Synthesis of (+/-)tylophorine by the intramolecular cycloaddition of an azide with an [omega]-chloroalkene

Abstract

Cyclization of (Z)-1-(2-chloromethyl)phenyl-5-azidopent-1-ene 10 in benzene at 120[deg]C followed by treatment with sodium borohydride produced 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinoline 11 in 71% yield. A similar cyclization of (Z)-2,3,6,7-tetramethoxy-9-(5-azido-1-pentenyl)-10-chloromethylphenanthrene 3 gave the phenanthroindolizidine alkaloid (+/-)- tylophorine 5 in 82% yield. These reactions proceed by intramolecular 1,3-dipolar cycloaddition of the azide onto the alkene followed by loss of nitrogen from the triazoline intermediate to give an imine The imine is N-alkylated in situ by the pendant benzyl chloride to provide an iminium ion, which is reduced by sodium borohydride to afford the indolizidines. The synthesis of (+/-)-tylophorine was acomplished in 11 steps from homoveratric acid in 5% overall yield.