Wh. Pearson et R. Walavalkar, SYNTHESIS OF (+ -)-TYLOPHORINE BY THE INTRAMOLECULAR CYCLOADDITION OFAN AZIDE WITH AN OMEGA-CHLOROALKENE/, Tetrahedron, 50(43), 1994, pp. 12293-12304
Cyclization of(Z)-1-(2-chloromethyl)phenyl-5-azidopent-1-ene 10 in ben
zene at 120 degrees C followed by treatment with sodium borohydride pr
oduced 1,2,3,5,10, 10a-hexahydropyrrolo[1,2-b]isoquinoline 11 in 71% y
ield. A similar cyclization of 9-(5-azido-1-pentenyl)-10-chloromethylp
henanthrene 3 gave the phenanthroindolizidine alkaloid (+/-)tylophorin
e 5 in 82% yield. These reactions proceed by intramolecular 1,3-dipola
r cycloaddition of the azide onto the alkene followed by loss of nitro
gen from the triazoline intermediate to give an imine The imine is N-a
lkylated in situ by the pendant benzyl chloride to provide an iminium
ion, which is reduced with sodium borohydride to afford the indolizidi
nes. The synthesis of (+/-)-tylophorine was accomplished in 11 steps f
rom homoveratric acid in 5% overall yield.