Benzo phenanthridine derivatives

Benzo [A] quinoline, Benzo [/] quinoline, and Benzo [c] phenanthridine Derivatives... 

The synthesis of 6-amino-ll,12-dihydrobenzo[c]phenanthridine 133 and 6-amino-benzo[c]phenanthridine derivatives 134 was accomplished in a very straightforward approach by the condensation of 2-methylbenzonitrile 135 with aromatic aldehydes 136 resulting in the 6-amino-ll,12-dihydrobenzo[c]phenanthridine derivatives 133. Dehydrogenation of the dUiydro derivatives using DDQ yielded the 6-aminobenzo[c]phenanthridine derivatives 134 in Scheme 39 <0581052,05JMC2772, 05AG(1)635>. 

Stermitz et al. have recently reviewed the chemotaxonomy and the systematization of Papaver and Argemone plants (36, 833). They have also pointed out the characteristic features of the individual genera and sections from the viewpoint of the alkaloids. On the basis of the contained alkaloids, they have tried to differentiate the A. subfusiformis taxa from A. poly-anthemos (Scheme 20). According to these authors, the benzo-phenanthridine alkaloids (including the N-nor derivatives) may not be significant chemotaxonomic markers because they are formed in callus tissues (269). The alkaloids contained in the seeds of A. mexicana (grown in the U.S.S.R. and in Vietnam) have been studied (834). 

Treus et al. synthesized benzo[c]phenanthridine derivatives 85 and 86 from dihydroisoquinolines 80 (Scheme 32) (10T9986). Reaction of dihydroisoquinolines 80 with ethyl chloroformate and Na2C03 (10%) in... 

Benzo[c]phenanthridine alkaloids are widespread in Papaveraceae, Fumariaceae, and Rutaceae. Fagaridine (118), the structure of which had to be revised, is a derivative of the unknown 5-methyl-benzo[c]phenan-thridine-8-olate (119) which is isoconjugate with the 2-methyl-chrysene anion (Scheme 43). Thus, Fagaridine is a member of class 1 of conjugated heterocyclic mesomeric betaines, which are isoconjugate with odd alternant hydrocarbon anions. 

Zhu et al. [55] also synthesized a series of ester/amide derivatives of 2,3-dimethoxy-8,9-methylenedioxy-benzo[z]phenanthridine-12-carboxyhc acid (X) and evaluated their topo I-targeting activity as well as cytotoxicity against different cell lines. Topo I cleavage values are given as REC, the relative ef-... 

At first, acid-catalyzed cyclization of Hofmann degradation products was undertaken however, the cyclization proceeded via the 5-exo-trigonal mode instead of the 6-endo-trigonal mode, resulting in no benzo[c]phenanthridine skeleton. Dyke and Brown (114-117) reinvestigated Perkin s results (118,119) and established the structure of the cyclized products 196 and 197 derived from the methine base 194 (Scheme 36). Onda et al. (120,121) obtained the five-membered spiro compounds 198 and 199 by treatment of 195 with dilute hydrochloric acid. 

Lead tetraacetate oxidation was applied to construct a benzo[c]-phenanthridine skeleton. The Hofmann degradation product 224 derived from the phenolic protoberberine 59a was oxidized with lead tetraacetate to afford the p-quinol acetate 225, which was cyclized to the benzo[c]-... 

A biomimetic synthesis of benzo[c]phenanthridine alkaloids from a protoberberine via the equivalent of a hypothetical aldehyde enamine intermediate has been developed (130,131). The enamide 230 derived from berberine (15) was subjected to hydroboration-oxidation to give alcohol 231, oxidation of which with pyridinium chlorochromate afforded directly oxyche-lerythrine (232) instead of the expected aldehyde enamide 233. However, the formation of oxychelerythrine can be rationalized in terms of the intermediacy of 233 as shown in Scheme 41. An alternative and more efficient... 

The reaction of 6.36 with allyl and benzyl anions was examined with a view to develop an efficient method for the synthesis of phenanthridines and their benzo[/]-derivatives. The dithioacetal 6.36 when reacted with allyl anions yielded the corresponding... 

