Ellipticine synthesis from indole

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... 

Zee and Su (49) have modified the original Woodward et al. (7) synthesis of ellipticine, as improved by Sainsbury and Schinazi (50) and Berman and Carlsson (51), to achieve a convenient and reasonably efficient synthesis of ellipticine (1) (Scheme 9). Bergman s improved method (57) was used to prepare 3-vinylindole 53, which, after catalytic hydrogenation to 54, was reductively acetylated directly to afford 2-acetyl-1,2-dihydroellipticine (55). Hydrolysis and aromatization completed the synthesis of ellipticine (1) in 12% overall yield from indole (50). 

In unpublished work, Gribble and Obaza-Nutaitis (60) have adapted the Saul-nier-Gribble ellipticine synthesis (61) to the synthesis of olivacine (Scheme 14).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. 

Gansser et al. (76) have employed a Cranwell-Saxton synthesis (56) to prepare 9-(dimethylamino)ellipticine (130) from 5-(dimethylamino)indole (127) (Scheme 21). To avoid formylation of the carbazole N-9 position, it was necessary to use the hydrochloride of 128. However, the yield of the desired aldehyde 129 was still very poor (3%) as formylation at C-5 was a side reaction. Finally, the Dalton modification (7) was used to form the D ring. Gansser and co-workers... 

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. 

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... 

The only synthetic work in this area reported during the year provides yet more syntheses of the ellipticine ring system. Oikawa and Yonemitsu have applied their carbazole synthesis to a very efficient, if lengthy, preparation of olivacine (191) (Scheme 18) 108 the overall yield of olivacine from the starting indole ester (192) is... 

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>. 

Early examples of the total synthesis of naturally occurring indole alkaloids employing the Suzuki reaction include ellipticine (10) as repotted by Miller et al. [34], The aryl bromide, 6-amino-7-bromo-5,8-dimethylisoquinoline (45) was derived from 2,5-dimethylanilinc in nine steps. The Suzuki coupling of 45 with phenylboronic acid was carried out using catalytic tetrakis(triphenylphosphine)palladium in benzene and with Na,CO, serving as the base to furnish... 

Diels-Alder reactions using 2-vinylindoles as the diene were used as the key step in syntheses of olivacine derivatives (155), ellipticine derivatives (157), and ( )-3-epi-dasycarpidone (162) [65] (Scheme 39). In the synthesis of ( )-3-epi-dasycarpidone, the appropriate 2-vinylindole 159 was prepared via a one-pot procedure, and then subjected to deprotection of the aUyl carbamate, and subsequent enamine formation, followed by an intramolecular Diels-Alder reaction to produce 161, thereby producing the indole alkaloid framework in three steps from a rather simple starting material, 158. The attempted cycloaddition reaction... 

Ellipticine (E) 1 is an indolic alkaloid with antitumor activity. Some of its phenolic derivatives as N-methyl-9-hydroxyellipticine (Celiptinium), obtained from 9-hydroxy ellipticine (9-OH E), exhibit high cytotoxicity. 38 Syntheses of 9-OH E are not satisfactory considering yields and cost, justifying the attempts at the direct conversion of E to 9-OH E via 9-oxoellipticine (9-0X0 E). Potassium nitrosodisulfonate (Fremy s salt), a valuable oxidant for the synthesis of quinone-imine from heterocyclic amines,139 was used. Under these conditions the conversion of E to 9-0X0 E was observed for the first time. Its reduction to 9-OH E is then easily achieved with ascorbic acid. The radical nature of Fremy s salt [ 0-N(S03K)2] led us to carry out the oxidation reaction under sonication in order to increase the yields via an easier electron transfer.1 1... 

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