Synthesis and Characterization of Optically Pure Gamma‐PNA Backbones by SIBX‐Mediated Reductive Amination

Abstract

Chiral peptide nucleic acid (PNA) is a derivative of regular PNA by introducing a chiral center to its backbone, and is known to bind more strongly to DNA or RNA than regular PNA. In particular, in the case of a γ‐backbone, the L isomer stabilizes the PNA/DNA duplex, and the D‐isomer has the opposite effect. Therefore, the synthesis of an optically pure γ‐backbone is very important. Here, we report a novel synthetic strategy for the suppression of epimerization during the synthesis of the γ‐PNA backbone. A stabilized form of 2‐iodoxybenzoic acid (SIBX) was used as an oxidative reagent in the key intermediate of the N‐Boc‐amino acetaldehyde synthesis. This paper reports (1) the synthesis and comparison of three different γ‐PNA backbones (lysine, alanine, and glutamate) by three different synthetic routes (SIBX, lithium aluminum hydride, and Red‐Al) and (2) the determination of chiral purity from their derivative compounds. The enantiomeric excess purity of SIBX‐mediated γ‐PNA backbones was determined to be more than 99.4%, as ascertained by the high‐performance liquid chromatography (HPLC) chromatogram on a standard RP‐C18 column. It is comparatively higher than that of the other methods examined in this work.