Solid-phase synthesis of a library of linear oligoester ion-channels

A solid-phase synthesis protocol was used to prepare fifteen new linear tetra-, and penta-esters structurally related to an active lead compound. The structures were assembled from three types of hydroxyl protected building blocks: monoalkyl esters of hydroxyglutaric acid, omega-hydroxyacids, and alpha-hydroxymethylalkanoic acids. The standard methodology gave acceptable quantities of material free of small molecule impurities. Mass spectrometric analysis revealed the presence of deletions due to incomplete coupling, as well as additions and macrolactones due to partial acidic rearrangement on release from the solid-support. The amount of these impurities could be estimated from the (1)H NMR spectra, and their implications for subsequent activity analysis are discussed.