Sidechain-Backbone Tetrel Bonding Interactions Provide a General Mechanism for trans-Peptoid Stabilization.

Cis-trans isomerization of amide bonds impedes de novo design of folded peptoids (poly-N-substituted glycines) with precise secondary structures and affects peptoid-biomolecule binding affinity. Herein, from X-ray, NMR and DFT studies of azapeptoids, we have discovered a tetrel bonding interaction that stabilizes trans-peptoids. We show that peptoids having α-heteroatoms and N-aryl groups in the sidechain adopt trans-amide geometries due to the presence of a nX /πAr →σ*Cα-N tetrel bonding interaction between the sidechain α-heteroatom lone pair (nX ) or π-electrons (πAr ) and the σ* orbital of the backbone Cα -N bond. Further, CD spectroscopic studies of oligo-proline host-guest model peptides showed that azapeptoid residues stabilize polyproline II helical conformation. These data indicate that the sidechain-backbone tetrel bonding could be leveraged to design peptoids with precise secondary structures for a wide range of biological and material applications.

Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers.

We report the solid-phase synthesis of N,N'-di(acylamino)-2,5-diketopiperazine, an acylhydrazide-based conformationally rigid 2,5-DKP scaffold having exocyclic N-N bonds. We also show that different combinations of acylhydrazides, carbazates, semicarbazides, amino acids, and primary amines can be used to synthesize a highly diverse collection of hybrid DKP molecules via the solid-phase submonomer synthesis route. Finally, we show incorporation of a methyl substituent in one of the carbon atoms of the DKP ring to generate chiral daa- and hybrid-DKPs without compromising the synthetic efficiency.

Stabilization of Azapeptides by Namide···H-Namide Hydrogen Bonds.

An unusual Namide···H-Namide hydrogen bond (HB) was previously proposed to stabilize the azapeptide ß-turns. Herein we provide experimental evidence for the Namide···H-Namide HB and show that this HB endows a stabilization of 1-3 kcal·mol-1 and enforces the trans-cis-trans (t-c-t) and cis-cis-trans (c-c-t) amide bond conformations in azapeptides and N-methyl-azapeptides, respectively. Our results indicate that these Namide···H-Namide HBs can have stabilizing contributions even in short azapeptides that cannot fold to form ß-turns.

Conformational control of N-methyl-N,N'-diacylhydrazines by noncovalent carbon bonding in solution.

In recent years, some X-ray structural and computational evidence has emerged for noncovalent carbon bonding (C-bond). However, evidence of C-bonds in solution is limited. Herein, from the conformational analyses of strategically designed N-methyl-N,N'-diacylhydrazines, we for the first time show that C-bonds can be modulated to control the conformational preferences of small molecules in solution. We show that unusual N(amide)C-X noncovalent carbon bonding interactions stabilize the trans-cis (t-c) amide bond rotamers of N-methyl-N,N'-diacylhydrazines over the expected trans-trans (t-t) rotamers.