Ellipticine Diels-Alder cycloaddition

May and Moody (52) have reported a full account of their Diels-Alder cycloaddition route to ellipticine (1) and isoellipticine (27) (Scheme 10). Conversion of indole (50) to 3-indole-2-propionic acid (56) with lactic acid was followed by a Plieninger cyclization to the pyranoindole 57. Reaction of 57 with 3,4-pyridyne (59), as generated from triazene 58, afforded equal amounts of ellipticine (1) and isoellipticine (27). Although the overall yield of 1 from indole is only 3%, the sequence involves only three steps. 

The furo[3,4-h]indole analogs serve as fused indolo-2,3-qumodimethanes and have been widely used in Diels-Alder cycloaddition reactions. Recent publications have reviewed the various methods developed for the synthesis of furo[3,4-b]indoles [126], as well as the pioneering work on the utility of these precursors in cycloaddition reactions to produce various heterocychc derivatives [127]. The early application of [4-1-2] cycloaddition reactions with furo[3,4-b]indoles to the synthesis of natural products was highlighted by the first regioselective Diels-Alder synthesis of ellipticine (385), which involved a cycloaddition reaction of the furoindole 382 with a dihydropyridone derivative 381 as the key step (Scheme 86) [128]. 

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. 

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 ... 

Although the regiochemistry of oxazole-olefin cycloadditions has not been extensively studied, some generalizations can be made. The major product is the 4-substituted pyridine in those instances when the alkene dienophile bears an electron-withdrawing substituent. This regioselectivity is exemplified by the Diels-Alder reaction used in a synthesis of the natural product ellipticine by Kozikowski and Hasan," starting from the reaction of oxazole 21 with acrylonitrile to give 4-cyanopyridine 22 (Fig. 3.6). 

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... 

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