Diastereomeric Right‐ and Left‐Handed Helical Structures with Fourteen (R)‐Chiral Centers

Abstract

The relationship between chiral centers and the helical-screw control of their peptides has already been reported, but it has yet to be elucidated in detail. A chiral four-membered ring α,α-disubstituted α-amino acid with a (R,R)-butane-2,3-diol acetal moiety at the γ-position, but no α-chiral carbon, was synthesized. X-ray crystallographic analysis unambiguously revealed that its homo-chiral heptapeptide formed right-handed (P) and left-handed (M) 3 -helical structures at a ratio of 1:1. They appeared to be enantiomeric at the peptide backbone, but diastereomeric with fourteen (R)-configuration chiral centers. Conformational analyses of homopeptides in solution also indicated that diastereomeric (P) and (M) helices existed at approximately equal amounts, with a slight preference toward right-handedness, and they quickly interchanged at room temperature. The circumstances of chiral centers are important for the control of their helical-screw direction.

Left-Handed Helix of Three-Membered Ring Amino Acid Homopeptide Interrupted by an N–H···Ethereal O-Type Hydrogen Bond

“…The left-handedness of the helix was exclusively controlled by the chiral centers at the side-chain β-carbons of cyclopropane. These results are in contrast to those of the uncontrolled helical screw direction of ( R , R )-Ac 4 c 3BD , ( R , R )-Ab 5,6= c, and ( R , R )-Ac 6 c 35 dBu homopeptides but are in accordance with the one-handed helical screw of ( S , S )-Ac 5 c dOM homopeptides …”

“…Homopeptides composed of a chiral five-membered ring dAA (S,S)-Ac 5 c dOM with two side chain chiral centers preferentially formed left-handed (M) helical structures without an α-chiral center. 7 Contrary to the one-handed helical structure of (S,S)-Ac 5 c dOM homopeptides, the homopeptides composed of a five,six-membered bicyclic ring dAA (R,R)-Ab 5,6= c with two side-chain chiral centers, 8 a fourmembered ring dAA (R,R)-Ac 4 c 3BD with a chiral acetal moiety, 9 or a six-membered ring dAA (R,R)-Ac 6 c 35dBu with two chiral acetal moieties 10 showed uncontrolled right-handed (P) and left-handed (M) helical-screw structures.…”

Artificial Cell-Penetrating Peptide Containing Periodic α-Aminoisobutyric Acid with Long-Term Internalization Efficiency in Human and Plant Cells

“…The incorporation of nonproteinogenic amino acids such as α,α-disubstituted amino acids (dAAs) is one molecular strategy for creating and stabilizing helical structures. − In particular, α-aminoisobutyric acid (Aib), the simplest dAA, is often utilized as a helical inducer. Peptides bearing Aib favor the formation of α- and 3 10 -helices because of the steric repulsion of the α,α-dimethyl groups. − Kodama and coworkers have demonstrated the importance of Aib residues in CPPs by replacing the Aib residues of the peptide derived from trichorovin-XIIa, a class of peptaibols, with Ala residues; Ala replacement of Aib diminished the helicity of the peptide, leading to lower cell-penetrating ability.…”

Synthetic Mitochondria-Targeting Peptides Incorporating α-Aminoisobutyric Acid with a Stable Amphiphilic Helix Conformation in Plant Cells

“…The incorporation of α,α-disubstituted α-amino acids (dAAs), such as α-aminoisobutyric acid (Aib), is a useful method for inducing and stabilizing helical conformations of peptides. − It has been reported that amphiphilic cell-penetrating peptides (CPPs) containing dAAs form stable helices, which enhance peptide uptake efficiency. − We have also reported that Aib-containing CPPs adopting helical conformations exhibit long-term internalization into both mammalian and plant cells with higher efficiency than conventional CPPs …”