Chirality and template-mediated induction of helical preferences in achiral β-peptides.

This study describes chirality- or template-mediated helical induction in achiral beta-peptides for the first time. A strategy of end capping beta-peptides derived from beta-hGly (the smallest achiral beta-amino acid) with a chiral beta-amino acid that possesses a carbohydrate side chain (beta-Caa; C-linked carbo beta-amino acid) or a small, robust helical template derived from beta-Caas, was adopted to investigate folding propensity. A single chiral (R)-beta-Caa residue at the C- or N-terminus in these oligomers led to a preponderance of right-handed 12/10-helical folds, which was reiterated more strongly in peptides capped at both the C- and N-terminus. Likewise, the presence of a template (a 12/10-helical trimer) at both the C- and N-terminus resulted in a very robust helix. The propagation of the helical fold and its sustenance was found in a homo-oligomeric sequence with as many as seven beta-hGly residues. In both cases, the induction of helicity was stronger from the N terminus, whereas an anchor at the C terminus resulted in reduced helical propensity. Although these oligomers have been theoretically predicted to favor a 12/10-mixed helix in apolar solvents, this study provides the first experimental evidence for their existence. Diastereotopicity was found in both the methylene groups of the beta-hGly moieties due to chirality. Additionally, the beta-hGly units have shown split behavior in the conformational space to accommodate the 12/10-helix. Thus, end capping to assist chiralty- or template-mediated helical induction and stabilization in achiral beta-peptides is a very attractive strategy.