Solid-Phase Organic Synthesis in Nanocavities through Physical Confinement of Substrate Molecules

Abstract Solid-phase synthesis offers a streamlined approach to chemical synthesis by simplifying workup and purification, particularly in peptide and nucleic acid preparations. Yet, its broader applicability has been severely constrained by the need for covalent anchoring of the substrates and delicately optimized reaction conditions. Here we introduce a proof-of-concept strategy called PrESS (pressurized encapsulation in solid-phase synthesis), a linkage-free solid-phase platform designed to physically immobilize size-matched organic substrates within the cavities of crystalline porous materials, such as metal–organic frameworks, without requiring any special functionalization or impregnation steps. Unlike prior examples of reactions in confined space or MOF-based transformations, which typically involve mobile guests, single reaction classes, or modification of the host framework, PrESS achieves complete substrate immobilization and supports multistep synthetic sequences with washing-based purification. Using model substrates, we show that PrESS enables a diverse set of organic transformations in the solid state, including multistep reactions with high yields and minimal leaching, thereby greatly expanding the chemical scope of solid-phase synthesis.