Ellipticine reaction

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. 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

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). 

Intramolecular Mannich type reaction of the conjugated iminium salt 426 should lead to ellipticine (228) via an intermediate 427. Alternatively, the conjugated iminium salt 426 could hydrolyze to afford the 2-vinylsubstituted indole 428, which, on cyclization through an intermediate 429, would lead to guatambuine (233). This alkaloid, on demethylation and dehydrogenation, should afford olivacine (238a) (375) (Scheme 3.11). 

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... 

Diels-Alder reaction of the furoindole 544 with 3,4-pyridyne (1193), generated in situ via two different ways, led to a mixture of the two possible cycloadducts 1194 and 1195 in approximately equal amounts. Without purification, the crude adducts 1194 and 1195 were treated with basic sodium borohydride (NaBH4) to afford a separable mixture of ellipticine (228) and isoellipticine (1196) in 23% and 29% yield, respectively (527) (Scheme 5.197). 

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). 

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... 

Ishikura et al. reported the total synthesis of ellipticine (228) starting from N-Boc indole (1256) and the vinyl bromide 1258 (719-721). This methodology involves a palladium-catalyzed, tandem cyclization-cross-coupling reaction of the indolyl borate 1257 with the vinyl bromide 1258 as the key step. Using a literature procedure, the vinyl bromide 1258 was prepared as an E/Z mixture starting from CIS- and trans-crotyl alcohol. The indolyl borate 1257 was generated in situ from... 

Guitian et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves... 

Mai et al. reported a formal total synthesis of ellipticine (228) starting from the furoindolone 649 (583,724). In this strategy, the key step is the anionic [4+2] cycloaddition of furoindolone 649 with 3,4-pyridyne (1193). Reaction of compound 1270 with 3,4-pyridyne (1193) in the presence of LDA gave ellipticine quinone (1272)... 

Bowman et al. reported the total synthesis of ellipticine (228) involving an imidoyl radical cascade reaction (730). For this key step, the required imidoyl radical was generated from the imidoyl selanide 1290, which was obtained from ethyl 2-(4-pyridyl)acetate (1286). Reaction of 1286 with LDA, followed by addition of methyl iodide, led to the corresponding methyl derivative 1287. Treatment of 1287 with 2-iodoaniline (743) in the presence of trimethylaluminum (AlMes) afforded the amide 1288. Using Sonogashira conditions, propyne is coupled with the amide 1288 to afford the aryl acetylene 1289. The aryl acetylene 1289 was transformed to the... 

The formation of Reissert derivatives of the antineoplastic agent ellipticine (225) (Scheme 29) and their reactions have been extensively studied by Popp and co-workers 39,49-51). The ellipticine Reissert compound 226 could be prepared either with benzoyl chloride and potassium cyanide in a dichloromethane-water system or, better, with benzoyl chloride and trimethylsilyl cyanide in dichloromethane. In similar manner 9-methoxyellipticine and a number of 6-substituted ellipticines have also been converted to the corresponding Reissert compounds. 

The regioselectivity of 2,4-cycloaddition of furo- and pyrrolo[3,4-, ]indoles with 3,4-didehydropyridines was studied <2001EJ04543>. The results of this key reaction step in the synthesis of ellipticines are summarized in Equation (1). 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

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