Microwave heating for solid-phase peptide synthesis: General evaluation and application to 15-mer phosphopeptides

Here we present a comprehensive study of microwave heating in manual solid-phase peptide synthesis. Three different solid Supports and three different handles (linkers) were evaluated for the synthesis of one short and two medium length peptides, including a phosphopeptide. Microwave heating to 60 degrees C was applied to different kinds of amide bond formation, reductive amination, removal of the Fmoc protecting group, and to the acidolytic release of peptides from different handles. Using microwave heating, reaction times were significantly reduced, while maintaining the high purity of the crude products. However, control experiments showed that reaction times as short as 3-4 min at rt, at least for some applications, are sufficient for acylations (couplings). While microwave heating can be used in all steps in solid-phase peptide synthesis, particularly relatively slow steps benefit from this method.