Solid-Phase Synthesis of Peptoid Oligomers Containing Crowded tert-Butyl Side Chains

Area of Science:

• Peptide and Peptidomimetic Chemistry
• Polymer Synthesis
• Organic Chemistry

Background:

• N-tert-butyl-glycine (NtBu) is a peptoid monomer known to induce specific secondary structures.
• The steric bulk of the tert-butyl group favors cis-amide bond geometry, promoting turns and helices.
• Previous solid-phase synthesis of NtBu-containing peptoids was hindered by steric challenges.

Purpose of the Study:

• To report the first successful solid-phase synthesis of NtBu-containing peptoids.
• To develop and optimize a modified submonomer protocol for incorporating NtBu monomers.
• To demonstrate the protocol's effectiveness with various challenging peptoid sequences.

Main Methods:

• Utilized a modified submonomer protocol for solid-phase synthesis.
• Optimized the DIC-mediated acylation step by adding a base or basic resin pretreatment.
• Employed chloroacetic acid instead of bromoacetic acid and included a halogenoacetic acid preactivation step.

Main Results:

• Successfully synthesized NtBu-containing homooligomers up to a 12-mer length.
• Demonstrated the protocol's applicability to synthesizing peptoids with highly congested side chains.
• Identified key modifications for successful acylation and improved synthesis efficacy.

Conclusions:

• The modified submonomer protocol enables efficient solid-phase synthesis of NtBu-containing peptoids.
• This advancement allows for the construction of complex peptoid structures previously inaccessible.
• The protocol opens new avenues for exploring peptoid-based materials and therapeutics.