Prebiotic synthesis of 3′-amino-TNA nucleotide triphosphates

24 August 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


origins of life

Supplementary materials

Supporting Information
Experimental details, NMR spectra and full characterisation of isolated compounds can be found in this Supporting Information


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