Ellipticines, synthesis

In unpublished work, Gribble and Obaza-Nutaitis (60) have adapted the Saul-nier-Gribble ellipticine synthesis (61) to the synthesis of olivacine (Scheme 14). Keto lactam 85, available from indole in four steps (71% yield) (61), was treated sequentially with methyllithium and lithium triethylborohydride to give diol 86, which, without isolation, was reduced with sodium borohydride to give 1-de-methylolivacine (87). This had been previously converted to olivacine (4) by Kutney and co-workers (62). The success of this synthesis of 87 was due to the fact that Saulnier and Gribble (63) had previously established that the ketone carbonyl of keto lactam 85 is more reactive than the lactam carbonyl group. 

Gribble and Saulnier (79) have extended their ellipticine synthesis 43) to the synthesis of 9-methoxyellipticine (2) (Scheme 24). One of the key features of this approach is the regioselective nucleophilic addition to the C-4 carbonyl group of pyridine anhydride 28. The other noteworthy transformation is the conversion of keto lactam 142 to the diol 143 with methyllithium, a process that presumably involves cleavage of the initial adduct to a methyl ketone which undergoes cyclization at the C-3 position of the indolyl anion. Reduction of 143 with sodium borohydride completes the synthesis of 2, in 47% overall yield from 5-methoxyindole (139). Gribble and students 80) have also used this method to synthesize 8-methoxyellipticine (134), 9-fluoroellipticine (144), and the previously unknown 7,8,9,10-tetrafluorellipticine (145), each from the appropriate indole. 

Archer and co-workers (84) have used the original Stillwell ellipticine synthesis (87), as later exploited by Gouyette et al. (88) to prepare the simple 9-hydroxy-6//-pyrido[4,3-fe]carbazole (158) (Scheme 27). V-Benzyl-4-piperidone was converted via enamine 154 to the enone 155. Hydrogenation gave a mixture of cis- and trawj-ketones 156 which were separately converted to indole 157 by Fischer indolization. Some of the nonlinear pyrido[3,4-c]carbazole (17%) was formed from the cis-ketone. Dehydrogenation and demethylation gave the desired 158. 

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. 

Bergman and Carlsson have adapted their brief ellipticine synthesis to a new synthesis of olivacine (179). Condensation of 2-ethylindole with 2-methyl-3-methylpyridine gave the bis-indolyl condensation product (180), which lost 2-ethylindole on pyrolysis, and cyclized to give olivacine directly (Scheme 25). 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

The antitumor alkaloid ellipticine (5,1 l-dimethyl-6//-pyrido[4,3-b]carbazole) has been isolated from many species of Ochrosia and Aspidosperma. Ellipticine and its derivatives are highly active versus several experimental neoplasms, and the compound has been widely subjected to studies devoted to its total synthesis, the preparation of derivatives, and metabolism. Metabolic transformation studies with ellipticines have been conducted, using microorganisms, in vivo and in vitro... 

The UV spectrum (7max 235, 270 (sh), 279,301,312, and 378 nm) of 236 indicated a dihydropyrido[4,3-l7]carbazole framework. This assignment was supported by the IR spectrum (v ax 843, 1028, 1167, 1410, 1595, and 1615 cm ). The structure for 3,4-dihydroellipticine was confirmed by synthesis from ellipticine and comparison of the IR and UV spectra, melting points and Rf values. Additional support for this assignment derived from the transformation into derivatives of 3,4-dihydroellipticine (216). 

The strong interest in the synthesis of pyrido[4,3-h]carbazole alkaloids started in the late 1960s with the disclosure of the antitumor activity of ellipticine (228) and 9-methoxyellipticine (229) (see Scheme 2.56) in several animal and human tumor systems. This discovery made these alkaloids to important synthetic targets and induced extensive studies of structure modification. These synthetic efforts have... 

As an extension of this methodology, Gribble et al. reported a formal total synthesis of olivacine (238a). This synthesis starts from the same keto lactam 1181, used for the synthesis of ellipticine (228), and exploits the lower reactivity of the lactam carbonyl as compared to the carbonyl of the keto lactam. Reaction of the keto lactam 1181 sequentially with methyllithium and superhydiide (LiBHEts) led to 11-demethylellipticine (1191) in 57% yield, along with 30% of ellipticine (228). Finally, using Kutney s procedure (220), ll-demethylellipticine (1191) could be transformed to olivacine (238a) (701) (Scheme 5.195). 

Gribble et al. also reported a new annulation strategy for the total synthesis of ellipticine (228) (527). This methodology utilizes a Diels-Alder reaction between... 

Six years later, the same authors reported an improved version of their earlier synthesis of ellipticine (228) (527) (Scheme 5.197) by using the l-(p-methoxybenzyl)-5,6-dihydropyridone (1197) as 3,4-pyridyne surrogate (702,703). Thus, the dimethyl-furoindole 544 was treated with the unsaturated lactam 1197 (prepared from 5-valerolactam in three steps) in the presence of trimethylsilyl triflate (TMSOTf) to afford the carbazole 1199 as a single product in 40% yield. The low yield is presumably a consequence of decomposition of the intermediate adduct 1198 during... 

Backvall and Plobeck reported a formal synthesis of ellipticine (228) starting from indole (707). The [4+2] cycloaddition of 1-indolylmagnesium iodide (1208) with 3-(phenylsulfonyl)-2,4-hexadiene (1209) afforded the tetrahydrocarbazole... 

Addition of methyllithium to the lactone 1219, followed by reduction with sodium borohydride in refluxing ethanol, afforded, almost quantitatively, ellipticine (228). Reaction of the compound 1219 with the lithio derivative of formaldehyde diethylmercaptal, and reduction with sodium borohydride in refluxing ethanol, led to the mercaptal 1221. Cleavage of the mercaptal 1221 with bis(trifluoroacetoxy) iodobenzene [Phl(OCOCF3)2] in aqueous acetonitrile gave the 11-formyl derivative, which was reduced with sodium cyanoborohydride (NaBHsCN) to 12-hydroxyellipticine (232) (710,711) (Scheme 5.202). The same group also reported the synthesis of further pyiido[4,3-fc]carbazole derivatives by condensation of 2-substituted indoles with 3-acetylpyridine (712). 

Sha and Yang reported the total synthesis of ellipticine (228) using the... 

Miki et al. reported the total synthesis of ellipticine (228) starting from N-benzylindole-2,3-dicarboxylic anhydride (852) (714,715). Reaction of (3-bromo-4-pyridyDtriisopropoxyltitanium (1232) with 852 gave 2-acylindole-3-carboxylic acid 1233 in 86% yield. Decarboxylation and debenzylation of 1233 led to the ketone 1234. Wittig olefination of the ketone 1234, followed by catalytic hydrogenation. 

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

Recently, the same authors reported a different route for the total synthesis of olivacine (238a) and ellipticine (228) starting from 2,4,6-tiimethoxypyiidine (1244) with N-benzylindole-2,3-dicarboxylic anhydride (852) (717,718). Interestingly, this method also uses the same common precursor, N-benzylindole-2,3-dicarboxylic anhydride (852) as shown in Schemes 5.204 and 5.205. Contrary to the earlier route, this sequence involves a Friedel-Crafts acylation of 2,4,6-trimethoxypyridine (1244) with N-benzylindole-2,3-dicarboxylic anhydride (852) (717,718). 

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