An easy access to bioactive 13-hydroxylated and 11,13-dihydroxylated sesquiterpene lactones (SLs) through Michael addition of a nucleophilic hydroxyl group

The addition of a hydroxyl group to α,β-unsaturated carbonyl systems provides a new and easy access to bioactive difunctionalized sesquiterpene lactones (SLs) through a Michael addition to the α-methylene-γ-lactone system. The use of HMPA to enhance the nucleophilic properties of the hydroxyl groups and to stabilize the enolate is discussed. Also, we present a proposal for the mechanism based on the experimental data obtained. The scope and usefulness of the reaction are explored with other substrates and is limited by the need for a certain level of steric hindrance to avoid chain polycondensations. Nevertheless, the reaction works with esters, ketones and aldehydes. The absolute stereochemistry of some products has been elucidated by X-ray diffraction analysis. The synthesis of a natural SL using this methodology and the correction of the structure of another illustrate the usefulness of this reaction.