On‐Resin Recycling of Acid‐Labile Linker Enables the Reuse of Solid Support for Fmoc‐Based Solid Phase Synthesis

In this study, the first recyclable and reusable polystyrene solid support (resin with functional linker) for Fmoc-based solid phase synthesis (SPS) for the synthesis of sequence-defined oligoamides and peptides is presented. By introducing an acid-labile cyclic acetal linker, efficient oligomer cleavage under mildly acidic conditions comparable to conventional linkers is achieve while also enabling efficient on-resin regeneration of the linker. This regeneration ability allows the support to be reused for multiple synthesis cycles without compromising the flexibility, high reproducibility, and structural control inherent to solid-phase synthesis. As a proof of concept, the robustness of this approach is demonstrated by synthesizing different dimeric structures in an alternating manner on the same resin. For each cycle, the oligomer is first elongated through building block coupling, followed by cleavage from the solid support to release the product. The linker is then regenerated on the functionalized solid support, allowing the cycle to be repeated for the synthesis of subsequent oligomers. This approach maintains high yields and purity across multiple cycles, illustrating the potential as a versatile and more sustainable methodology for Fmoc-based solid phase synthesis.