Radical methodologies with indole and synthetic strategies towards the indole alkaloids, echitamine and prenostodione

A novel radical cyclization of 2-bromoindoles was examined, generating a series of hexahydropyrrolo[3,4-b]indoles in fair yield. This process involved the generation of a variety of indole-3-carboxamides followed by the introduction of bromine at the C-2 position of the indoles using lithiation chemistry. Treatment of indoles 131, 149, and 183 with tri-n-butyltin hydride afforded the cyclized dihydroindoles 132, 150, and 184, respectively, in 34–51% yields, via a 1,5-radical translocation process followed by a 5-endo-trig cyclization to the indole C-2 position.;The preparation of suitable 1,6-radical translocation reaction precursors has also been investigated. Attempted C-2 bromination of indoles 194 and 195 using metallation yielded the unexpected 2,2 ′-biindoles 197 and 199, respectively, in fair yields. The preparation of N-tosyl amide alcohol 221 is also presented. Bromination attempts of 221 yielded ketoamide 220 as the exclusive product.;Attempts towards a novel approach to the core of the natural product echitamine (256) via an intramolecular oxidative cyclization or nucleophilic addition are also described. 2-(5-Cyano-12b-keto-5,12b- seco-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine) malonic acid diethyl ester (477) was synthesized in 9 steps from tryptophan (311) in 5% overall yield. The synthesis involved the formation of 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (298), utilizing a Pictet-Spengler condensation, followed by further derivatization to the cyano enones 475a and 475b , generated in 57% overall yield from phenylselenide 474. The Michael addition of diethyl malonate to the enones 475 afforded the desired diester 477 in 86% yield.;Investigations towards the synthesis of the natural product prenostodione (492) are also presented. This biomimetic approach involves the facile synthesis of N-benzyl indoles 604 and 611, in 54–57% yield, from N-benzyl phenylhydrazine hydrochloride (608) and dialkyl acetone-1,3-dicarboxylates 597 and 610. Base-catalyzed condensation of p -methoxybenzaldehyde (601) with N-butoxycarbonyl diethyl and dimethyl esters 600 and 613, respectively, generated the corresponding Z-alkenes 603 and 614 in 54 and 69% yields, respectively. However, condensation of 613 with 4-[(t-butyldimethylsilyl)oxy] benzaldehyde (563) gave the desired E-alkene 617 in 43% yield. Removal of the silyl group was accomplished in a facile manner using TBAF. Suitable conditions for the selective saponification of the C-3 methyl ester remain to be explored and could yield the natural product.