Diffusion-Enhanced Amide Bond Formation on a Solid Support

Mixing of polystyrene resins in solid-phase synthesis\nis performed\nby shaking or gentle agitation of the reaction vessel to avoid breaking\nthe brittle beads. These mixing strategies result in poor diffusion\nto and into the beads. Using a large excess of reagents is the common\nway to compensate for these deficiencies. We use fast overhead stirring\nfor performing coupling reactions on a solid support. We show that\nfast overhead stirring enhances the efficiency of amide bond formation\non the solid support compared to the state-of-the-art mixing method,\nwhile preserving the integrity of the beads. We find that fast overhead\nstirring minimizes the effect of decomposition of the activated species\nby increasing the diffusion-dependent coupling reaction. This allows\ndecreasing the excess of reagents used for the multistep synthesis\nof peptides, thus providing a greener and more sustainable alternative\nfor peptide synthesis on solid supports.