Oxidation ellipticine

Oxidations of 9-Hydroxyellipticine. 9-Hydroxyellipticine is the major metabolite of ellipticine formed by mammalian cytochrome P-450 hydroxylation (147,153). The reaction is a good example of a bioactivation process because 9-hydroxyellipticine is many times more active as an antineoplastic agent than is ellipticine itself (154). Auclair, Meunier, Paoletti, and co-workers have extensively studied further oxidations of 9-hydroxyellipticine and its derivatives (155-158). 

The UV spectrum (Tmax 240, 268, 278, 288, 295, and 330 nm) of N-oxyellipticine (240) resembled that of ellipticine (228) (see Scheme 2.56), indicating a similar pyrido[4,3-l ]carbazole framework (222). Comparison of the mass spectrum of N-oxyellipticine at m/z 262 (M" ), with that of ellipticine (228) show only the presence of an additional oxygen as an N-oxy function. This conclusion was supported by comparison with the spectral data of synthetic Af-oxyellipticine, obtained by oxidation of ellipticine (228) with H2O2 in dichloromethane, and by reduction of Af-oxyellipticine with zinc to ellipticine. Based on these comparisons. 

Biochemical oxidation of the ellipticine derivative 241 to the o-quinone 242 has been achieved using hydrogen peroxide and horseradish peroxidase (HRP) as a catalyst (83JMC574). Compound 242 was easily protonated to form a tautomeric equilibrium between 243 and 244 it gave an addition product with methanol and was reduced by cysteine (Scheme 41). 

In a sequence that proceeds by tandem directed ortho metalation steps (Scheme 133) the N,N-diethyl isonicotinamide (447a) has been converted into the chemotherapeutic alkaloid ellipticine (589) (Scheme 182) (80JA1457). Thus, in a rapid, one-pot procedure, metalation of 447a followed by condensation with N-protected indole-3-carboxaldehyde derivatives leads to the intermediates 615 which, upon second metalation and aerial oxidation affords the quinones 616 in modest to good yields. Established steps were used to convert 616, R = CH2OMe into ellipticine (589), concluding a route which complements that based on the oxazolino DMG (Scheme 175). 

Generally high yields of substituted carbazoles can be obtained by oxidative cyclization of diphenylamines using Pd(OAc)2 to effect cyclization (equation 59) (75JOC1365). This method has been used, for example, to close the carbazole ring in the synthesis of the anti-tumor alkaloid ellipticine (equation 60) (80TL3319). 

The intermediates (66), (67), upon in situ oxidation, afford 2(or 3)-pyridynes or 2(or 3)-quinolynes <71JCS(C)3948> which are highly reactive in Diels-Alder reactions, as shown in Schemes 10 and 11 for syntheses of ellipticine (69), isoellipticine (70) (84JOC4518,92T10645), and furo[3,4-c]pyridine (72) (77TL1741). Nitrosation of the aminotriazolopyridines affords the parent triazolopyridines. 

Ellipticine is the major alkaloid of the trunk bark of Ochrosia moorei F. von Muell., in which it occurs in association with 27 other alkaloids, including 10-methoxyellipticine, ellipticine 7Vb-oxide, and 3,14-dihydroellipticine.43rf A point of chemotaxonomic interest is that the genera Ochrosia and Neisosperma can be distinguished on the basis of their ellipticine/10-methoxyellipticine content one or both of these alkaloids are present in Ochrosia species, but absent from Neisosperma species. 

Attention was centered on radical precursors in which the 3-pyridyl moiety was attached at the indole-3-position with the aim of directly producing the pyrido[4,3-b]carbazole skeleton of ellipticine by regioselective cyclization upon the 4-position of the pyridine ring. Satisfactorily, A-methyl and A-benzyl selenoesters 52a and 52b led to the ellipticine quinones 53a and 53b in acceptable yields (60 and 42% yield, respectively), after the radical cyclization and the in situ oxidation at the interannular methylene group. The cyclization was clearly less efficient from A-(methoxymethyl) selenoester 52c and no reaction was observed... 

A further extension of this strategy has been employed as a route to carbazoles, as illustrated by the synthesis of the system 116 from the 2-nitrobiphenyl derivative 117 (Equation 30) <20040L533>. A substituted 2-nitrobiphenyl derivative has been cyclized to a carbazole using P(OEt)3 en route to the pyridocarbazole alkaloid ellipticine <2006HCA111>. It should also be mentioned that annulation of o-(alkynyl)nitrobenzene precursors with TBAF or pyridine gave access to indol-3-one-l-oxides (isatogens) <2003T2497>. 

NaH, dimethylformamide (DMF), CH3I], undergoes electrophilic nitration (89), Friedel-Crafts acylation (90), and alkylation (91) at the C-9 position. Although attempts to effeet a Baeyer-Villiger oxidation of ketone 90 were successful, the route was laborious since oxidation to amine oxide 92 preceded oxidation of the methyl ketone 90. However, a Dakin reaction of aldehyde 91 gave 9-hydroxy-6-methylellipticine (93) in excellent yield. It remains to be seen if this methodology can be extended to an N-unsubstituted ellipticine. 

Sainsbury and co-workers (121) have synthesized several ellipticine dimers tethered through the C-5 methyl group (333) (Scheme 53) or the C-9 position (334). The 9-methoxy derivative of 333 was also prepared. The nitrile 329 was available from the Sainsbury ellipticine synthesis (122) and was transformed into the alkaloid 17-oxoellipticine (148). A clever maneuver was to add nitric acid to protonate the pyridine nitrogen of 330. This precluded A-oxide formation during dithiane hydrolysis. Reductive amination in two steps afforded the amine 332. Coupling with adipic acid gave the target bisellipticine 333. 

Another aspect of the mode of action of ellipticine and its derivatives that has been intensely scrutinized in recent years is the chemistry of ellipticine quinone imines 6 and 256. The oxidation product of 9-hydroxyellipticine (3), formed by horseradish peroxidase-hydrogen peroxide or chemical (e.g., manganese dioxide) oxidation of 3, undergoes a rich array of chemical reactions. Meunier et al. 

Carbon-carbon bond formation by intramolecular cyclization of conjugated iminium ions is also possible, as illustrated by the transformation of amine oxide (36) to (37), a key intermediate in the synthesis of the pyridocarbazole alkaloid ellipticine (38 Scheme 7). ... 

Phenethylamine-type N-oxides also undergo carbon-carbon bond fragmentation under modified Polo-novski conditions, as illustrated by the reaction of N,A -dimethyltryptamine N-oxide (66), wherein cleavage of the side chain is facilitated through participation of the electrons on the indole nitrogen (equation 18). The ease with which N-oxide (66) undergoes fragmentation implies that the in vivo equivalent of this reaction is important in the biosynthesis of certain indole alkaloids, such as ellipticine (38) and val-lesamine (67 Scheme 13), whose derivation from tryptophan is not immediately obvious. 

S. Bernard, M. A. Schwaller, J. Moiroux, E. A. Bazzaoui, G. Ldvi, and J. Aubard, SERS identification of quinone-imine species as oxidation products of antitumour ellipticines, I. Raman Spectrosc. 27, 539-547 (1996). 

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