 (46JCS151; 47JA1543; 62JMC546; 72JMC739), and 7-anilino derivatives 82 (87MI1; 93JPS262) of benzo[b][l,lO]phenanthrolines by the route described in Scheme 1, but using 8-aminoquinolines instead of 7-aminoquinoline, and their biological evaluation has been reported. Benzo[b][l,lO]phenanthrolin-7-ones 83 were also separated during these syntheses. Some of the alkylamino derivatives 81 were found to be highly effective against ascites tumors at low dosage (72JMC739). The anilino derivatives 82 were found to be active against L1210 murine leukemia (93JPS262), P388 leukemia cells (87MI1), and a Lewis lung solid tumor (87MI1). Using the same strategy, Wilkinson and Finar (48JCS288) have prepared some 7-aminobenzo[b][l,l0]phenanthrolines 84 and related compounds. None of the amino derivatives showed significant antibacterial or Cyclocondensation of 2-aminobenzoylformic acid 98 and cyclohexane-1,2-dione dioxime 99, followed by decarboxylation with concomitant dehydrogenation of the diacid 100, gave quino[3,2-c]acridine 101 (Scheme 19) (70JPR1105). The same skeleton 102 was obtained from the Ullmannamine coupling reaction of 2-aminobenzophenone and 1,2-diiodobenzene, followed by ring closure (85LA1501).

In a search for dyestuffs, o-phenylenediamine was reacted with l-nitroanthraquinone and the resulting bisquinone 103 was cyclized with H2S04 to give 104 (Scheme 20) (74MI1). 

The pentacyclic pyridoacridine alkaloids (amphimedine 105, neoamphimedine 106, petrosamine 107, and debromopetrosamine 108) also contain this ring skeleton (see pyrido[2,3-4-kl]acridines). (Benzo[b] [l,9] phenanthrolines) Kubo and Nakahara have reported the formation of an isomer 119 of amphimedine 105, which possesses this novel ring system (Scheme 24) (88H2095).

SCHEME 24. (a) 10% Pd/C, Et3N, MeOH, rt 20 h, 18%.

In this class, the extra pyridine ring is fused at bonds k and 1 of the acridine. Three types of pyrido[kl]acridines 120 are possible, depending on the position of the nitrogen in the fused pyridine ring.

H H 120a 120b 120c

a. Isolation and Biological Activity. The polycyclic aromatic alkaloids based on the pyrido[2,3,4-kl]acridine skeleton are members of a fastgrowing class of marine sponge and ascidian (tunicate) metabolites. More than 50 alkaloids of this class have been isolated and characterized during the past 12 years.

Norsegoline 121 is the simplest member of this class isolated from Eudistomu sp., a tunicate (88TL3861; 89JOC5331). Other tetracyclic alkaloids include varamines A 122 and B 123, lissoclins A 124 and B 125, diplamine 126, cystodytins A-J 128-137, and pantherinine 138. Varamines A 122 and B 123, isolated from the ascidian Lissoclinum vareau, are brilliant red pigments that were found to be cytotoxic toward L1210 murine leukemia, with IC50 values of 0.03 and 0.05 kg/ml, respectively (89JOC4256). Lissoclins A 124 and B 125, isolated from Lissoclinum sp. collected from the Great Barrier Reef, Australia, did not show significant activity against the fungus Candidu albicans (94JOC6600). Diplamine 126, another tetracyclic alkaloid isolated from the tunicate Diplosomu sp., showed cytotoxicity towards L1210 murine leukemia cells (IC50 = 0.02 pg/ml) (89TL4201) and human colon cancer cell lines (IC50 < 1.4 p M ) (94JMC3819). DNA intercalation and topoisomerase I1 inhibition = 9.2 p M ) by diplamine 126 was also observed (94JMC3819). The isolation of another homolog of this series, "isobutyramide" 127, from an unidentified tunicate has been reported (93CRV1825).

