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

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.

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Figure 1: Previous prebiotic syntheses of pyrimidine β-ribonucleotides via 2,2′-anhydronucleoside intermediates.
Figure 2: Synthesis of pyrimidine β-ribonucleosides and β-ribonucleotides involving photoanomerization of α-2-thioribocytidine 13.
Figure 3: 1H NMR spectra that demonstrate the inherently favoured nature of the individual reactions of the newly discovered synthetic sequence.
Figure 4: Reaction mechanisms.
Figure 5: Mechanism of the key photoanomerization reaction.

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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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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.

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Correspondence to Rafał Szabla or John D. Sutherland.

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The authors declare no competing financial interests.

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Xu, J., Tsanakopoulou, M., Magnani, C. et al. A prebiotically plausible synthesis of pyrimidine β-ribonucleosides and their phosphate derivatives involving photoanomerization. Nature Chem 9, 303–309 (2017). https://doi.org/10.1038/nchem.2664

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