External Chirality-Triggered Helicity Control Promoted by Introducing a β-Ala Residue into the N-Terminus of Chiral Peptides

The noncovalent chiral domino effect (NCDE), defined as chiral interaction upon an N-terminus of a 3<INF>10</INF>-helical peptide, will provide a unique method for structural control of a peptide helix through the use of external chirality. On the other hand, the NCDE has not been considered to be effective for the helicity control of peptides strongly favoring a one-handed screw sense. We here aim to promote the NCDE on peptide helicity using two types of nonapeptides:  H-β-Ala-Δ^ZPhe-Aib-Δ^ZPhe-X*-(Δ^ZPhe-Aib)<INF>2</INF>-OCH<INF>3</INF> [Δ^ZPhe = α,β-didehydrophenylalanine, Aib = α-aminoisobutyric acid], where X* as the single chirality is <SCP>l</SCP>-leucine (<BO>1</BO>) or <SCP>l</SCP>-phenylalanine (<BO>2</BO>). NMR, IR, and CD spectroscopy as well as energy calculation revealed that both peptides alone form a right-handed 3<INF>10</INF>-helix. The original CD amplitudes or signs in chloroform, irrespective of a strong screw-sense preference in the central chirality, responded sensitively to external chiral information. Namely added Boc-<SCP>l</SCP>-amino acid stabilized the original right-handed helix, while the corresponding <SCP>d</SCP>-isomer destabilized it or transformed it into a left-handed helix. These peptides were also shown to bind more favorably to an <SCP>l</SCP>-isomer from the racemate. Although similar helicity control was observed for analogous nonapeptides bearing an N-terminal Aib residue (Inai, Y.; et al. Biomacromolecules <BO>2003</BO>, 4, 122), the present findings demonstrate that the N-terminal replacement by the β-Ala residue significantly improves the previous NCDE to achieve more effective control of helicity. Semiempirical molecular orbital calculations on complexation of peptide <BO>2</BO> with Boc-(<SCP>l</SCP> or <SCP>d</SCP>)-Pro-OH reasonably explained the unique conformational change induced by external chirality.