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

N-tert-butyl-glycine (NtBu) is a known peptoid structure-inducing monomer. The hindered tert-butyl group exerts a major effect on the cis/trans isomerization of the NX-NtBu peptoid-amide bond, which adopts exclusively the cis-geometry. Incorporating this monomer into peptoid oligomers is therefore an excellent way of promoting specific secondary structures such as turns and polyproline type-I helices. However, the steric hindrance of the tert-butyl group has so far prevented the solid-phase synthesis of peptoid oligomers incorporating NtBu monomers. We report here for the first time solid-phase syntheses of NtBu-containing peptoids using a modified submonomer protocol. We have found that the success of the critical DIC-mediated acylation step depends on the addition of a base and/or basic pretreatment of the resin prior to the reaction. The use of chloroacetic acid instead of bromoacetic acid also improved the efficacy of the syntheses, as did a halogenoacetic acid preactivation stage. To demonstrate the effectiveness of the modified submonomer protocol, we synthesized homooligomers at sequence lengths of up to 12-mer and also applied it to the synthesis of various peptoids with highly congested NCα-gem-dimethyl side chains.