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 ordain conformational pre-organization for preferential binding to DNA or RNA. The bulky gemdimethyl (gdm) substitution on carbons...

Perspectives on conformationally constrained peptide nucleic acid (PNA): insights into the structural design, properties and applications

“…10). 28 Theoretical calculation confirmed the similar stability and indicated the absence of significant stabilization interactions including the n p* interaction in both rotamers. In contrast to mono-gsubstituted PNA, the helicity induction by the chirality of the gsubstituent will be absent.…”

“…The values of the torsional angle χ 1 are close to 0° in all PNA·DNA and PNA·PNA duplexes indicating the preferred Z -rotamers of the amide bond connecting the nucleobase to the PNA backbone, resulting in the side-chain CO being pointed in the C-terminus direction and interacting with the backbone CO by the n → π* interaction. Thus, any conformation constraint should observe this requirement, and an example in the case of α- gem -dimethyl PNA 27,28 has illustrated the point very well. On the other hand, locking χ 1 by replacement of the tertiary amide bond with an alkene resulted in substantial destabilization regardless of the configuration of the double bond.…”

“…4). 28 On the other hand, previous studies indicate that a mixture of Z/E rotamers are formed in the case of aegPNA monomers and dimers, [29][30][31] while only the Z-rotamers were observed in the NMR and crystal structures of PNA duplexes. 32 The steric repulsion between the a-gem-dimethyl substituent and the CH 2 B on the tertiary amide group favored the formation of the Z-rotamer, which was also further stabilized by the np* interaction.…”

“…The values of the torsional angle w 1 are close to 01 in all PNAÁDNA and PNAÁPNA duplexes indicating the preferred Z-rotamers of the amide bond connecting the nucleobase to the PNA backbone, resulting in the side-chain CQO being pointed in the C-terminus direction and interacting with the backbone CQO by the np* interaction. Thus, any conformation constraint should observe this requirement, and an example in the case of a-gem-dimethyl PNA 27,28…”

“…In contrast to the α-gem-dimethylated PNA, the analogous NMR and theoretical study on the β-gem-dimethylated PNA monomer indicated that the E -rotamer was preferred over the Z -rotamer. 28 In fact, only the E -rotamer was observed by NMR in the monomer. According to the simulation of the mono-β-methyl-substituted PNA above, the Z -rotamer would result in a severe steric clash with the pro- R methyl group, thus necessitating the adoption of the E -rotamer despite the loss of the stabilizing n → π* interaction ( Fig.…”