First Series of -alkylamino Peptoid Homooligomers: Solution Phase Synthesis and Conformational Investigation

The synthesis and conformational analysis of the first series of peptoid oligomers composed of consecutive -(alkylamino)glycine units is investigated. We demonstrate that -(methylamino)glycine homooligomers can be readily synthesized in solution using -Boc--methylhydrazine as a peptoid submonomer and stepwise or segment coupling methodologies. Their structures were analyzed in solution by 1D and 2D NMR, in the solid state by X-ray crystallography (dimer ), and implicit solvent QM geometry optimizations. -(Methylamino)peptoids were found to preferentially adopt amide bonds with the side chain N-H bonds oriented approximately perpendicular to the amide plane. This orientation is conducive to local backbone stabilization through intra-residue hydrogen bonds but also to intermolecular associations. The high capacity of -(methylamino)peptoids to establish intermolecular hydrogen bonds was notably deduced from pronounced concentration-dependent N-H chemical shift variation in H NMR and the antiparallel arrangement of mirror image molecules held together via two hydrogen bonds in the crystal lattice of dimer .