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Regioselective ribonucleoside synthesis through Ti-catalysed ribosylation of nucleobases

Nature Synthesis volume 2, pages 348–356 (2023)Cite this article

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Abstract

The regioselective synthesis of ribonucleosides via direct ribosylation of nucleobases is a major synthetic challenge, owing to the low nucleophilicity of the N9 position of purine and the N1 position of pyrimidine. Here, we report a regioselective Ti-catalysed ribosylation method for the synthesis of purine and pyrimidine ribonucleosides. Ti minerals were found to be key in enhancing the selectivity for N9 purine nucleosides over the undesired exocyclic NC6 isomers. N9-ribosylated adenines could be obtained at a 14% yield with excellent levels of regiocontrol (N9 to NC6 ratio up to 13:1). The developed process has been applied to the synthesis of ribosylated guanine and uracil, with, by far, the highest yield and selectivity of β-guanosine. Infrared and X-ray photoelectron spectroscopic analyses reveal a potential reaction mechanism, with interactions between the substrate and mineral surface being key to the observed regioselectivity.

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Fig. 1: The nucleosidation problem and its significance in the glycosylation reaction and the RNA world hypothesis.
Fig. 2: Pilot ribosylation of adenine with Ti mineral and calculated geometries of the AN9 nucleosides.
Fig. 3: Ti-catalysed regioselective ribosylation of nucleobases.
Fig. 4: Preservation of protons on Ti minerals and the ribosylation at higher pH.
Fig. 5: Mechanistic studies of the Ti-catalysed ribosylation and the rationalization of the high regioselectivity.

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The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information. Source data are provided with this paper.

References

  1. Gilbert, W. Origin of life: the RNA world. Nature 319, 618 (1986).

    Article  Google Scholar 

  2. Orgel, L. E. Prebiotic chemistry and the origin of the RNA world. Crit. Rev. Biochem. Mol. Biol. 39, 99–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Yadav, M., Kumar, R. & Krishnamurthy, R. Chemistry of abiotic nucleotide synthesis. Chem. Rev. 120, 4766–4805 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Ross, W. C. in The Biochemistry of Plants Vol. 6 (ed A. Marcus) 169–205 (Academic, 1981).

  5. Fuller, W. D., Sanchez, R. A. & Orgel, L. E. Studies in prebiotic synthesis. VI. Synthesis of purine nucleosides. J. Mol. Biol. 67, 25–33 (1972).

    Article  CAS  PubMed  Google Scholar 

  6. Fuller, W. D., Sanchez, R. A. & Orgel, L. E. Studies in prebiotic synthesis. VII. Solid-state synthesis of purine nucleosides. J. Mol. Evol. 1, 249–257 (1972).

    Article  CAS  PubMed  Google Scholar 

  7. Sanchez, R. A. & Orgel, L. E. Studies in prebiotic synthesis. V. Synthesis and photoanomerization of pyrimidine nucleosides. J. Mol. Biol. 47, 531–543 (1972).

    Article  Google Scholar 

  8. Powner, M. W., Gerland, B. & Sutherland, J. D. Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Nature 459, 239–242 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Becker, S. et al. A high-yielding, strictly regioselective prebiotic purine nucleoside formation pathway. Science 352, 833–836 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Becker, S. et al. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science 366, 76–82 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Saladino, R. et al. Meteorite-catalyzed syntheses of nucleosides and of other prebiotic compounds from formamide under proton irradiation. Proc. Natl Acad. Sci. USA 112, E2746–E2755 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Saladino, R. et al. Proton irradiation: a key to the challenge of N-glycosidic bond formation in a prebiotic context. Sci Rep. 7, 14709 (2017).

    Article  PubMed  Google Scholar 

  13. Kim, H.-J. & Benner, S. A. Prebiotic stereoselective synthesis of purine and noncanonical pyrimidine nucleotide from nucleobases and phosphorylated carbohydrates. Proc. Natl Acad. Sci. 114, 11315–11320 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Suárez-Marina, I. et al. Integrated synthesis of nucleotide and nucleosides influenced by amino acids. Commun. Chem. 2, 28 (2019).

    Article  Google Scholar 

  15. Nam, I., Nam, H. G. & Zare, R. N. Abiotic synthesis of purine and pyrimidine ribonucleosides in aqueous microdroplets. Proc. Natl Acad. Sci. USA 115, 36–40 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Young, I. S. & Baran, P. S. Protecting-group-free synthesis as an opportunity for invention. Nat. Chem. 1, 193–205 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Johnson, T. B. & Hilbert, G. E. The synthesis of pyrimidine-nucleosides. Science 69, 579–580 (1929).

