A New Class of Folding Oligomers:  Crescent Oligoamides

Abstract

The assembly of well-defined protein secondary structures, leads to a bewildering array of tertiary structures. 1 As the first step toward developing artificial oligomers and polymers that fold like biomacromolecules, there is currently an intense interest in designing unnatural building blocks that adopt well-defined secondary structures. 2,3 Here we report a new class of oligoamides with backbones that adopt well-defined, crescent conformations.Our design is based on diaryl amide oligomers, shown as 1. The presence of the three-center hydrogen bonding system consisting of the S(5) and S(6) type 4 intramolecularly hydrogen bonded rings should lead to rigidification of the amide linkage. Oligoamides containing such amide linkages should have a rigid backbone. With the two amide linkages on the same benzene ring being meta to each other, the resulting oligomer should have a crescent conformation. 5 Ab initio molecular orbital calculations (in vacuo) were performed on amide 2. 6 Conformations 2a-b are constrained to be planar. The relative energy of each conformation is shown in parentheses. The computational results indicated significant differences in the relative energies of the four conformations: 2 was overwhelmingly favored over the alternative conformations 2a,b. The desired conformation, 2, was planar and had two strong intramolecular hydrogen bonds with O‚‚‚H ) 1.87 Å (S(6)) and 2.14 Å (S(5)), respectively.

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“…However, the crystal structures of 2b, 4c, 5b, and, as shown in Fig. 4, 8 and 9, and two other short oligomers previously reported by us (12) revealed that the two amide bond angles, ␣ (aryl-N-C(O)) and ␤ (N-C(O)-aryl), deviate from 120°(␣ Ϸ 127°, ␤ Ϸ 117°), resulting in the curving of the amide linkages toward the NH side. Such slightly curved amide linkages appear to be responsible for the ''opening up'' of the backbone of 2b.…”

“…Our previous studies have demonstrated that short oligomers with m-backbones adopt a well-defined crescent conformation (12,19,20). Our results indicated that the three-center hydrogen-bonding system, consisting of the S(5) and S(6) type (21) hydrogen-bonded rings, was particularly stable in the solid state and in solution (19,20).…”

“…Strong nuclear Overhauser enhancements (NOEs) exist between each of their amide NH signals and the protons of the methyl, or ␣͞␤-methylene of the two substituents on the S(5) and S(6) type hydrogen-bonded rings (see supporting information). These NOEs, which are typical for these three-center hydrogen bonds (12,19,20), suggest that the backbones of both 2a and 3 are rigidified and adopt crescent conformations. An obvious and significant difference is observed when comparing the NOESY spectra of 2a and 3: while an obvious NOE between the end methyl protons and the aromatic Hb1, and a weaker contact between the end methyl H atoms and the amide Hb, can be detected for 2a (Fig.…”

“…All compounds described herein gave satisfactory NMR and electrospray ionization (ESI) MS results consistent with their structures. The short oligomer intermediates were prepared by iterative coupling steps based on similar procedures described before (12).…”

“…In recent years there has been intense interest in developing folding oligomers and polymers (foldamers) with unnatural backbones that adopt well-defined structures (1-3), which may eventually lead to protein-like molecular objects with sizes in the nanometer range. Many foldamer systems have been described (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Despite the progress made so far, the foldamer field is still in its infancy.…”