Stapling strategy for slowing helicity interconversion of α-helical peptides and isolating chiral auxiliary-free one-handed forms.

In nature, α-helical peptides adopt right-handed conformations that are dictated by L-amino acids. Isolating one-handed α-helical peptides composed of only achiral components remains a significant challenge. Here, this goal is achieved by optical resolution of the corresponding racemic (quasi-)static α-helical peptide with double stapling, which effectively freezes the interconversion between the right-handed (P)- and left-handed (M)-α-helices. An as-obtained doubly stapled analogue having an unprotected L-valine residue at the C-terminus transforms from a kinetically trapped (M)-α-helix to a thermodynamically stable (P)-α-helix upon heating. In contrast, the corresponding singly stapled α-helical peptide undergoes an acid/base-triggered and solvent-induced reversible inversion of its preferred helicity within minutes. The interconversion rates of the singly and doubly stapled α-helical peptide foldamers are approximately 10 6 and 10 12 times slower, respectively, than that of a non-stapled dynamic helical peptide. Therefore, the enantiopure doubly-stapled (quasi-)static α-helical peptide would retain its optical activity for several years at 25 °C.