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


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


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound

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

  • Compound

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

  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • Compound


  • 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

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Studies in prebiotic synthesis. V. Synthesis and photoanomerization of pyrimidine nucleosides. J. Mol. Biol. 47, 531–543 (1970).

  2. 2.

    et al. On the prebiotic synthesis of ribonucleotides: photoanomerisation of cytosine nucleosides and nucleotides revisited. ChemBioChem 8, 1170–1179 (2007).

  3. 3.

    , & Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Nature 459, 239–242 (2009).

  4. 4.

    , , & Direct assembly of nucleoside precursors from two- and three-carbon units. Angew. Chem. Int. Ed. 45, 6176–6179 (2006).

  5. 5.

    & Phosphate-mediated interconversion of ribo- and arabino-configured prebiotic nucleotide intermediates. Angew. Chem. Int. Ed. 49, 4641–4643 (2010).

  6. 6.

    & Prebiotic synthesis of simple sugars by photoredox systems chemistry. Nat. Chem. 4, 895–899 (2012).

  7. 7.

    & Synthesis of aldehydic ribonucleotide and amino acid precursors by photoredox chemistry. Angew. Chem. Int. Ed. 52, 5845–5847 (2013).

  8. 8.

    et al. Enzymatic reactivity and anti-tumor activity of 1-(β-D-arabinofuranosyl)-2-thiocytosine derivatives. Chem. Pharm. Bull. 48, 454–457 (2000).

  9. 9.

    , & Transition state stabilization by deaminases: rates of nonenzymatic hydrolysis of adenosine and cytidine. Bioorg. Chem. 15, 100–108 (1987).

  10. 10.

    Prebiotic phosphorylation of nucleosides in formamide. Orig. Life 7, 399–412 (1976).

  11. 11.

    &. Urea–inorganic phosphate mixtures as prebiotic phosphorylating agents. Science 171, 490–494 (1971).

  12. 12.

    Principles of Nucleic Acid Structure (Springer, 1984).

  13. 13.

    & 612. Pyrimidine reactions. Part IV. The methylation of 2,4- and 4,5-diaminopyrimidine and related compounds. J. Chem. Soc. 3172–3179 (1962).

  14. 14.

    et al. Excited-state hydrogen atom abstraction initiates the photochemistry of β-2′-deoxycytidine. Chem. Sci. 6, 2035–2043 (2015).

  15. 15.

    , & Intersystem crossing pathways in the noncanonical nucleobase 2-thiouracil: a time-dependent picture. J. Phys. Chem. Lett. 7, 1978–1983 (2016).

  16. 16.

    , , & Competing ultrafast intersystem crossing and internal conversion: a time resolved picture for the deactivation of 6-thioguanine. Chem. Sci. 5, 1336–1347 (2014).

  17. 17.

    & Communication: the dark singlet state as a doorway state in the ultrafast and efficient intersystem crossing dynamics in 2-thiothymine and 2 thiouracil. J. Chem. Phys. 140, 071101 (2014).

  18. 18.

    , & Relaxation of the T1 excited state of 2-thiothymine, its riboside and deoxyriboside-enhanced nonradiative decay rate induced by sugar substituent. J. Photochem. Photobiol. Chem. 275, 89–95 (2014).

  19. 19.

    & 2-Thiouracil deactivation pathways and triplet states population. Comput. Theor. Chem. 1040, 195–201 (2014).

  20. 20.

    , & A static picture of the relaxation and intersystem crossing mechanisms of photoexcited 2-thiouracil. J. Phys. Chem. A 119, 9524–9533 (2015).

  21. 21.

    & Ab initio study of the electronic spectrum of formamide with explicit solvent. J. Am. Chem. Soc. 121, 8559–8566 (1999).

  22. 22.

    , , & The case for an ancestral genetic system involving simple analogues of the nucleotides. Proc. Natl Acad. Sci. USA 84, 4398–4402 (1987).

  23. 23.

    , & Deciphering synonymous codons in the three domains of life: co-evolution with specific tRNA modification enzymes. FEBS Lett. 584, 252–264 (2010).

  24. 24.

    , , , & Replacing uridine with 2-thiouridine enhances the rate and fidelity of nonenzymatic RNA primer extension. J. Am. Chem. Soc. 137, 2769–2775 (2015).

Download references


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.

Author information


  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


  1. Search for Jianfeng Xu in:

  2. Search for Maria Tsanakopoulou in:

  3. Search for Christopher J. Magnani in:

  4. Search for Rafał Szabla in:

  5. Search for Judit E. Šponer in:

  6. Search for Jiří Šponer in:

  7. Search for Robert W. Góra in:

  8. Search for John D. Sutherland in:


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.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

About this article

Publication history





Further reading