Electrophilic substitution in indoles. Part 19. Facile syntheses of the 2a,5a-diazacyclopenta[j,k]fluorene, indolo[2,3-a]quinolizinone and aspidosperma alkaloid ring systems from N-acyltryptamines

Abstract

Reaction of tryptamine with diketene gave N-[2-(1H-indol-3-yl)ethyl]-3-oxobutyramide (80%) which with phosphoryl chloride in dichloromethane gave (9bS*, 9cS*)-1,2,9b,9c-tetrahydro-5-methyl-2a,5a-diazacyclopenta[j,k]fluoren-3-one 13(73%). Hydrogenation gave the 4,5-dihydro and perhydro derivatives. Michael addition of ethyl acetoacetate to benzyl acrylate gave 5-benzyl 1-ethyl 2-acetylpentanedioate (57%) which was hydrogenolysed to 4-ethoxycarbonyl-5-oxohexanoic acid (100%), the mixed anhydride of which condensed with tryptamine to give 4-ethoxycarbonyl-N-[2-(1H-indol-3-yl)ethyl]-5-oxohexanamide 19(78%). The latter, with trifluoracetic acid anhydride gave (±)-cis and trans 1-(ethoxycarbonyl)-2,3,6,7-tetrahydro-12b-methyl-12H-indolo[2,3-a]quinolizin-4(1H)-one (21 and 22)(95%). N-[2-(1-Methylindol-3-yl)ethyl]piperidin-2-one 31 was synthesised in three stages. The anion of 31 with diketene gave (a)N-[2-(1-methylindol-3-yl)ethyl]-3-(1,3-dioxobutyl)piperidin-2-one, 29 and (b) in a three-stage process, N-[2-(1-methylindol-3-yl)ethyl]-3-(1-oxo-2-methoxycarbonylethyl)piperidin-2-one 30. Treatment of the dione 29 with excess of trifluoroacetic acid anhydride gave (2S*, 3R*, 12R*)-3-acetyl-5-deethyl-5,19-didehydro-1-methyl-4-oxoaspidospermidine, 34. Reduction of 34 with sodium cyanoborohydride gave the 20,21-dihydro derivative 35 and two (±)-diastereoisomeric alcohols 36 and 37. Cyclisation of the ester 30 with trifluoracetic acid anhydride gave (2S*, 3S*, 12R*)-5-deethyl-5,19-didehydro-3-methoxycarbonyl-1-methyl-4-oxoaspidospermidine 39.