Solid-Phase Synthesisof Peptoid Oligomers ContainingCrowded <i>tert</i>-Butyl Side Chains

<i>N</i>-<i>tert</i>-butyl-glycine (<i>Nt</i>Bu) is a known peptoid structure-inducing monomer. The hindered <i>tert</i>-butyl group exerts a major effect on the <i>cis</i>/<i>trans</i> isomerization of the <i>N</i>X-<i>Nt</i>Bu peptoid-amide bond, which adopts exclusively the <i>cis</i>-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 <i>tert</i>-butyl group has so far prevented the solid-phase synthesis of peptoid oligomers incorporating <i>Nt</i>Bu monomers. We report here for the first time solid-phase syntheses of <i>Nt</i>Bu-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 <i>NC</i>α<i>-gem</i>-dimethyl side chains.