The use of isoquinolinetriones in the synthesis of benzo[c]phenanthridine alkaloids

Reaction of isoquinolinetriones 1 with phosphonates 2 yields E-ethyl α-benzylidene-1,2,3,4-tetrahydro-2-methyl-1,3-dioxo-4-isoquinolineacetates 3. Treatment of them with diazomethane leads to the corresponding E-ethyl α-benzylidene-1,2-dihydro-3-methoxy-2-methyl-1-oxo-4-isoquinolineacetates 4. Irradiation of the latter affords benzo[c]phenanthridones of type 5.     

A versatile total synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition

A new versatile synthesis of benzo[c]phenanthridine and protoberberine alkaloids using lithiated toluamide-benzonitrile cycloaddition was carried out. The coupling reaction between benzonitrile 6 with o-toluamides (8a-c) afforded 3-arylisoquinolines (9a-c) that were transformed to the protoberberines (11a-c) or benzo[c]phenanthridines (14a-c). These compounds were synthesized by ring closure of the two-carbon chain on either position 2 or 4 of the 3-arylisoquinolinone (9a-c). Several kinds of substituted benzo[c]phenanthridine alkaloids such as oxysanguinarine, oxyavicine, and oxynitidine as well as protoberberines such as 8-oxocoptisine, 8-oxopseudoberberine, and 8-oxopseudocoptisine were synthesized.     

Total synthesis of oxyfagaronine, phenolic benzo[c]phenanthridine and general synthetic way of 2,3,7,8- and 2,3,8,9-tetrasubstituted benzo[c]phenanthridine alkaloids

Benzo[c]phenanthridine alkaloids such as oxynitidine, oxysanguinarine, oxyavicine and phenolic oxyfagaronine were synthesized from easily available starting benzonitriles 5 and toluamides 6 using a lithiated toluamide-benzonitrile cycloaddition reaction. The coupling reaction provided 3-arylisoquinolinones that were transformed to the benzo[c]phenanthridones. This method is highly efficient and could be useful for preparing diverse substituted aromatic benzo[c]phenanthridine compounds on a multi gram scale.     

The first stereocontrolled synthesis of 12-methyl-hexahydrobenzo[c]phenanthridine alkaloids

12-Methyl B/C hexahydrobenzo[c]phenanthridines have been synthesized stereoselectively starting from chiral nonracemic 2-aryl-4-pentenoic acids prepared by asymmetric allylation of (+)-(S,S)-pseudoephedrine-based arylacetamide enolates. Subsequent transformations (Friedel–Crafts acylation, stereocontrolled reductive amination, Pictet–Spengler cyclization and PPA catalyzed cationic cyclization) led to the synthesis of enantiomerically enriched hexahydrobenzo[c]phenanthridines in which the sequential formation of all the new stereogenic centres was controlled by the starting chiral acids.     

Palladium-catalyzed intramolecular O-arylation of enolates: application to benzo[b]furan synthesis

[reaction: see text] A catalyst generated from Pd2(dba)3 and the ligand DPEphos effects intramolecular C-O bond formation between enolates and aryl halides in the conversion of 1-(2-haloaryl)ketones directly into the corresponding benzofurans. Both cyclic and acyclic ketones are efficient substrates. Thio ketones can also be employed allowing the preparation of the corresponding benzothiophenes.     

Interaction of oligonucleotides with benzo[c]phenanthridine alkaloid sanguilutine

Benzo[c]phenanthridine alkaloid sanguilutine was extracted and purified from the dried roots of Sanguinaria canadensis. The interaction of the positively charged iminium form of alkaloid with double-stranded DNA oligonucleotides was studied using luminescence spectroscopy. The results showed that the interaction with various double-stranded oligonucleotides was not specific to A-T or G-C base pairs; also, no preference was found for either homogeneous or heterogeneous base composition of strands. The association constants were calculated to be in the range of (1.31–14.36) × 10⁵ M^?1. The luminescence intensity response at 610 nm to low concentrations of double-stranded DNA was found to be linear and can potentially be used for the fluorometric quantification of DNA. The limit of detection was estimated to be 120 ng mL^?1 of DNA (calculated by 3σ method).     

Synthesis and cytotoxic activities of a new benzo[c]phenanthridine alkaloid, 7-hydroxynitidine, and some 9-oxygenated benzo[c]phenanthridine derivatives

[formula: see text] A new benzo[c]phenanthridine alkaloid, 7-hydroxynitidine, was synthesized by a novel synthetic procedure. The cytotoxic activity of this compound against HeLa S3 cells was strong, but not greater than those of its mother compounds, nitidine and NK109. We also synthesized other 9-oxygenated benzo[c]phenanthridine alkaloids, 7-methoxynitidine, 9-demethylnitidine, nitidine, and fagaronine, and tested their cytotoxic activities. These results suggest that the 7-hydroxy group enhances antitumor activity and an 8- or 9-hydroxy group weakens this activity.     

Approaches to the synthesis of benzo[c]phenanthridines

6-Methylbenzo[c]phenanthridine derivatives were synthesized via an established route and their cytotoxic activity determined. Attempts to synthesize benzo[c]phenanthridines lacking the 6-methyl group via a 2-ben-zopyrylium intermediate were unsuccessful.     

