Synthesis of 3-Methoxyellipticine and Ellipticine by Friedel-Crafts Reaction of Indole-2,3-dicarboxylic Anhydride and Selective Demethylation

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

“…In 2004, Miki et al reported the total synthesis of olivacine ( 28.10 ) and ellipticine ( 28.9 ) starting from common precursors, N -benzylindole-2,3-dicarboxylic anhydride ( 318.1 ) and 2,4,6-trimethoxypyridine ( 318.2 ) (Scheme ). , Previously, the same group had already reported a synthesis of ellipticine ( 28.9 ) starting from the same indole precursor 318.1 . − Friedel–Crafts acylation of 2,4,6-trimethoxypyridine ( 318.2 ) with N -benzylindole-2,3-dicarboxylic anhydride ( 318.1 ) in the presence of titanium(IV) chloride in dichloromethane afforded regioselectively the 3-acylindole-2-carboxylic acid 318.3 , which was transformed to ketone 318.4 by reaction with copper chromite in quinoline. , The ketone 318.4 was transformed to the monomethyl derivative 318.5 by regioselective methyl ether cleavage with 47% hydrobromic acid, treatment with triflic anhydride (Tf 2 O), and subsequent reaction of the corresponding triflate with MeMgBr in the presence of NiCl 2 (dppe) 2 (70% yield over 3 steps) . Regioselective O-demethylation of 318.5 by treatment with boron tribromide followed by reductive removal of the ketone oxygen atom with diborane and subsequent treatment with triflic anhydride (Tf 2 O) afforded the 4-pyridyl triflate 318.6 .…”

“…Transformation of 319.3 to the corresponding triflate by reaction with triflic anhydride in the presence of triethylamine, palladium(0)-catalyzed cross-coupling with (1-ethoxyvinyl)tributyltin ( 318.7 ), and subsequent cyclization of the intermediate ethoxyvinyl derivative with 10% hydrochloric acid afforded 6-benzyl-3-methoxyellipticine ( 319.4 ) in 71% yield. Finally, 6-benzyl-3-methoxyellipticine ( 319.4 ) was converted to ellipticine ( 28.9 ) in 4 steps and 23% yield by a similar sequence as described above (see Scheme ) …”

Transition metals in organic synthesis: Highlights for the year 2005

“…Palladium complexes, together with a hydride source, such as tributyltin hydride, triethylsilane, and triethylamine-formic acid catalyzed the reduction organic bromides, iodides, and triflates. Synthetic applications include, 1,8-naphthyrine C-nucleosides [592], cylindramine [324], azadirachtin [593], dihydroxerulic and xerulinic acid [38], bergapten [594], 3-methoxyelipticine and elipticine [595], (−)-scabronine G [44], (−)-galanthamine and (−)-morphine [447], toward (+)-sorangicin [268], 2-fluoro-11-hydroxy-N-propylnoraporphine [596], hetsine alkaloids [597], pancracine [430] and the DEF-rings of FR182877 [598].…”

“…Synthetic targets include, the heterocyclic core of GE 2270 [34], peridinin [35], pyrones isolated from placobranchus ocellatus [36], terpenepolyketide natural products [37], dihydroxerulic and xerulinic acid [38], bipinnatin J [39], elipticine [40], (+)-7-deoxytrans-dihydronarciclasine [41], gambierol [42], taiwaniaquinol [43], (−)-scabronine G [44], garsubellin A [45], piericidin A1 and B1 [46], lucilactaene [47], fostriecin [48], lupine alkaloids [49], ␤-C-glycosides [50], (+)-crocacin D [51], lobatamide analogs [52], epoxyquinoid compounds [53,54], (+)-SCH 351448 [55], 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids [56], (+)-ochromycinone and (+)-rubiginone B 2 [57], EI-1941-1 and EI-1941-2 [58], mycothiazole [59], 6 -epiperidinin [60], aureothin and N-acylaureothamine [61], cyercene A and placidenes [62], herbindole B [63], (+)-tubelactomicin A [64], saudin [65], peroxyacarnoates A and D [66], aureothin, N-acetylaureothamine, aureonitrile [67], elysiapyrones [68], altromycin B [69], (+)-phorboxazole A and analogues [70,71], (−)-SNF4435 C and (+)-SNF4435 D [72], A2E [73], paracentrone [74]<...>…”

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

“…A total synthesis of the antitumor active pyridocarbazole, ellipticine 85, isolated from the leaves of Ochrasia elliptica, 45 has been completed through Friedel-Crafts reaction of indole-2,3dicarboxylic anhydride 86 with 2,4,6-trimethoxypyridine followed by selective demethylations as the key steps (Scheme 13). 46 The pentacyclic metabolite, calothrixin B 88, isolated from Calothrix cyanobacteria, 47 displays potent inhibitory effects on the in vitro growth of both the human malarial parasite and human cancer cells and inhibition of a bacterial RNA polymerase. The total synthesis of 88 has been established through an allene-mediated electrocyclic reaction of 89 as the key step (Scheme 14).…”