Small-Molecule Organocatalysis Facilitates In Situ Nucleotide Activation and RNA Copying

[Image: see text] A key challenge in origin-of-life research is the identification of plausible conditions that facilitate multiple steps along the pathway from chemistry to biology. The incompatibility of nucleotide activation chemistry and nonenzymatic template-directed RNA copying has hindered attempts to define such a pathway. Here, we show that adding heteroaromatic small molecules to the reaction network facilitates in situ nucleotide phosphate activation under conditions compatible with RNA copying, allowing both reactions to take place in the same mixture. This is achieved using Passerini-type phosphate activation in concert with nucleophilic organocatalysts that intercept high-energy reactive intermediates; this sequence ultimately affords 5′,5′-imidazolium-bridged dinucleotides—the active species in template-directed RNA polymerization. Our results suggest that mixtures of prebiotically relevant heteroaromatic small molecules could have played a key role in the transition from chemistry to biology.