The tunicate Cystodytes dellechiujei is a very rich source of pyrido[2,3,-4-kllacridine alkaloids. Nine tetracyclic alkaloids, cystodytins A-I 128-136, have been isolated from this species (88JOC1800; 91 JNP1634). Except for cystodytin C 130, all other cystodytins were isolated as inseparable isomeric pairs (3.5 : 1) of cystodytins, P,P-dimethylacrylate and tiglate amides L1210 cells and epidermoid carcinoma KB cells was also observed for other cystodytins (91JNP1634). A bromo-substituted tetracyclic alkaloid pantherinine 138 has been isolated from the ascidian Aplidiumpantherinum, and a moderate cytotoxic activity (EDs0 = 4.5 pg/ml) against P388 murine leukemia cells has been reported by Kim et al. (93JNP1813) . Pentacyclic alkaloids contain an additional fused heterocyclic ring, such as tetrahydropyridine, pyridine (pyridone), thiazine, or thiazole. Calliactine was shown to be a pyridoacridine alkaloid (87T4023) nearly half a century after its isolation from the Mediterranean anemone Calliactis parasitica in 1940 (40BSF608). Although the exact structure of the alkaloid is still unclear, the structural analysis shows that it contains an additional tetrahydropyridine ring (87T4023). The structure of neocalliactine acetate 139, derived from calliactine by heating with water (aromatization) followed by reaction with acetic anhydride, has been established by a total synthesis (92LA1205; 93H943). On the basis of spectral data and the establishment of the neocalliactine acetate 139 structure, structure 32 is the most favorable among the four proposed by Cimino et al. for calliactine (87T4023).

Amphimedine 105, the first pyridoacridine to be fully characterized, was isolated from the Guamanian sponge, Amphimedon sp. (83JA4835). Its regioisomer, neoamphimedine 106, was isolated from the Micronesian sponge Xestospongia cf. carbonaria, along with amphimedine 105 and debromopetrosamine 108 (93CRV1825). Neoamphimedine 106 was found to be a potent inhibitor of mammalian topoisomerase I1 (I& = 1.3 p M ) , but not of topoisomerase I. Intercalation of neoamphimedine 106 into DNA was observed with a K , of 2.8 X los M-' and a binding site size of 1.8 base pairs per molecule. Amphimedine 105, debromopetrosamine 108, and petrosamine 107 (from the sponge (Petrosia sp.) have little effect on topoisomerase I or I1 activity, despite comparable cytotoxicity (40BSF608).

Ascididemin 28, from Didenum sp. (88TL1177), and 2-bromoleptoclinidone 29, from Leptoclinides sp. (87JA6134; 89TL1069), were the first polycyclic aromatic metabolites to be isolated from ascidians. Both compounds show cytotoxcity toward leukemia cell lines with ICsos of 0.4 pg/ml, whereas ascididemin also inhibits topoisomerase I1 (ICso = 75 p M ) and causes release of calcium ions in the sarcoplasmic reticulum (91JOC804). Two Sec. II.D] HETEROCYCLE-FUSED ACRIDINES 115 regioisomers, meridine 50 and 11-hydroxyascididemin 30 were isolated from the ascidians Amphicarpa meridina and Leptoclinides sp., respectively (91JOC804). Both of these isomers, along with 8,9-dihydro-ll-hydroxyascididemin 31, have also been isolated from the Okinawan marine sponge Biemna sp. (93T8337). Meridine 50 exhibits cytotoxicity against P388 murine leukemia cells (ICs0 = 0.3-0.4 pg/ml) (91JOC804), and 8,9-dihydro-11-hydroxyascididemin 31 exhibits cytotoxicity against human epidermoid carcinoma KB (IC50 = 0.2 pg/ml) and murine lymphoma L1210 (IC50 = 0.7 pg/ml) cells in vitro (93T8337). A new pentacyclic alkaloid, cystodamine 51, has been isolated from the ascidian Cystodytes dellechiajei (94TL7023). The new alkaloid shows cytotoxicity against CEM human leukemic lymphoblasts (IC50 = 1.0 pglml).

Shermilamines A 140, B 141, and C 142 are thiazinone-containing pentacyclic alkaloids isolated from the purple tunicate Trididemum sp. A series of pentacyclic aromatic alkaloids that incorporate a thiazole ring were isolated from sponges, ascidians (tunicates), and the lamellariidae molusk Chelynotus semperi. Dercitin 143 (88JA4356; 92JOC1523), a metabolite of deep-water sponge Dercitus sp., exhibits a remarkable biological activity. It inhibits a variety of cultured cell clones at nanomolar concentrations and exhibits antitumor activity (in mice) and antiviral activity (against herpes simplex and A-59 murine corona virus) at micromolar concentrations. Two hexacyclic alkaloids, cyclodercitin 151 and stelletamine 152 from Stelleta sp. (89TL4359; 92JOC1523), and three optically active hexacyclic alkaloids, segoline A 153, segoline B 154, and isosegoline A 155 from the Red Sea tunicate, Eudistoma sp., have been isolated along with tetra-and pentacyclic alkaloids (88TL3861; 89JOC5331). Another interesting compound isolated from Eudistoma sp. was the symmetrical, heptacyclic eilatin 33 (88TL6655; 94JMC3819). Cytotoxicity (ICso = 5.3 p M ) of eilatin 33 against HCT cell lines has been reported (94JMC3819). This compound was also found to regulate cell growth and to affect CAMP-mediated cellular processes (93MI1). Because of the presence of the 1,lO-phenanthroline skeleton, eilatin 33 is capable of chelating metal ions such as Ni(I1) (88TL6655).

