While the non-enzymatic ligation and template-directed synthesis of peptide nucleic acids (PNA) have been reported since 1995, a case of self-replication of PNA has not been achieved yet. Here, we present evidence for autocatalytic feedback in a template directed synthesis of a self-complementary hexa-PNA from two trimeric building blocks. The course of the reaction was monitored in the presence of increasing initial concentrations of the product by RP-HPLC. Kinetic modeling with the SimFit program revealed parabolic growth characteristics. The observed template effect, as well as the rate of ligation, was significantly influenced by nucleophilic catalysts, pH value, and uncharged co-solvents. Systematic optimization of the reaction conditions allowed us to increase the autocatalytic efficiency of the system by two orders of magnitude. Our findings contribute to the hypothesis that PNA may have served as a primordial genetic molecule and was involved in a potential precursor of a RNA world.

A platinum-catalyzed domino process with intermediate benzopyrylium cations reaches its optimum utility in the formation of 7- and 8-membered rings. With iron(III) chloride, a tetracyclic product is isolated, derived from an oxidative transformation of a metal-carbene intermediate.

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.