Similar types of nucleophilic substitutions have also been carried out when PIFA is activated by two equivalents of Lewis acids such as trimethylsilyl triflu-oromethanesulfonate (TMSOTf) and BF3 Et20 or heteropolyacid in standard solvents such as CH2C12 and MeCN. These reactions were applied to intramolecular reactions by the same authors leading to biaryls (49) [54-57], quinone imine derivatives (50) [58], and dihydrobenzothiophens (51) [59], which are important structures of bioactive natural products [Eqs. (7)-(9)]. Dominguez and co-workers have expanded the above biaryl coupling reaction to the syntheses of benzo[c]phenanthridine system (52) [60] and heterobiaryl compounds (53) [61] [Eqs. (10,11)]. 

Takao and co-workers (60) have examined a number of hydro-benzo[c]phenanthridine alkaloids and their derivatives by a variety of physical methods in order to determine the conformation of the B/C rings (Fig. 18). The 13C chemical shifts (Table XVII) were particularly sensitive to the influence of substituents on the conformation of the B and C rings. Chelidonine (94) for example, with a cis ring junction, has both the B and C rings as half-chairs [see Fig. 1 in (60)]. Acetylation of the hydroxy l group to form 95 shielded C-6, C-12, and C-13 relative to 94. The interpretation of these observations was that ring C in 94 adopted a twist half-chair conformation which increased the number of gauche interactions for these carbons. 

Benzo[c]phenanthridines are an important class of the isoquinoline alkaloid family. It was possible to synthesize a variety of these compounds based on the S l reactions of appropriate derivatives of o-iodobenzylamines with nucleophiles328. For instance, the pho-tostimulated reaction of 281 (R1 = R2= H, OMe R1 = OPr-/, R2= OMe R R2 = 0CH20) with the appropriate derivative of tetralone enolate ions 284 (R3 = R4 = H, OMe R3 = OMe, R4 = H R3 = OPr-/, R4 = OMe R3R4 = 0CH20) gave the substitution compound, which spontaneously cyclizes to 285 (equation 176). 

Region C Introduction of the dihydroazine moiety into region C derived from the aromatic heterocycles such as phenanthridine, benzo[c]quinoline, quinolines, or isoquinolines and azines increases the ty2 values constantly. In going from left to right, the positive charge in betaine 9 is stabilized more efficiently (Scheme 15). 

Subsequently, Abramovitch et al. employed the Pschorr cyclisation of 100 in a synthesis of benzo[c]phenanthridine 102 <63CJC2265>. The key step involved addition of an aryl radical to C3 of an isoquinoline and proceeded in good yield (Scheme 33). Notably, no products derived from cyclisation to the pendent arene were observed [see also Scheme 56]. 

On the route to benzo[c]phenanthridine alkaloids [37], naphthol 51 (Scheme 20) was 0-alkylated with 2-bromo-2-methylpropionoamide under forcing conditions to give 52 in 93% yield. The rearrangement of 52 was executed with sodium hydride in DMF-DMPU and the hydroxy-amide 53 was hydrolyzed to give the aminonaphthyl derivative 54. 

Dimethyl azodicarboxylate (164) has been reported to undergo a [ 4 + 2] photocycloaddition to the diene (165) to give the 2,3-diazabicyclo[2.2.2]octene (166). An analogous solid-state addition has been described in the ox-azolone (167) to give the photodimer (IbS), and oxidation of the photoadduct derived from 1-oxoanhydromethylberberine and nitrosobenzene has been used in a synthesis of ring C-substituted benzo[c]phenanthridines. ... 

Attempts to achieve the thermal ring closure of the Meerwein salt 137 to the benzo[c]phenanthridine system failed the major product was the 4-acyliso-quinolinium salt 138 (79T1861). The reaction between )V-benzylaminoacetal-dehyde dialkyl acetals (139) with methyl vinyl ketone in acidic solution, leading to benzo[h]quinolizine derivatives, was newly investigated. The... 

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