Two octacyclic alkaloids, eudistones A 48 and B 49, along with ascididemin 28, have been isolated from another tunicate of the genus Eudistoma (from the Seychelles) (91 JOC5369). These compounds are optically active, but their absolute configurations are still unknown. Another octacyclic alkaloid, biemnadin 34, isolated from the Okinawan marine sponge Biemna b. Syntheses. The biological activity and the novel ring systems of these pyridoacridine alkaloids make them appealing targets for synthesis. A number of approaches have been developed for the synthesis of these compounds.

An example of this route is Echavarren and Stille's use of a simple intramolecular imine formation between a quinone moiety and an amino group to complete the nucleus (Scheme 25) of amphimedine 105 (88JA4051). The quinone 159 was prepared by a palladiumcatalyzed cross-coupling of 5,8-dimethoxyquinolin-4-y1 triflate 157 (from 5,8-dimethoxyquinolin-4-one 156) with 2-t-butoxycarbonyl-aminophenyltrimethyltin 158, followed by deprotection of the amino group, reprotection by the triflouroacetyl group, and then oxidation with ceric ammonium nitrate (CAN). The aza-Diels-Alder reaction of the resultant quinone 159 with Ghosez's diene 160 afforded an intermediate 161. Deprotection of the amino group with aq. HC1 and in sifu formation of the imine gave a precursor 162 of the amphimedine 105, which was obtained by methylation with dimethyl sulfate.

Similar strategies have been employed by Kubo and Nakahara (88H2095) for the synthesis of amphimedine 105; by Szczepankiewicz and Heathcock (94JOC3512) for the synthesis of diplamine 126; by Nakahara et ai. phenone was used for oxidative amination of p-quinolinoquinone 170 in the presence of air and cerium ions, to give intermediate 171, which cyclized to the linear pyridoacridine 172 on heating in a mixture of conc. sulfuric and acetic acids. Condensation of the side-chain methyl group of 172 with dimethylformamide diethyl acetal afforded an enamine 173, which cyclized to ascididemin 28.

The same strategy has been applied to the preparation of a number of pyridoacridine alkaloids, which include 2-bromoleptoclinidone 29 (90LA205), 11-hydroxyascididemin 30 (93H943) and kuanoniamine A 146 (93H943), and also for the synthesis of neocalliactine acetate 139 (92LA1205; 93H943) (a derivative of calliactine 32).

Kashman and his co-workers have reported novel biomimetic syntheses of pyrido[2,3,4-kl]acridines by the reaction of kinuramine 174 or its derivatives, such as 177, and other analogs, such as 178, with a variety of diones (e.g., 175), quinones (e.g., 170), and hydroquinones (e.g., 179) (Scheme 28) (93TL1823; 93TL1827; 948239, 94T12959). Using this strategy they have prepared a number of pyridoacridines, including the marine alkaloids, eilatin 33 (93TL1827), ascididemin 28 (94S239), their derivatives, and other analogs such as 176 and 180 (93TL1823; 94T12959). 

No natural or synthetic compounds based on this ring system 190 have been reported. The only natural product based on this ring system is necatorone 193. This alkaloid was isolated from a toadstool, Lacfarius necafor (84TL3575). This fungal metabolite showed a considerable mutagenic activity in the Ames test. A synthesis of necatorone 193 involving oxidative cyclization has been reported (Scheme 33) (85TL5975). 

Only a few pyranoacridine ring systems have been reported in the literature.

The pentacyclic alkaloid bicyclo-N-methylatalaphylline 194, isolated from Atluntiu monophyllu Correa, possesses this ring system as a part of its structure (72JOC3035). Formation of this ring system (e.g., 196) from isoprene-containing acridone alkaloids or their derivatives (3-OH protected, e.g., 195) has been reported (Scheme 34) [70T2905; 82P1771; 83JCS(P1)1681]. 

