A Potentially Prebiotic Synthesis of a 3′-Amino-3′-deoxyribonucleoside

A central challenge in origins of life research is understanding how primitive genetic polymers could have replicated nonenzymatically prior to the evolution of macromolecular catalysts. Such a process would have required the formation of inter-nucleotide linkages, high fidelity in nucleobase pairing, and the ability to produce oligomers of sufficient length within short timescales. While modern ribozymes capable of catalyzing phosphodiester bond formation provide a model for RNA-based catalysis, they require a typical minimum length of ~50 nucleotides, a size unlikely to arise spontaneously without enzymatic intervention. Studies have demonstrated that the substitution of the canonical 3′-OH group with the much more nucleophilic 3′-NH2 group significantly enhances nonenzymatic template-directed oligomerization, and may have enabled early genetic polymers to bypass the need for enzymatic catalysis. Here, we report the synthesis of a 3′-amino-3′-deoxyribocytidine from prebiotic feedstocks. Our results support the hypothesis that 3′-amino-modified ribonucleotides could have served as substrates for the nonenzymatic synthesis of phosphoramidate nucleic acids on the early Earth prior to the emergence of RNA and ribozymes.