Prebiotic synthesis of 3′-amino-TNA nucleotide triphosphates

Nucleic acid replication is essential to the emergence of life. Unlike canonical ribonucleotides, aminonucleotides have shown great promise in non-enzymatic replication, but are assumed to be prebiotically irrelevant due to perceived difficulties with their selective formation on the early earth. Here we demonstrate that, contrary to expectation, 3′-amino-TNA is formed diastereoselectively and regiospecifically from prebiotic feedstocks in four high-yielding steps. Our results suggest that 3′-amino-TNA may have been present on the early earth. Formation of the amino-sugar moiety by 3-component coupling of glycolaldehyde 1, 2-aminooxazole 3 and an aminonitrile 6 regiospecifically positions both the 3′-amine and glycosidic bond. Phosphate provides an unexpected resolution of the two diastereomers formed, leading to purification of the genetically relevant threo-isomer. Under phosphate catalysis, the inhibitory erythro-isomer rearranges to an unreactive guanidinium salt, whilst the Watson-Crick base paring threo-isomer co-crystalises with phosphate, leading to its spontaneous purification and accumulation. Nucleobase construction on the amino-sugar scaffold is observed upon reaction with cyanoacetylene 8, and subsequent thiolysis and photochemical anomerisation sets up the ideal stereochemistry for Watson-Crick base pairing. The resulting 3′-amino-TNA can be phosphorylated directly in water, under mild conditions with cyclic trimetaphosphate (PO3Na)3, forming a nucleotide triphosphate (NTP) in a manner not feasible for canonical nucleosides. The ease with which these activated NTPs form, and the inherent selectivity for the Watson-Crick base pairing structure, warrants further study of 3′-amino-TNA as a precursor to the genetic material of life.