Total Synthesis of (−)-7-Epicylindrospermopsin, a Toxic Metabolite of the Freshwater Cyanobacterium Aphanizomenon ovalisporum, and Assignment of Its Absolute Configuration
journal contributionposted on 18.03.2005, 00:00 authored by James D. White, Joshua D. Hansen
The Z and E nitrones 38 and 39 from condensation of aldehyde 20 with hydroxylamine 36 underwent intramolecular dipolar cycloaddition to give the substituted 1-aza-7-oxobicyclo[2.2.1] heptanes 40 and 41 in a ratio of 2:1, respectively. Reductive N−O bond cleavage of 40 followed by carbonylation gave cyclic urea 47 in which inversion of the secondary alcohol was effected via an oxidation−reduction sequence. After conversion of the p-bromobenzyl ether 50 to azide 54, activation of the cyclic urea as its O-methylisourea and reduction of the azide led to spontaneous cyclization to afford the tricyclic nucleus 59 of cylindrospermopsin. Global deprotection, including hydrolysis of the 2,4-dimethyoxypyrimidine appendage to a uracil, and then monosulfation of the resultant diol 60 afforded a substance identical with natural (−)-7-epicylindrospermopsin (1). The asymmetric synthesis of (−)-7-epicylindrospermopsin defines its absolute configuration as 7S,8R,10S,12S,13R,14S.
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ReductiveGlobal deprotectionAssignmentactivationcyclic ureainversionintramolecular dipolar cycloadditiondimethyoxypyrimidineToxic Metabolitecleavagehydroxylamine 36bondTotal Synthesissequenceconfigurationbromobenzyl ether 50valisporumFreshwater Cyanobacterium Aphanizomenonmethylisoureaoxidationmonosulfationepicylindrospermopsincyclic urea 47Absolute Configurationdiol 60cylindrospermopsincarbonylationheptanesynthesiscondensationazahydrolysisazide 54appendageconversioncyclizationEpicylindrospermopsinaldehyde 20uraciltricyclic nucleus 59E nitrones 38