Most of the pyranoacridone alkaloids are based on this ring system. Acronycine (acronine) 208 was the first pyranoacridine alkaloid to be isolated, in 1948 by Hughes and co-workers from the bark of Baurella simplicifolia (Acronychia baueri, an Australian Rutaceae plant) [48NAT(L)223] and in 1949 by Lahey and Thomas from Vepris amphody (49MI1). The correct structure was established in 1966 by degradative studies supported by NMR studies (66AJC275,66T3245) and finally by X-ray crystallographic studies [70AX(B)853]. Acronycine 208 has broad-spectrum antineoplastic activity (85MI1; 89MI1; 92MI1), although its poor solubility in aqueous media is a major hindrance to its development as a clinical agent. Efforts were continued to isolate more alkaloids based on this skeleton, from other plants of Rutaceae family and also through molecular variation, to improve the cytostatic activity of acronycine 208. Other alkaloids based on this system include noracronycine 

Various approaches have been used to synthesize acronycine 208 and its derivatives. Lahey and Stick's synthesis (Scheme 38) involves the condensation of 2,3-dimethylchroman-5,7-diol236 with anthranilic acid, followed by N-methylation of the minor product 238 to produce 1,2-dihydronoracronycine 239 (73AJC2311).

Beck et al. (68JA4706) have reported three interrelated syntheses of acronycine. One synthesis (Scheme 39) used 5,7-dimethoxy-l,2,3,4-tetrahydroquinolin-2( 1H)-one 240, which was coupled with 2-iodobenzoic acid to give the acid 241. Ring methanolic HCl, afforded methyl 1,3-dimethoxy-9-oxacridin-4-propionate 242. Ether cleavage at C-1, followed by reaction with an excess of MeLi, yielded the tertiary alcohol 243. Fusion with pyridinium chloride at high temperature caused 0-demethylation at C-3 with concomitant ring closure. Treatment of the crude product with Me1 under basic conditions produced dihydronoracronycine 239. Dehydrogenation with DDQ afforded noracronycine 209, which was converted to acronycine 208 by 0-methylation with dimethyl sulfate.

Loughhead (9OJOC244S) coupled S-amino-2,2-dimethyl-7-methoxychromene 244 with 2-bromobenzoic acid, and the resultant product 245 was cyclized with TFAA. The de-N-methylacronycine 210 was then converted to acronycine 208 by methylation under phase-transfer conditions (Scheme 40). The same approach has been used by Elomri et al. to prepare 6demethoxyacronycine 246 which was found to be more potent than acronycine 208 in some biological assays (92H799). 

tane in pyridine at 150°C, followed by methylation of the angular pyranoacridine 211, which was isolated by repeated crystallization. Methylation of the unpurified condensation product also gave isoacronycine 249 and noracronycine 209, in addition to acronycine 208. Use of citral and farnesal in place of 1 ,l-dimethoxy-3-hydroxy-3-methylbutane provided mono-or diprenyl-substituted acridones and their cyclized product. The same approach was used by Ramesh and Kapil [86IJC(B) 684] to prepare 11hydroxynoracronycine 215 and atalaphyllidine 219.

Lewis and his co-workers have reported three interrelated syntheses of acronycine 208 (8lT209). In one synthesis, 2,6-dimethoxy-4-hydroxy-2'nitrobenzophenone 250, obtained as a minor product from Friedel-Crafts acylation of 3,5dimethoxyphenol with 2-nitrobenzoylchloride, was treated with 3-chloro-3-methylbut-1-yne under basic conditions. The resultant nitro compound 251 was reduced to the amine 252 with zinc. Upon reaction with sodium hydride in DMSO, this amine provided a mixture of de-N-methylisoacronycine 253 and de-N-methylacronycine 210. De-Nmethylacronycine 210 was converted to acronycine 208 by methylation with methyl iodide (Scheme 42).

Coppola ( which was converted to acronycine 208 by methylation with methyl iodode.

In another reaction, glycocitrine I1 265 was converted to noracronycine 209 by oxidative cyclization with benzeneselenyl chloride followed by hydrogen peroxide [83JCS(P1)1681]. 

The syntheses of acronycine 208 and its derivatives, such as 266, 267 reported by Blechert et al., have novelty in that they involve the formation of ring "A" (Scheme 46) (78CB439; 80LA503).

Microbial conversions of acronycine 208 to its hydroxy derivatives have been reported by two research groups (74JMC599, 74JMC653). Among many microbial agents, Aspergillus alleaceus, Cunninghamella echinulata, and Streptomyces spectablicus are found to be effective.

