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

Koba, Yurie; Ueda, Atsushi; Oba, Makoto; Doi, Mitsunobu; Kato, Takuma; Demizu, Yosuke; Tanaka, Masakazu

doi:10.1021/acs.orglett.8b03331

Cited by 7 publications

(3 citation statements)

References 48 publications

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“…Accordingly, carbocyclic α,α-disubstituted α-amino acids (dAAs) , are suitable for this purpose. Furthermore, carbocyclic dAAs enhance the efficacy of the peptide coupling reaction, , while side-chain stereogenic centers control the helical screw direction and the secondary structure of their peptides . We have recently reported the synthesis of l -arginine-enriched stapled peptides containing 3-allyloxy-1-aminocyclopentanecarboxylic acids (Ac 5 c 3OAll ) possessing a high cell permeability and a high stability against peptidases .…”

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confidence: 99%

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

et al. 2022

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We present an E-selective ring-closing metathesis reaction in α-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic α,α-disubstituted α-amino acids, (1S,3S)-Ac5c3OAll and (1R,3S)-Ac5c3OAll, provides a high E-selectivity of a ≤59:1 E:Z ratio, while mixtures with E:Z ratios of 2.1–0.5:1 were produced with standard acyclic (S)-(4-pentenyl)alanine amino acids. A stapled octapeptide composed of (1S,3S)- and (1R,3S)-Ac5c3OAll amino acids showed a right-handed α-helical crystal structure.

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confidence: 99%

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

et al. 2022

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“…In the crystal structure of a pentapeptide of a ribose-derived amino acid, a fully extended 2.0 5 -helix was evident with each C5 interaction accompanied by a C6γ N–H···O (acetal) H-bond, implicating the ring oxygen of each ( i − 1) residue ( Figure 1 d) [ 31 ]. In contrast, for Ac n c oligomers with exocyclic ether functions whose oxygen atoms occupy the δ-position, the conformational preferences reverted to the helical mode; the pentapeptide of an Ac 3 c bearing two methoxymethyl substitutents adopted a bent 3 10 -helix in which one N–H···O=C interaction was replaced by a 10-membered ring N–H···O (ether) H-bond [ 32 ], while the trimer of Ac 6 c bearing a spiroacetal at the ring 3-position adopted a helical shape, devoid of backbone N–H···O=C interactions, stabilized only by intraresidue C6δ N–H···O(acetal) H-bonds [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds

et al. 2023

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Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain–backbone N–H···N C6γ H-bonds that accompany—and thereby stabilize—C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

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“…From this point of view, the introduction of allyl tethered cis -4-hydroxy- l -proline or ( R )-α-allyl-proline can be suitable for this purpose. Secondary structures, as well as helical screw directions, can be controlled by introducing 1-aminocycloalkane-1-carboxylic acid in homopeptides [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ] and heteropeptides [ 41 , 42 , 43 ], and these constrained peptides catalyze asymmetric 1,4-addition reactions [ 44 , 45 , 46 ]. Therefore, poly l -leucine-incorporating 1-aminocyclopentane-1-carboxylic acid was used as an α-helix-inducing motif.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Helical N-Terminal l-Prolyl Oligopeptides Possessing Hydrocarbon Stapling

et al. 2020

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We designed and synthesized helical short oligopeptides with an l-proline on the N-terminus and hydrocarbon stapling on the side chain. Side-chain stapling is a frequently used method for the development of biologically active peptides. Side-chain stapling can stabilize the secondary structures of peptides, and, therefore, stapled peptides may be applicable to peptide-based organocatalysts. Olefin-tethered cis-4-hydroxy-l-proline 1 and l-serine 2 and 8, and (R)-α-allyl-proline 18 were used as cross-linking motifs and incorporated into helical peptide sequences. The Z- and E-selectivities were observed for the ring-closing metathesis reactions of peptides 3 and 11 (i,i+1 series), respectively, while no E/Z-selectivity was observed for that of 19 (i,i+3 series). The stapled peptide B’ catalyzed the Michael addition reaction of 1-methylindole to α,β-unsaturated aldehyde, which was seven times faster than that of unstapled peptide B. Furthermore, the high catalytic activity was retained even at lower catalyst loadings (5 mol %) and lower temperatures (0 °C). The circular dichroism spectra of stapled peptide B’ showed a right-handed helix with a higher intensity than that of unstapled peptide B. These results indicate that the introduction of side-chain stapling is beneficial for enhancing the catalytic activity of short oligopeptide catalysts.

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

Cited by 7 publications

References 48 publications

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds

Design and Synthesis of Helical N-Terminal l-Prolyl Oligopeptides Possessing Hydrocarbon Stapling

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