Intramolecular cycloadditions of azides with olefins: Synthetic approaches to pyrrolizidine and indolizidine alkaloids.

Abstract

Alkyl azides were found to undergo intramolecular cycloadditions with various olefins to provide 4,5-dihyro-3H-pyrroles, 2,3,5,6,7,7a-hexahydro-1H-pyrrolines (pyrrolizidines) and 1,2,3,5,6,7,8,8a-octahydroindolizines (indolizidines). Thermolysis of racemic mixtures of (Z)-7-azido-5-(methoxy)methoxy-3-phenylthio-1,3-heptadiene and (Z)-8-azido-5-(methoxy)methoxy-3-phenylthio-1,3-octadiene provided racemic mixtures of (1R*,7aR*)-2,3,5,7a-tetrahydro-1-(methoxy)methoxy-7-phenylthio-$ 1$H-pyrrolizine and (8R*,8aR*)-3,5,6,7,8,8a-hexahydro-8-(methoxy)methoxy-$ 1$-(phenylthio)indolizidine. The cyclization of these chiral substrates proceeded with high diastereoselectivity to produce materials closely related to the naturally occurring alkaloids heliotridine and swainsonine. Preparation of (Z)-7-azido-5-(methoxy)methoxy-3-phenylthio-1,3-heptadiene and (Z)-8-azido-5-(methoxy)methoxy-3-phenylthio-1,3-octadiene relied on the reduction of propargyl alcohols with sodium bis-(2-methoxy)ethoxy aluminum hydride followed by treatment with phenylsulfenyl chloride. Heating (S)-5-azido-3- ((benzyl)oxy) methoxypentene, which was derived from (S)-malic acid, at 120$\sp\circ$C. gave (S)-3- ((benzyl)oxy) methoxy-4,5-dihydro-2-methyl-3H-pyrrole. Treatment of this compound with butyllithium followed by 3-chloro-(2-chloromethyl)proprene and NaBH$\sb4$ provided (1S,8aS)-1- ((benzyl)oxy) methoxy-1,2,3,5,6,7,8,8a-octahydro-6-(methylene)indolizidine. This compound was closely related to the indolizidine alkaloid slaframine. The synthesis of slaframine from (1S,8aS)-1- ((benzyl)oxy) methoxy-1,2,3,5,6,7,8,8a-octahydro-6-(methylene)indolizidine was impossible due to the apparent instability of subsequent intermediate compounds.