The reaction of organolithium compounds with noracronycine provided 7-substituted derivatives [95JCS(P1)511]. The reaction of acronycine with P4Sl0 produced the thio analog 268 (79JPS36; 82S493), and oxidation of acronycine 208 resulted in one or more products that include acronycine epoxide 224, l-hydroxy-2-oxo-1,2-dihydroacronycine 269, cis-1,2dihydroxy-1 ,Zdihydroacronycine 270, and 5-hydroxyacronycine 271, de- The coupling of 2,3-dihydroxy-lO-methylacridin-9( 10H)-one 276 with 3chloro-3-methylbut-1 -yne afforded a pyrano[3,2-~]acridine 277 (Scheme 48) (83MI1).

6-Aminobenzopyran-2-ones 279 undergo the Conrad-Limpach reaction with 2-ethoxycarbonylcyclohexanone 278 to give anils 280, which, on heating in diphenyl ether at reflux, give cyclized products 281 (Scheme 49) (83JHC775).

We have prepared a series of pyrano[3,2-a]acridines (e.g., 282) by the route described in Scheme 34, but using 6-0~0-5,6,7,8-tetrahydroflavone instead of 7-0~0-5,6,7,8-tetrahydroflavone (84TH1). 

Pyrroloacridines have been scarcely reported in the literature; only a few ring systems have been described. aminoacridine with ethyl 2-methylacetoacetate provided a hydrazone 299, which was cyclized to pyrrolo[2,3-~]acridine 300 in the presence of ZnClz (Scheme 54) (78KGS1277; 79KGS1092). Wardani and Lhomme (93TL6411) used a different pathway for the construction of the pyrrole ring. Base-catalyzed alkylation of N-acetyl-N'tosylproflavine 60 with bromoacetaldehyde diethyl acetal, followed by deprotection of the acetal function with concomitant ring closure and deacylation in acidic media yielded 9-amino-3-tosylpyrrolo[2,3-c]acridine 301. Detosylation was achieved by basic hydrolysis to give 9-aminopyrrolo[2,3-c]acridine 302 (Scheme 55).

We have prepared pyrrolo [2,3-c] acridines 304 by our standard method, involving the base-catalyzed cyclization of the enamines 303, followed by oxidation (Scheme 56) (96TH1). 

Three polycyclic alkaloids that contain this ring system as part of their structures, plakinidines A 78, B 79, and C 80, were isolated from the marine sponge Plakortis sp. (see Section II,C,l on pyrido[3,2-~]acridines).

Gellerman et al. (94T12959) have described the biomimetic synthesis of a pyrrolo [2,3,4-kl] acridine 305 (Scheme 57).

Only a few thienoacridine ring systems are known, and all are synthetic.

The Pfitzinger reaction of 6,7-dihydrobenzothiophen-4(5H)-ones 306 with isatins 307 produced 4,5-dihydrothieno[2,3-c]acridine-6-carboxylic acids 308 (Scheme 58) (50RTC1053; 55BSF1252, 55JCS21; 58JCS2418). Decarboxylation of the acid 308 (R = Me, X = H) upon heating above the melting point has been reported to give the dihydro derivative 309 (50RTC1053; 55BSF1252), and Buu-Hof has reported the decarboxylation with concomitant dehydrogenation of the acid 308 (R = Et, X = Br) to give 6-bromo-2-ethylthieno[2,3-c]acridine 310 (Scheme 58) (58JCS2418). The Fetvadjian-Ullmann reaction between 4-hydroxy-7-( p-toly1)benzothiophene 314, aniline, and paraformaldehyde provides another pathway for the construction of thieno[2,3-~]acridines, such as 315 (Scheme 61) (81JHC1519).

Suresh et al. (93SUL7) have described a novel route for the preparation of thieno[2,3-c]acridines 316 that involves photocyclization (Scheme 62).

We have used the strategy developed for the synthesis of pyrido[2,3clacridines to prepare thieno[2,3-c]acridines, such as 317 (96TH1).

Buu-Hoi' and Royer (46CR806) obtained a series of thieno[3,2-c]acridines 320 by using the Pfitzinger reaction between 4,5-dihydrobenzothiophene-7(6H)-one 318 and isatins 319, followed by decarboxylation at high temperature (Scheme 63). One of the decarboxylated products 320 (R' = Me, R2 = H) was dehydrogenated with PbO at 310°C to give the fully aromatic system 321. 

