Ellipticine approach

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. 

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... 

Three years later, the same authors also reported a modified Moody approach for the total synthesis of ellipticine (228). In this route, an indolopyrone is used as a stable equivalent of indolo-2,3-quinodimethane in a Diels-Alder reaction with 2-chloro-3,4-pyridyne (1267) (723). 

A convergent approach to the 11-nor-ellipticines 536, which constitute promising antitumor agents currently in clinical trials, begins with directed... 

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... 

In addition to the reviews cited earlier 10-14,16,19), several other reviews covering the previous synthetic efforts toward ellipticine are available 34-37). This section deals with new synthetic approaches to the ellipticine skeleton only ... 

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. 

Hetarynes (dehydroaromatic heterocycles) can also act as dienophiles in Diels-Alder reactions. 2 This capacity and the inherent regiochemical problems are illustrated by two syntheses of the alkaloid ellip-ticine, which both feature a [4 + 2] cycloaddition of 3,4-pyridyne (533) (Scheme 126). 2 The first approach used the triazenylcarboxylic acid (534) as a precursor for hetaryne (533), which then underwent an addition to pyranoindolone (535) spontaneous CCh extrusion of the initial cycloadducts (536 X = N, Y = CH) and (536 X = CH, Y = N) gave directly a 50 50 mixture of ellipticine (537) and its undesired regioisomer (538). 2 ... 

The total synthesis of ellipticine by Miller el al. [11] is one of the first syntheses of naturally occurring indole alkaloids using Pd(OAc), via the oxidative cyclization mechanism (Scheme 2). Exposure of 6-anilino-5,8-dimethylisoquinoline (9) to two equivalents of Pd(OAc)j in TFA/AcOH facilitated the oxidative cyclization to the desired ellipticine (10). Recently, the same indole formation strategy that uses the Pd(OAc),-mediated oxidative cyclization has been the cornerstone of several synthetic approaches directed toward ellipticine analogs. For instance, oxidative cyclization of diphenylamine 11 was carried out with Pd(OAc), in acetic acid to provide... 

A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones <05JOC9077>. A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,l-rf][l,5]benzodiazocines <05T941> and indolo[3,2-d][l]benzazepin-6-ones <05T5489>. 3,3-... 

A key step employed in the Kozikowski-Hasan approach to the antitumor agent ellipticine (6) was the regioselective [4 + 2] cycloaddition of acrylonitrile with the oxazole 7 [Eq. (3)]. 

Earlier synthetic approaches to ellipticine (267) were described in Volume XI (p. 279) of this series. In the intervening years, several new approaches to this important alkaloid have been developed. 

Two new synthetic approaches to ellipticine have been reported (312, 313). One of these (312), developed by Jackson and co-workers, does not rely on preformed indoles. The initial steps are formylation of... 

An entirely new approach to the synthesis of ellipticine (267) has been reported by Kozikowski and Havan (315). Crucial in this synthesis is the Diels-Alder addition of an acrylic acid moiety to an oxazole followed by elimination of the oxygen bridge to give a pyridine. Thus, heating the oxazole 738 in acetic acid-acrylonitrile at 145° gave the indolyl-ethyl pyridine 739 in 16% yield (Scheme 59). The iV-acetyl derivative of this intermediate had previously been converted to 267 (266). 

A further modification of methods which have already been described has been discussed by French workers (316) for the formation of 9-methoxy ellipticine (743). It combines the Borsche (317) synthesis of tetrahydrocarbazoles with the Cranwell-Saxton approach (318) for the pyridine ring, to produce the carbazole aldehyde 744 (Scheme 60). 

In a conceptually similar approach to ellipticine, Guitian and coworkers [129] used the Diels-Alder reaction of the same indolofuran derivative 382 with the 3,4-didehydropyridine derivative 386, to produce a mixture of two cycloadducts 387 and 388 (2.4 1) in 89% yield (Scheme 87). The intermediate 387 was then... 

The numerous existing syntheses of ellipticine (173) and olivacine have been discussed in a general review devoted to the synthesis of 6/f-pyrido[4,3-i]carbazoles. New routes to ellipticine continue to be reported. Kozikowski s oxazole approach (Scheme 26) affords a low yield in the critical Diels-Alder stage [(174)-> (175)] but is otherwise efficient and, it is claimed, should be sufficiently versatile to allow the introduction of substituents into ring D as desired. 

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. 

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). 

Derivatives of the new 6H-indolo[2,3-h]-l,8-naphthyridine ring system 99, which resemble the tumor inhibitor ellipticine, have been prepared by this approach. ... 

---