Ellipticine methodology

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. 

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... 

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... 

NaH, dimethylformamide (DMF), CH3I], undergoes electrophilic nitration (89), Friedel-Crafts acylation (90), and alkylation (91) at the C-9 position. Although attempts to effeet a Baeyer-Villiger oxidation of ketone 90 were successful, the route was laborious since oxidation to amine oxide 92 preceded oxidation of the methyl ketone 90. However, a Dakin reaction of aldehyde 91 gave 9-hydroxy-6-methylellipticine (93) in excellent yield. It remains to be seen if this methodology can be extended to an N-unsubstituted ellipticine. 

Using their earlier methodology to synthesize ellipticine (1), Gribble and... 

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. ... 

One approach to the anti-tumor compound ellipticine (228) " used the Kondrat eva pyridine methodology to form pyridinyl derivative 227. Addition of methyllithium and hydrolysis of 227 then led to 228. 

The Graebe-Ullmann methodology has proved especially valuable in the synthesis of ellipticine and analogues. Using flash vacuum pyrolysis, Miller and StoweU... 

---