Sebastian Bell, BSc
New York University
Optimizing Photolabile Resins for Peptoid Synthesis
Due to the basic nature of standard submonomer solid-phase peptoid (N-substituted glycine) synthesis, the base-lability orthogonality available for peptide synthesis is lost. Current methods rely on various acidic conditions for resin cleavage, with cleavage limited to 1-95% trifluoroacetic or acetic acid, or specific chemical orthogonalities. This has led to challenges in the synthesis of acid-sensitive peptoids, which show degradation at 1% TFA cleavage. With growing calls to phase out TFA due to environmental concerns, alternative solid-phase supports for peptoid synthesis may offer solutions to these problems.
Nitrobenzyl-based resins allow for the selective cleavage of attached compounds under UV light while maintaining stability under both acidic and basic conditions. Although used frequently in peptide synthesis, they have seen very limited use in peptoid synthesis. This work sets out to adapt the submonomer synthesis to photolabile resins, offering several benefits over conventional resins. A low-cost method for benchtop cleavage was optimized for peptoid release. A wide array of peptoids with various applications were successfully synthesized with high crude purities, including acid-sensitive peptoids, and novel peptoid architectures using orthogonal protecting groups. The possibility of minimally invasive peptoid release from resins has exciting implications for synthetic versatility, biological release of peptoids, and high-throughput screening methods.
Due to the basic nature of standard submonomer solid-phase peptoid (N-substituted glycine) synthesis, the base-lability orthogonality available for peptide synthesis is lost. Current methods rely on various acidic conditions for resin cleavage, with cleavage limited to 1-95% trifluoroacetic or acetic acid, or specific chemical orthogonalities. This has led to challenges in the synthesis of acid-sensitive peptoids, which show degradation at 1% TFA cleavage. With growing calls to phase out TFA due to environmental concerns, alternative solid-phase supports for peptoid synthesis may offer solutions to these problems.
Nitrobenzyl-based resins allow for the selective cleavage of attached compounds under UV light while maintaining stability under both acidic and basic conditions. Although used frequently in peptide synthesis, they have seen very limited use in peptoid synthesis. This work sets out to adapt the submonomer synthesis to photolabile resins, offering several benefits over conventional resins. A low-cost method for benchtop cleavage was optimized for peptoid release. A wide array of peptoids with various applications were successfully synthesized with high crude purities, including acid-sensitive peptoids, and novel peptoid architectures using orthogonal protecting groups. The possibility of minimally invasive peptoid release from resins has exciting implications for synthetic versatility, biological release of peptoids, and high-throughput screening methods.
