Solution-Phase Synthesis of Sequence-Specific Peptoids Using a Rink Amide Soluble Support

Abstract Peptoids (N-substituted glycines) are a promising material platform for next-generation biomedical applications, as control over monomer sequence enables the design of functional materials with defined morphologies, which in turn allow for precise interactions with biological targets. Traditional synthetic approaches for peptoids suffer from a tradeoff between scalability and synthetic versatility. Solid-phase submonomer synthesis methods facilitate sequence specificity and side chain diversity but require large reagent excesses and remain challenging to monitor. Meanwhile, solution-phase methods have limited sequence definition and intensive purification requirements. Here, we present a Rink amide soluble support to synthesize peptoids via the submonomer method using reduced reagent excesses and a simple workup procedure while supporting iterative synthesis of diverse linear and cyclic peptoid architectures. This solution-phase approach allows for real-time reaction monitoring via ReactIR and mass spectrometry. The Rink amide soluble support is a flexible platform that bridges the gap between solid- and solution-phase methods and can simplify synthesis in future peptoid studies.