Total Synthesis of (−)-7-Epicylindrospermopsin, a Toxic Metabolite of the Freshwater Cyanobacterium <i>Aphanizomenon </i><i>o</i><i>valisporum</i>, and Assignment of Its Absolute Configuration

2005-03-18T00:00:00Z (GMT) by James D. White Joshua D. Hansen
The <i>Z</i> and <i>E</i> nitrones <b>38</b> and <b>39</b> from condensation of aldehyde <b>20</b> with hydroxylamine <b>36</b> underwent intramolecular dipolar cycloaddition to give the substituted 1-aza-7-oxobicyclo[2.2.1] heptanes <b>40</b> and <b>41</b> in a ratio of 2:1, respectively. Reductive N−O bond cleavage of <b>40</b> followed by carbonylation gave cyclic urea <b>47</b> in which inversion of the secondary alcohol was effected via an oxidation−reduction sequence. After conversion of the <i>p</i>-bromobenzyl ether <b>50</b> to azide <b>54</b>, activation of the cyclic urea as its <i>O</i>-methylisourea and reduction of the azide led to spontaneous cyclization to afford the tricyclic nucleus <b>59</b> of cylindrospermopsin. Global deprotection, including hydrolysis of the 2,4-dimethyoxypyrimidine appendage to a uracil, and then monosulfation of the resultant diol <b>60</b> afforded a substance identical with natural (−)-7-epicylindrospermopsin (<b>1</b>). The asymmetric synthesis of (−)-7-epicylindrospermopsin defines its absolute configuration as 7<i>S</i>,8<i>R</i>,10<i>S</i>,12<i>S</i>,13<i>R</i>,14<i>S</i>.