Gem-dimethyl peptide nucleic acid (α/β/γ-gdm-PNA) monomers: synthesis and the role of gdm-substituents in preferential stabilisation of Z/E-rotamers

Abstract

The flexible backbone of aminoethylglycine (aeg) PNA upon substitution becomes sterically constrained to enable conformational pre-organization for preferential binding to DNA or RNA. The bulky gem-dimethyl (gdm) substituent on carbons adjacent to the t-amide sidechain either at Cα (glycyl) or Cβ/Cγ (aminoethylene) sides may influence the Z/E rotamer ratio arising from a restricted rotation around the t-amide bond. Employing 2D NMR (NOESY), it is shown here that the Cα-gdm-PNA-T monomer exhibits exclusively the Z-rotamer, while the Cβ-gdm-PNA-T monomer shows only the E-rotamer. The unsubstituted aeg-PNA-T and Cγ-gdm-PNA-T monomers display a mixture of Z/E rotamers. The rotamers with t-amide carbonyl pointing towards the gem-dimethyl group always prevailed. The results are supported by computational studies that suggested that the preferred rotamers are the outcome of a net energetic benefit from the stabilising n–π* interactions of carbonyls (amide backbone and t-amide sidechain), and C–H⋯O interactions and the destabilising steric clash of gem-dimethyl groups with the t-amido methylene group. The E-rotamer structure in Cγ-gdm is also characterised by X-ray crystallography. The exclusive E-rotamer for the Cβ-gdm monomer seen in solution here is the first such example among several modified PNA monomers. Since the conformation of the sidechain is important for inducing base stacking and effective base pairing, the exclusive E-rotamer in the Cβ-gdm monomer may have significance in the properties of the derived PNA : DNA/RNA duplexes with all E-rotamers.