Isatins 307 on reaction with 1,3-dimethyl-6,7-dihydroisothiophene-4(5H)-one 322 gave 2,3-dimethyl-4,5-dihydrothieno[3,4-c]acridine-6-carboxylic acids 323 (Scheme 64) (50RTC1053).

Only three furoacridine ring systems have been reported.

The reactions of copper(1) phenylacetylide 325a and copper(1) isopropenylacetylide 325b with l-hydroxy-2-iodo-3-methoxy-lO-methylacridin-9(10H)-one 324 gave furo[2,3-a]acridones 236a and 236b (Scheme 65) (84LA3 1). 

This ring system is the basic skeleton of a number of acridone alkaloids isolated from intact plants or cell tissue cultures of various species from the Rutaceae family. Most of the dihydrofuroacridone alkaloids have been isolated from Ruta graveolens: rutacridone 327 (67MI1; 81MI1; 87PHA67; 88MI1; 90PHA500; 91MI3), rutacridone epoxide 328 (81MI1, hydroxyrutacridone epoxide 329 (82ZN132; 85MI2), 1-hydroxyrutacrodine epoxide 330 (85MI2), gravacridonol 331 (81MI1; 85MI2), gravacridone chloride 332 (73P2359; 87PHA67; 88MI1), isogravacridone chloride 333 (77P151; 91MI1), gravacridondiol334 (72P2121; 76MI1,76P240), gravacridondiol acetate 335 (91MI2), gravacridondiol monomethyl ether 336 (72P2121), gravacridontriol 337 (76MI1, 76P240), gravacridonolchlorine 338 (72P2121,72P2359), and rutagravin 339 (85MI2). Rutacridone 327 and its epoxide 328 have also been detected in Boenninghausenia albiflora (78P169). Hallacridone 347 was isolated from Ruta graveolens by Baumert et al., along with the dihydrofuroacridones 327,328, and 332 (87PHA67; 88MI1). Its structure was revised by Reisch and Gunaherath [89JCS(P1) 1047] on the basis of spectroscopic evidence and total synthesis. It was also isolated from tissue cultures of Ruta graveolens (90PHA500) and Thamnosma montuna (94MI1). Isolation of two new alkaloids, thehaplosine 348 (93MI2) and furoparadine 349 (95H187), has been achieved from the aerial parts of Halophyllum thesioides and roots of Marsh grapefruit (Rutaceae), respectively.

Rutacridone 327 was synthesized for the first time by Mester et al. (81H77) by base-catalyzed alkylation, with concomitant cyclization, of 1,3-dihydroxy-lO-methylacridin-9(1OH)-one 69 with 1,4-dibromo-2-methylbut-2ene. The linear isomer, isorutacridone 350, was also obtained as a byproduct (Scheme 66). A better yield of rutacridone 327 was obtained when A1203 was used as the catalyst (90M829). Once again, isorutacridone 350 was obtained as a by-product (Scheme 66). Takagi and Ueda have prepared a number of 4,5-dihydrofuro[2,3clacridines 358a-c from 4,5,6,7-tetrahydrobenzofuran-4-ones 356 by condensing with isatin, anthranilic acid, and 2-aminophenylcarbonyl hydrochlorides 357 using a range of conditions (Scheme 69) (71CPB1218; 72CPB380, The method of Jayabalan and Shanmugan is novel in that it involves the construction of a ring between a quinoline and furan moieties to complete this skeleton (Scheme 71) (91ZN558).

Once again, we have used the strategy developed for the synthesis of pyrido[2,3-~]acridines to prepare furo[2,3-c]acridines 362 (96TH1). Reisch and co-workers have isolated isorutacridone 350 as a by-product during their base-catalyzed (81H77) and A1203-catalyzed (90M829) synthesis of rutacridone 327 (Scheme 66). They observed that the use of an ionexchange resin as the catalyst favored the formation of isorutacridone 350 as the major product (81H77). The same group also reported the formation of another linear furoacridine, 4-hydroxy-3-methylene-2,2,lO-trimethyl-2,3dihydrofuro[3,2-b]acridin-5( 10H)-one 363 (Scheme 72) (89JHC1849). 

Buu-HOT

Buu-HOT

The Alkaloids

Anti-Cancer Drug Des

Man-Made Text., India 30

Man-Made Text India 30

WO 91107

92JCS(CC)

95JCS(P1)

95JCS(P1)