Ellipticine-type alkaloids

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). 

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. 

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. 

This methodology has since been applied to constructing [6]-an-nelated carbazoles, and benz[/]indole, and the tetracyclic skeleton of the benzophenanthridine alkaloids. Arynes used in this type of reaction include 3,4-didehydropyridine in the synthesis of ellipticine 8 and isoellipticine 9," 3,4-(methylenedioxy)benzyne, and 2,3-naphthalyne. ... 

StiU with a tetrahydopyridine derivative alcohol 354, a high-yielding orthoester rearrangement was used in a synthesis of antitumor alkaloid ellipticine 353 [82] (Scheme 6.60). The same kind of reaction was applied to a synthesis of descarbo-methoxy vobasine 356b (Scheme 6.60) [83]. This type of rearrangement was also used by Kametani [84] in an approach to ervitsine 359 (Scheme 6.60). 

The alkaloids imder discussion share a common Corynanthe-type nucleus derived from secologanin. Yohimbine is a carbocyclic variant of ajmalicine, and the enzymes that convert deglycosylated strictosidine to yohimbine have not been identified [124, 125]. Strychnine and bmcine are synthesized from the preakuammicine structure by hydrolysis, decarboxylation, and condensation reactions to aldehyde (Wieland-Gumlich), and subsequently reaction with acetyl-CoA to make a hemiacetal form of aldehyde (Wieland-Gumlich) and strychnine and brucine. Brucine is a dimethoxy form of strychnine. Ellipticine is a representative member of pyrido[4,3-b] carbozole alkaloid, and the formation of ellipticine is from ajmalicine (corynanthean skeleton) [126] (Fig. 20.8). 

There are recognized at present three naturally occurring members of this group, cinchonamine, quinamine and conquinamine (3-epiquinamine), minor alkaloids of certain cinchona species. Elucidation of their structures lead to the suggestion that the cinchona bases may be derived biosynthetically from Type I precursor and tryptophan. It has since been shown that isotopi-cally labelled tryptophan is incorporated into these quinoline bases. It is convenient to point out here some other alkaloids in which Type I precursor may be dissected out, e.g. the bisiso-quinoline base, emetine the indoleisoquinoline, tubulosine and also the indoles uleine and ellipticine which appear to have lost (or never had) the tryptophan side chain. (Chart 7.1)... 

---