Peptide foldamers composed of six-membered ring α,α-disubstituted α-amino acids with two changeable chiral acetal moieties

Abstract

Graphical AbstractTo create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.Peptide foldamers composed of six-membered ring α,α-disubstituted α-amino acids with two changeable chiral acetal moieties IntroductionConformational freedom-restricted oligopeptides have attracted the attention of organic, peptide, and medicinal chemists because they are capable of developing peptide organo-catalysts for asymmetric reactions and are also drug candidates derived from biologically active natural peptides.1 α,α-Disubstituted α-amino acids (dAAs) have been used to restrict the conformational freedom of their peptides. 2Oligopeptides incorporating α-aminoisobutyric acid (Aib; αMeAla) have been shown to preferentially form 310-/α-helical structures, whereas peptides having α-ethylated dAAs, such as diethylglycine and (S)-butylethylglycine, are more likely to assume fully planar conformations.3 Differences in secondary structures (helix and planar conformations) are determined by the peptide-backbone torsion angles φ (C'-N-Cα-C') and ψ (N-Cα-C'-N). For example, the ideal right-handed (P) 310-helix has φ −60° and ψ −30° torsion angles, the right-handed (P) α-helix has φ −57° and ψ −47°, and the fully planar conformation has φ 180° and ψ 180°. The patterns of intramolecular hydrogen bonds also differ in these secondary structures. For example, the 310-helix forms an intramolecular hydrogen bond of the N(i+3)-H···O(i)=C(i) i←i+3 type, whereas the α-helix forms an intramolecular hydrogen bond of the N(i+4)-Moreover, the fully planar conformation forms an intramolecular hydrogen bond of the C5---- * Corresponding author. Tel/fax: +81 95 819 2423; e-mail: matanaka@nagasaki-u.ac.jpBy selecting appropriate dAAs, these secondary structures are partially controlled. However, the preferential conformations of known dAAs are limited to those of helix and planar conformations. Thus, the development of new dAAs with different conformational preferences is greatly desired.One such dAA may be the achiral O,O-isopropylidene-α-hydroxymethylserine {Hms(Ipr)} reported by Toniolo, Leplawy, and co-workers. Hms(Ipr) peptides formed destabilized 310-helical structures, in which hydrogen bonds were detected between peptide main-chain NH and side-chain acetonide -O-.We recently synthesized six-membered ring dAAs with a changeable chiral acetal moiety as well as the preferred secondary structures of their peptides.5 These findings prompted us to change the position of the acetal moiety on the cyclohexane ring and increase the number of acetal moieties on the cyclic amino acid. We designed six-membered ring dAAs with two chiral acetal moieties {(R,R)- Chiral cyclic α,α-disubstituted α-amino acids with four chiral centers at their acetal moieties were synthesized. An X-ray crystallographic analysis of homo-chiral tripeptide with (2R,3R)-butane-2,3-diol acetal moieties revealed that the tripeptide formed both (P) and (M) helical structures, and all peptide main-chain N(i)-H...

Helical l–Leu‐Based Peptides Having Chiral Five‐Membered Carbocyclic Ring Amino Acids with an Ethylene Acetal Moiety

“…[22] No band at approximately 3370-3390 cm −1 , which may have been derived from the intramolecular hydrogen bonds of the N-H···-O-(acetal) type, was observed. [23,24] In tripeptides 3a and 3b, no band or a very weak band was observed at approximately 3350 cm −1 . These results suggest that the β-turn structure (the peptide N-H group with N-H···O=C intramolecular hydrogen bond) was not formed or unstable in the CDCl 3 solution of 3.…”

“…[23] On the other hand, homopeptides (hepta-and octapeptides) composed of the five-membered carbocyclic ring amino acid (R)-Ac 5 c 3EG with an acetal moiety at the γ-position showed left-handed (M) helical structures in solution without the N(i)-H···-O-(i, acetal)-type intramolecular hydrogen bond. [20] The carbocyclic ring size difference of dAAs may affect the distance of N(i)-H and -O-(i, acetal), and the intramolecular hydrogen bond pattern may be different.…”

Synthesis of chiral five‐membered carbocyclic ring amino acids with an acetal moiety and helical conformations of its homo‐chiral homopeptides

“…This band was attributed to the peptide NH group with intramolecular hydrogen bonds between peptide N–H and acetal –O– (ether). This band was observed in the Ac 6 c 3, 5Bu homopeptides having acetal moieties …”

“…The preferred structure of peptides composed of the six‐membered ring amino acid ( R , R )‐Ac 6 c 3, 5Bu bearing acetal moieties at the γ‐position was a helical structure with the intramolecular hydrogen bonds of the N( i )–H···–O– ( i , acetal) type both in solution and a crystal state . On the other hand, peptides composed of the five‐membered carbocyclic ring amino acid ( R )‐Ac 5 c 3EG with a γ‐acetal moiety showed no intramolecular hydrogen bond of the N( i )–H···–O– ( i , ether) type.…”

“…We recently designed and synthesized the six‐membered ring amino acid Ac 6 c 4Bu with a changeable chiral acetal moiety, as well as the cyclic amino acid Ac 6 c 3, 5Bu with two chiral acetal moieties (Figure ) . In these six‐membered ring amino acids, the α‐carbon atom was not a chiral center, whereas the side‐chain acetal moiety had chiral centers.…”