Oligo(N-aryl glycines): A New Twist on Structured Peptoids

• DOI: 10.1021/ja804580n
• Publication Date: 2008-12-01T21:46:48Z
• Authors: Neel H. Shah; Glenn L. Butterfoss; Khanh Nguyen; Barney Yoo; Richard Bonneau; Dallas L. Rabenstein; Kent Kirshenbaum
• Keywords: Models, Molecular; Biomimetics; N-substituted Glycines; Polymers; Acetanilides; Computer Simulation; Stereoisomerism; Amides; 01 natural sciences; Protein Structure, Secondary; 0104 chemical sciences

We explore strategies to enhance conformational ordering of N-substituted glycine peptoid oligomers. Peptoids bearing bulky N-alkyl side chains have previously been studied as important examples of biomimetic "foldamer" compounds, as they exhibit a capacity to populate helical structures featuring repeating cis-amide bonds. Substantial cis/trans amide bond isomerization, however, gives rise to conformational heterogeneity. Here, we report the use of N-aryl side chains as a tool to enforce the presence of trans-amide bonds, thereby engendering structural stability. Aniline derivatives and bromoacetic acid are used in the facile solid-phase synthesis of a diverse family of sequence-specific N-aryl glycine oligomers. Quantum mechanics calculations yield a detailed energy profile of the folding landscape and substantiate the hypothesis that the presence of anilide groups establishes a strong energetic preference for trans-amide bonds. X-ray crystallographic analysis and solution NMR studies verify this preference. Molecular modeling indicates that the linear oligomers can adopt helical structures resembling a polyproline type II helix. High resolution structures of macrocyclic oligomers incorporating both N-alkyl and N-aryl glycine units confirm the ability to direct the presence of trans-amide bonds specifically at N-aryl positions. These results are an important step in developing strategies for the rational de novo design of new structural motifs in biomimetic oligopeptoid systems.