Olivacine, synthesis

An independent synthesis of ellipticine follows, in its initial stages, the first olivacine synthesis reported in Section VII, C. Instead of the mono-methylcyanophenylhydrazine (CCLXII), a corresponding dimethyl compound, 3-cyano-2,5-dimethylphenylhydrazine (CCXCI-A), was employed as starting material. As far as the ester, methyl 1,4-dimethyl-carbazole-2-carboxylate (CCXCI-B), the two syntheses are parallel. Ring D was then built up, however, by the series of reactions,... 

The final ring closure again paralleled the olivacine synthesis passing through the intermediate jV-formyl rather than the V-acetyl, amine, to give 1,2-dihydroellipticine (CCXCIII) from which ellipticine was obtained by palladium dehydrogenation (160a). 

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). 

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). 

Pyridines and their N- oxides undergo attack by enamines under acylating conditions (Scheme 168), and the results for reactions of N- oxides have been surveyed (B-71MI20500). A modification of this heteroarylation reaction has been employed in the first step of a new synthesis of the antitumor alkaloid olivacine (241 Scheme 169) (81CC44). Electron-withdrawing groups attached at C-4 in the pyridine nucleus appear to facilitate this reaction. 

The reaction of iminium ions with dihydropyridines is a method, suggested from biosynthetic studies, for the formation of carbon-carbon bonds to these six-membered heterocycles. The 1,4-dihydropyridine (8), a presumed intermediate from the reaction of ammonia with glutaraldehyde, reacts with the cyclic iminium ion (159) to give, after oxidation, nicotine (160) (72CC1091). Another example of this reaction has provided a total synthesis of olivacine (163). The 1,2-dihydropyridine ring system in (161), generated from its chromium tricarbonyl complex, was observed to undergo an intramolecular cyclization... 

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... 

Fused carbazoles related to pyrido[4,3-6]carbazole alkaloids were prepared by a Diels-Alder route, and a 3-aza bioisostere of the antitumor alkaloid olivacine was synthesized <02CPB1479>. Indoloid [3.3]cyclophane 40a gave the pentacyclic indoloid 41a upon heating <02OL127>. This led to a concise formal total synthesis of ( )-strychnine in 12 facile steps from tryptamine when a similar transannular inverse-electron-demand Diels-Alder reaction of indoloid [3.3]cyclophane 40b gave 41b <02AG(E)3261>. 

Besselievre and Husson have published full details of their syntheses of ellipticine, olivacine, and guatambuine.86 A new approach to the synthesis of ellipticine87 involves construction of an appropriately substituted anilino-isoquinoline, e.g. (166) closure of the five-membered ring then constitutes the last stage (Scheme 24). Other synthetic work in this area includes syntheses of 16-desmethyl-16-methoxyellipticine88 and 11-hydroxy- and 11-methoxy-ellipticines.89... 

The extension of the above regioselective 6-endo cyclization to appropriately substituted substrates provided a novel synthetic entry to the pyrido[4,3-b]carbazole skeleton of the indole alkaloid olivacine, which resulted in a concise total synthesis of its tetrahydro derivative ( )-guatambuine <6 IT 160 67CJC89>. 

This chapter deals with the synthesis and biological properties of the relatively small family of pyrido[4,3- lcarbazole alkaloids, exemplified by ellipticine (1), 9-methoxyellipticine (2), 9-hydroxyellipticine (3), and olivacine (4), and of the much larger number of structural analogs that have been synthesized and studied... 

Scheme 14. Gribble-Obaza-Nutaitis synthesis of olivacine (4) (60).

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. 

The only synthetic work reported recently in this area involves yet more syntheses of ellipticine (174) and olivacine (175), and one of guatambuine (176) (Scheme 21). It should be noted that in Kametani s synthesis the condensation of the dibromide (177) with indole to give olivacine is claimed to be regiospecific. 

A new synthesis of olivacine 1138) (Scheme 24) and guatarabuine takes advantage of the stabilization of dihydropyridine derivatives by complexation with tricarbonylchromium(o). Thus, the readily prepared intermediate (139) gives a tricarfaonylchromiun complex (140), which can be formylated by the Vilsmeier procedure and dehydrogenated to demethylolivacine (141) this can be readily converted into olivacine and its N-methyl tetrahydro derivative, gua tambuine. ... 

An improved synthesis of olivacine (Scheme 28), and thereby guatambuine also, follows from an efficient three-stage preparation of the carbazole aldehyde... 

Schmutz and Wittwer s synthesis of olivacine (CCCVII) has been improved and adapted to the preparation of modified pyridocarbozoles 90). Among simpler derivatives that have been prepared are CCCVIII 90) and CCCIX 89). 9-Methoxyolivacine has been found naturally (Table I, 55e). 

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