Peptide Mimics by Linear Arylamides: A Structural and Functional Diversity Test

Abstract

Hydrogen-bonded oligoamide foldamers represent a large family of peptide mimics. Pioneered by Gellman and Seebach (Appella , J. Am. Chem. Soc. 1996, 118, 13071- 13072; Seebach , Helv. Chim. Acta 1996, 79, 913- 941), aliphatic amino acid-based mimic structures have been extensively studied. Results of these studies have found many useful applications in areas including chemical biology and drug design. This Account describes our efforts in creating arylamide-based foldamers whose compact conformations are stabilized by hydrogen bonding. The aim of our study was to test whether this class of mimic structures is sufficiently rigid to lead to new interesting functions. It was envisioned that, if our approach was workable, it might be developed into a new family of useful soft frameworks for studies toward molecular recognition, self-assembly, and materials science. Three classes of mimic structures, that is, folded or helical, zigzag, and straight oligomers, have been constructed by simply changing the positions of the substituents at the benzene rings in the backbones. Both amide and hydrazide units have been employed to construct the frameworks. In most cases, O...H-N hydrogen bonding was chosen to stabilize the compact conformations. Notably, for the first time the F...H-N hydrogen-bonding pattern has been used to tune the size of the cavity. To test their usefulness, these frameworks have been extensively modified and functionalized. (1)H NMR, UV-vis, fluorescence, circular dichroism, and X-ray diffraction techniques have all been employed to establish the compact structures and their interactions with guest molecules. The properties or functions of the mimic structures have been studied in seven aspects. (1) Acyclic molecular receptors: The amide foldamers can bind amine cations, while the hydrazide foldamers can complex saccharides. (2) Acceleration of anisole hydrolysis: Several folded oligomers are able to bind alkali metal cations and consequently promote the hydrolysis of the nitro-substituted anisole by alkali hydroxides. (3) Facilitation of macrocyclization: The straight and zigzag backbones can be readily functionalized, from which two classes of macrocycles have been prepared. (4) Homoduplex assembly: Zigzag oligomers that are appended with amide units at one side can form stable homoduplexes through the cooperative self-binding of the amide units. (5) Assembly of molecular tweezers: Discrete binding moieties are introduced at the ends of the oligomers, which can bind structurally matched guests. (6) Assembly of nano networks: F...H-N hydrogen-bonded foldamers can stack with fullerenes; thus a mixture of fullerenes with a trifoldamer generates honeycomb-styled nanoarchitectures. (7) Assembly of dynamic [2]catenanes: A preorganized porphyrin tweezer has been synthesized, from which dynamic three-component [2]catenanes have been assembled in high yields. Our results demonstrate that hydrogen-bonding-driven arylamide oligomers are a class of structurally unique mimic structures. The folded oligomers themselves can be used as synthetic receptors for binding different guest molecules, while incorporation of different segments into one system can produce many desired shapes. In addition, all of the rigid frameworks can be readily functionalized at specific sites. We believe that our results have helped to open the door for some new chemistry in molecular recognition, self-assembly, and other related areas.