Next Generation Reusable Solid Support for Fmoc‐Based Solid‐Phase Synthesis

This study presents an efficient strategy for reusing polystyrene‐based solid supports for Fmoc‐based solid‐phase synthesis (SPS). In our previously established system, regeneration of the cleavable cyclic acetal linker required a two‐step process and was limited by on‐resin hydrolysis, reducing overall efficiency. To overcome these limitations, we redesigned the system by inverting the placement of the key functional groups—now immobilizing a stable diol moiety on the resin and introducing a second, soluble building block containing a preactivated dimethyl acetal moiety. This approach enables single‐step linker regeneration, eliminates hydrolysis‐prone intermediates, and improves synthetic efficiency. Additionally, the system generates oligomers bearing a terminal aldehyde group upon cleavage, providing a versatile handle for post‐synthetic bioconjugation. With our new system, we achieved near‐quantitative linker regeneration yields (98%) under mild conditions, reducing the building block amount by 75% and shortening the reaction time by 50%. We further demonstrate the robustness of this system by synthesizing multiple structurally distinct tetrameric oligomers—including an oligoamidoamine, peptide, and a hybrid oligoamide–peptide structure—in consecutive cycles with consistently high linker generation yields and purity on the same resin.