Copper(II) trifluoromethanesulfonate-induced cleavage oxygenation of allylic hydroperoxides derived from qinghao acid in the synthesis of qinghaosu derivatives: Evidence for the intermediacy of enols

Article abstract of DOI:10.1021/ja00150a009

The semisynthesis of qinghaosu (artemisinin) derivatives from qinghao (artemisinic) acid and related compounds is gaining increasing importance despite the fact that the key step in the transformation, the cleavage oxygenation of the intermediate allylic hydroperoxides to form peroxy hemiacetals, is not well understood. It has been found that the allylic hydroperoxide 10 derived from the methyl ester of qinghao acid under catalysis by trifluoromethanesulfonic acid (TfOH) in CH₂Cl₂ or copper(II) trifluoromethanesulfonate [Cu(OTf)₂] in MeCN forms a thermally labile intermediate. Chromatographic isolation of the intermediate at low temperature and analysis by low-temperature ¹H and ¹³C NMR spectroscopies showed it to be the simple enol 16a, a compound possessing unexpected stability. The enol 16a undergoes autoxidation at room temperature or facile oxygenation at -20°C in the presence of Cu(II) and oxygen to give the peroxy hemiacetal 12. Thus, the catalyzed cleavage of cyclic allylic hydroperoxides proceeds via enol intermediates and it would seem that the propensity for subsequent oxygenation is related to the stability of the enol.