A novel synthesis of benzo[c]phenanthridine skeleton and biological evaluation of isoquinoline derivatives.

Benzo[c]phenanthridine skeleton was synthesized from easily available starting N-methyl-o-toluamide 2 and o-methylbenzonitrile 5 in 7 steps. Radical cyclization of styrene 10 afforded 6,11-dimethyl-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one 13. Most 3-arylisoquinolines have displayed strong activities against human tumor cell lines. Especially, indenoisoquinolinone 13 exhibited excellent cytotoxicity (IC50 = 0.002 microgram/ml; HCT 15).     

A facile synthesis of benzo[c]phenanthridine alkaloids: oxynitidine and oxysanguinarine using lithiated toluamide-benzonitrile cycloaddition

Benzo[c]phenanthridine alkaloids oxynitidine and oxysanguinarine were synthesized from easily available starting benzonitrile 5 and toluamide 6 using toluamide-benzonitrile cycloaddition reaction in six steps. This method is so highly efficient that it could be a more useful way for preparing fully aromatized benzo[c]phenanthridine compounds.     

Rapid structural characterization of isomeric benzo[c]phenanthridine alkaloids from the roots of Zanthoxylum nitidium by liquid chromatography combined with electrospray ionization tandem mass spectrometry

The fragmentation mechanism of six alkaloids, namely: dihydronitidine, dihydrochelerythrine, 8-acetonyldihydronitidine, 8-acetonyldrochelerythrine, nitidine and 1,3-bis(8-dihydronitidinyl)acetone, was investigated by electrospray ionization multi-stage tandem mass spectrometry (ESI-MSn). Tandem mass spectrometry experiments indicated that different substitution sites of the methoxyl groups at C-9 and C-10 or at C-10 and C-11 determined the different abundances of the MS2 fragmentation ions using the same collision energy. According to the different abundances of MS2 product ions, positional isomeric benzo[c]phenanthridine alkaloids can be differentiated. Moreover, ten constituents in the crude alkaloidol extract from the roots of Zanthoxylum nitidium were rapidly identified by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MSn), through comparing the retention times and ESI-MSn spectra with the authentic standards. This work demonstrates that not only the characteristic fragments but also the characteristic abundances of the fragment ions can be used for detailed structural characterization.     

Intramolecular Diels-Alder reaction of 1-aminoisobenzofurans: Application to the synthesis of benzo[c]phenanthridines

Intramolecular Diels-Alder reactions of 1-aminoisobenzofurans give benzo[c]phenanthridines. The reactive intermediates are generated from o-(diazomethyl)benzamides.     

New nitro-benzo[c]phenanthridine and indolopyridoquinazoline alkaloids from Zanthoxylum atchoum

The first phytochemical investigation of the roots of Zanthoxylum atchoum has led to the isolation of two new nitro-benzo[c]phenanthridine alkaloids 6-nitronitidine (1) and 6-nitro-8-methoxy-7,8-dihydronitidine (2), two new salts of indolopyridoquinazoline alkaloids 3-hydroxy-8,13-dihydro-14-methyl-5-oxo-7H-indolo[2’,3’:3,4]pyrido[2,1-b]quinazolin-14-ium (3) and its zwitterionic form 3-phenolate-8,13-dihydro-14-methyl-5-oxo-7H-indolo[2’,3’:3,4]pyrido[2,1-b]quinazolin-14-ium (4) along with 18 (5–22) known compounds. Their chemical structures were elucidated by spectroscopic analysis including 1D and 2D NMR and MS techniques. This is the first report of the nitro group on the biosynthesis of the natural benzo[c]phenantridine alkaloids. Compound 2 exhibited potent antibacterial activity against Staphylococcus aureus of MIC₅₀ = 4 μg·mL⁻¹.     

Stereocontrolled synthesis of 2-aryl tetralones. Application in the synthesis of B/C hexahydrobenzo[c]phenanthridine alkaloids

Hexahydrobenzo[c]phenanthridines possessing a B/C cis ring junction have been synthesized in a stereoselective way starting from chiral non-racemic 2-aryl-tetralones prepared by asymmetric alkylation of (+)-(S,S)-pseudoephedrine based arylacetamide enolates with appropriately functionalized 2-aryl-1-iodoethane electrophiles. Subsequent transformations (intramolecular Friedel–Crafts acylation, stereocontrolled reductive amination and Pictet–Spengler cyclization) yielded the target heterocycles in good overall yields and in excellent stereoselectivities.     

5-Methyl-1,3-cydohexanedione in the synthesis of benzo[a]phenanthridine derivatives

By condensation of arylmethylene-2-naphthylamines with 5-methyl-l,3-cyclohexanedione 5-aryl-2-methyl-1,2,3,4,5,6-hexahydrobenzo[a]phenanthridin-4-ones were synthesizes.     

Transformation of protoberberines into benzo[C]phenanthridines a novel and efficient synthesis of antitumor benzo[C]phenanthridine alkaloids,fagaronine and nitidine

Antileukemic benzo[C]phenanthridine alkaloids, fagaronine (1a) and nitidine (1c) were synthesized from the corresponding protoberberines through C₆-N bond fission and subsequent cyclization between C₆ and C₁₃ position of the protoberberines.