| The first asymmetric synthesis of (−)-7-epicylindrospermopsin via intramolecular nitrone cycloaddition is described. The synthesis utilized a convergent approach to prepare the cycloaddition precursor 176, which was assembled by condensation of hydroxylamine 175 with aldehyde 145. Hydroxylamine 175 was synthesized from ethylene glycol (166) in seven steps. Aldehyde 145 was completed in 9 steps from (R)-methionine. Intramolecular nitrone cycloaddition of 176 afforded the unstable oxazabicyclo[2.2.1]heptane derivative 177 accompanied by two unidentified stereoisomers in a ratio of 10:5:1. Further transformations from 177 led to the crystalline diol 187 whose stereostructure was confirmed by X-ray crystallographic analysis. Diol 187 was converted to azide 189, and the remaining secondary hydroxyl group was protected as its triethylsilyl ether 198. O-alkylation of the urea function in 198 afforded the transient isourea 199 which was subjected to catalytic hydrogenation over palladium-on-carbon. The resultant primary amine underwent spontaneous cyclization to give guanidines 200–202. Subsequent exhaustive hydrolysis followed by reversed phase HPLC purification yielded 203 which was identical by comparison of 1H and 13C NMR spectra with the corresponding racemic substance prepared by Weinreb. Sulfation of 203 gave (−)-7-epicylindrospermopsin. The specific rotation of synthetic material establishes that the absolute configuration of natural (−)-epicylindrospermopsin is 7S, 8R, 10S, 12 S, 13R, 14S, as represented by 2. |
