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Prebiotic synthesis and triphosphorylation of 3′-amino-TNA nucleosides

Abstract

Nucleosides are essential to the emergence of life, and so their synthesis is a key challenge for prebiotic chemistry. Although amino-nucleosides have enhanced reactivity in water compared with ribonucleosides, they are assumed to be prebiotically irrelevant due to perceived difficulties with their selective formation. Here we demonstrate that 3′-amino-TNA nucleosides (TNA, threose nucleic acid) are formed diastereoselectively and regiospecifically from prebiotic feedstocks in four high-yielding steps. Phosphate provides an unexpected resolution, leading to spontaneous purification of the genetically relevant threo-isomer. Furthermore, 3′-amino-TNA nucleosides are shown to be phosphorylated directly in water, under mild conditions with cyclic trimetaphosphate, forming a nucleoside triphosphate (NTP) in a manner not feasible for canonical nucleosides. Our results suggest 3′-amino-TNA nucleosides may have been present on the early Earth, and the ease with which these NTPs form, alongside the inherent selectivity for the Watson–Crick base-pairing threo-monomer, warrants further study of the role they could play during the emergence of life.

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Fig. 1: Intersections of prebiotic peptide, sugar and nucleobase syntheses.
Fig. 2: Formation of amino-sugar derivatives from C2 and C3 sugars.
Fig. 3: Stereochemical resolution and crystallization of threo-7.
Fig. 4: Formation of anhydrocytidine threo-9 and its photochemical products.
Fig. 5: Aqueous phosphorylation of amino-nucleoside threo-20 and hydrolysis to canonical nucleobases.

Data availability

All data (experimental procedures and characterization data) supporting the findings of this study are available within the article and its Supplementary Information. Crystallographic data for the threo-7·H3PO4 reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number 2087673. Copies of the data can be obtained free of charge from CCDC via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

The Leverhulme Trust (RPG-2019-214 MWP), the Simons Foundation (318881FY19 MWP) and the Engineering and Physical Sciences Research Council (EP/P020410/1 MWP) provided financial support. We thank K. Karu and M. Puchnarewicz (mass spectrometry), M. Corpinot and K. Bucar (crystallography) and A. E. Aliev (NMR spectroscopy) for support.

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M.W.P. conceived the research. M.W.P. and D.W. designed and analysed the experiments and wrote the manuscript. D.W. conducted the experiments.

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Correspondence to Matthew W. Powner.

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Extended data

Extended Data Fig. 1 Three-component coupling of aldehyde 1, oxazole 3 and aminonitrile 6e to yield amino-nucleotide precursor 7 in water.

1H NMR spectra [400 MHz, H2O/D2O (9:1), 7.6–5.2 ppm] to show the: a, formation of oxazoline 12e (R = sBu) after 2 h at room temperature and pH 4.5 and b, retro-Strecker of 12e at room temperature and pH 4.5 to form 7 after 5 days.

Supplementary information

Supplementary Information

Experimental detail, expanded reactions conditions and reagent compatibility studies, experimental data and NMR spectra, Supplementary figures and tables, X-ray crystallographic data, synthesis of chemical standards and characterization data.

Supplementary Data 1

Crystal structure of threo-7 H3PO4; CCDC reference 2087673.

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Whitaker, D., Powner, M.W. Prebiotic synthesis and triphosphorylation of 3′-amino-TNA nucleosides. Nat. Chem. 14, 766–774 (2022). https://doi.org/10.1038/s41557-022-00982-5

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