Improved Large‐Scale Liquid‐Phase Synthesis and High‐Temperature NMR Characterization of Short ­(F‐)PNAs

Abstract

We report on a large-scale synthesis of F-PNA trimer 10 and PNA trimer 11. The key improvement is the facile two-step synthesis of (2,4-difluoro-5-methylphenyl)acetic acid (2). Water solubility of the corresponding F-PNA oligomer 10 was achieved by synthesizing solubility enhancer 5a, which is twofold positively charged and only consists of inherent structural elements of PNA. Protected and unpaired PNA n-mers exist in a mixture of 2 n conformers undergoing slow exchange and leading to complicated NMR spectra. Structure analysis was improved by recording 1 H-and 13 C-NMR spectra at elevated temperatures above the coalescence point. Fully protected backbone derivatives show sharp resonances where expected, and spectra of protected PNAs are remarkably simplified, thereby allowing an interpretation for the first time. Both trimers 10 and 11 are considered as building blocks for a selfreplicating system based on PNA.

Synthesis and NMR studies of malonyl-linked glycoconjugates of N-(2-aminoethyl)glycine. Building blocks for the construction of combinatorial glycopeptide libraries

“…It is obvious that the different saccharide moieties do not significantly influence the rotation barrier around the tertiary peptide bond. Furthermore, the calculated Δ G ‡ r values are in good accordance with those of other PNA derivates (17.9–19 kcal/mol) [27–28]. …”

Synthesis and structural characterization of monomeric and dimeric peptide nucleic acids prepared by using microwave-promoted multicomponent reactions

“…A possibility to simplify the analysis consists in accelerating the isomerization rate in order to approach the fast exchange regime and thus get a single averaged data set. This strategy was applied by Plöger et al to study fluor-containing short PNA oligomers in DMSO 34 . If working at elevated temperature effectively led to simplified spectra, improved but nevertheless still incomplete assignments were obtained.…”

A self-replicating peptide nucleic acid

“…General. The synthesis of F-PNA A and PNA B was reported elsewhere [41]. Hexa-PNA T was isolated from preliminary experiments without initially added template using semi-prep.…”

“…On the other hand, cases for PNA (self-)replication as a prerequisite for natural selection and evolution have not been identified so far. Recently, we designed a system to evaluate potential PNA self-replication and presented an efficient large-scale synthesis of the building blocks needed [41]. This system consists of two trimeric building blocks F-PNA A and PNA B leading to the selfcomplementary hexa-PNA T upon ligation (Scheme 1); consequently it will be able to compare this system with earlier studies from our laboratory [42][43][44][45][46].…”