Article | Published:

A prebiotically plausible synthesis of pyrimidine β-ribonucleosides and their phosphate derivatives involving photoanomerization

Nature Chemistry volume 9, pages 303309 (2017) | Download Citation

Abstract

Previous research has identified ribose aminooxazoline as a potential intermediate in the prebiotic synthesis of the pyrimidine nucleotides with remarkable properties. It crystallizes spontaneously from reaction mixtures, with an enhanced enantiomeric excess if initially enantioenriched, which suggests that reservoirs of this compound might have accumulated on the early Earth in an optically pure form. Ribose aminooxazoline can be converted efficiently into α-ribocytidine by way of 2,2′-anhydroribocytidine, although anomerization to β-ribocytidine by ultraviolet irradiation is extremely inefficient. Our previous work demonstrated the synthesis of pyrimidine β-ribonucleotides, but at the cost of ignoring ribose aminooxazoline, using arabinose aminooxazoline instead. Here we describe a long-sought route through ribose aminooxazoline to the pyrimidine β-ribonucleosides and their phosphate derivatives that involves an extraordinarily efficient photoanomerization of α-2-thioribocytidine. In addition to the canonical nucleosides, our synthesis accesses β-2-thioribouridine, a modified nucleoside found in transfer RNA that enables both faster and more-accurate nucleic acid template-copying chemistry.

  • Compound

    D-ribofuranosyl-aminooxazoline

  • Compound

    cyanoacetylene

  • Compound

    α-D-ribofuranosyl-2,2'-anhydrocytidine

  • Compound

    α-D-ribofuranosyl-cytidine

  • Compound

    β-D-ribofuranosyl-cytidine

  • Compound

    D-ribofuranosyl-oxazolidinone

  • Compound

    D-arabinofuranosyl-aminooxazoline

  • Compound

    α-D-arabinofuranosyl-2,2'-anhydrocytidine

  • Compound

    β-D-ribofuranosyl-cytidine-2',3'-cyclic phosphate

  • Compound

    β-D-ribofuranosyl-uridine-2',3'-cyclic phosphate

  • Compound

    glyceraldehyde

  • Compound

    2-aminooxazole

  • Compound

    α-D-ribofuranosyl-2-thiocytidine

  • Compound

    β-D-ribofuranosyl-2-thiocytidine

  • Compound

    2-thiocytosine

  • Compound

    α-D-ribofuranosyl-2-thiouridine

  • Compound

    β-D-ribofuranosyl-2-thiouridine

  • Compound

    2-thiouracil

  • Compound

    β-D-ribofuranosyl-uridine

  • Compound

    2,4-diaminopyrimidine

  • Compound

    formidoylphosphate

  • Compound

    β-D-ribofuranosyl-2-thiocytidine-2',3'-cyclic phosphate

  • Compound

    β-D-ribofuranosyl-2,5'-anhydrocytidine-2',3'-cyclic phosphate

  • Compound

    β-D-ribofuranosyl-2-aminocytidine-2',3'-cyclic phosphate

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Acknowledgements

This work was supported by the Medical Research Council (no. MC_UP_A024_1009), a grant from the Simons Foundation (no. 290362 to J.D.S.), grant 14-12010S from the Grant Agency of the Czech Republic and by the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustainability Programme II. Support from a statutory activity subsidy from the Polish Ministry of Science and Higher Education for the Faculty of Chemistry of Wrocław University of Technology is gratefully acknowledged. Theoretical calculations were partly performed at the Wrocław Center for Networking and Supercomputing and Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw.

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Affiliations

  1. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK

    • Jianfeng Xu
    • , Maria Tsanakopoulou
    • , Christopher J. Magnani
    •  & John D. Sutherland
  2. Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 61265 Brno, Czech Republic

    • Rafał Szabla
    • , Judit E. Šponer
    •  & Jiří Šponer
  3. CEITEC – Central European Institute of Technology, Masaryk University, Campus Bohunice, Kamenice 5, CZ-62500 Brno, Czech Republic

    • Judit E. Šponer
    •  & Jiří Šponer
  4. Department of Physical and Quantum Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland

    • Robert W. Góra

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Contributions

J.D.S. supervised the experimental research, and J.X., M.T. and C.J.M. performed the experiments. J.E.S., J.S. and R.W.G. oversaw the theoretical work, which was carried out by R.S. All the authors contributed intellectually as the project unfolded. J.D.S. wrote most of the paper and J.X., M.T., C.J.M. and R.S. further contributed and assembled the Supplementary Information.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Rafał Szabla or John D. Sutherland.

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DOI

https://doi.org/10.1038/nchem.2664

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