    Article  CAS  PubMed  Google Scholar 

  18. Niedballa, U. & Vorbrüggen, H. A general synthesis of pyrimidine nucleosides. Angew. Chem. Int. Ed. 9, 461–462 (1970).

    Article  CAS  Google Scholar 

  19. Wright, R. S., Tener, G. M. & Khorana, H. G. The synthesis of 9-α-D-ribofuranosyladenine. J. Am. Chem. Soc. 80, 2004–2006 (1958).

    Article  CAS  Google Scholar 

  20. Downey, A. M. & Hocek, M. Strategies toward protecting group-free glycosylation through selective activation of the anomeric center. Beilstein J. Org. Chem. 13, 1239–1279 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Gudmundsdottir, A. V. & Nitz, M. Protecting group free glycosidations using p-toluenesulfonohydrazide donors. Org. Lett. 10, 3461–3463 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Downey, A. M., Richter, C., Pohl, R., Mahrwald, R. & Hocek, M. Direct one-pot synthesis of nucleosides from unprotected or 5-O-monoprotected D-ribose. Org. Lett. 17, 4604–4607 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Pelletier, G., Zwicker, A., Allen, C. L., Schepartz, A. & Miller, S. J. Aqueous glycosylation of unprotected sucrose employing glycosyl fluorides in the presence of calcium ion and trimethylamine. J. Am. Chem. Soc. 138, 3175–3182 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Barksdale, J. in The Encyclopedia of the Chemical Elements (ed Hampel, C. A.) 732–738 (Reinhold Book Corporation, 1968).

  25. Aarons, S. M. et al. Titanium isotopes constrain a magmatic transition at the Hadean-Archean boundary in the acasta gneiss complex. Sci. Adv. 6, eabc9959 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Dooley, G. J. Titanium production: ilmenite vs. rutile. JOM 27, 8–16 (1975).

    Article  CAS  Google Scholar 

  27. Thambiliyagodage, C., Wijesekera, R. & Bakker, M. G. Leaching of ilmenite to produce titanium based materials: a review. Discov. Mater. 1, 20 (2021).

    Article  Google Scholar 

  28. Saladino, R. et al. One-pot TiO2-catalyzed synthesis of nucleic bases and acyclonucleosides from formamide: implications for the origin of life. ChemBioChem 4, 514–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Civiš, S. et al. TiO2-catalyzed synthesis of sugars from formaldehyde in extraterrestrial impacts on the early Earth. Sci. Rep. 6, 23199 (2016).

    Article  PubMed  Google Scholar 

  30. Martra, G. Lewis acid and base sites at the surface of microcrystalline TiO2 anatase: relationships between surface morphology and chemical behaviour. Appl. Catal. A Gen. 200, 275–285 (2000).

    Article  CAS  Google Scholar 

  31. Halevy, I. & Bachan, A. The geologic history of seawater pH. Science 355, 1069–1071 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Kristoffersen, H. H., Shea, J.-E. & Metiu, H. Catechol and HCl adsorption on TiO2(110) in vacuum and at the water–TiO2 interface. J. Phys. Chem. Lett. 6, 2277–2281 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Luschtinetz, R., Frenzel, J., Milek, T. & Seifert, G. Adsorption of phosphonic acid at the TiO2 anatase (101) and rutile (110) surfaces. J. Phys. Chem. C 113, 5730–5740 (2019).

    Article  Google Scholar 

  34. Artoshina, O. V., Vorob’eva, M. Y., Dushanov, E. B. & Kholmurodov, K. T. Molecular dynamics simulations of formamide interaction with hydrocyanic acid on a catalytic surface TiO2. Russ. J. Phys. Chem. 88, 951–958 (2014).

    Article  CAS  Google Scholar 

  35. Pettibone, J. M., Cwiertny, D. M., Scherer, M. & Grassian, V. H. Adsorption of organic acids on TiO2 nanoparticles: effects of pH, nanoparticle size, and nanoparticle aggregation. Langmuir 24, 6659–6667 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Zhao, Z.-R. & Wang, X. A plausible prebiotic selection of ribose for RNA - formation, dynamic isolation, and nucleotide synthesis based on metal-doped clays. Chem 7, 3292–3308 (2021).

    Article  CAS  Google Scholar 

  37. Kruse, F. M., Teichert, J. S. & Trapp, O. Prebiotic nucleoside synthesis: the selectivity of simplicity. Chem. Eur. J. 26, 14776–14790 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Garcia, A. K., Schopf, J. W., Yokobori, S.-I., Akanuma, S. & Yamagishi, A. Reconstructed ancestral enzymes suggest long-term cooling of Earth’s photic zone since the Archean. Proc. Natl Acad. Sci. U S A 114, 4619–4624 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Pawelka, Z., Kryachko, E. S. & Zeegers-Huyskens, T. Theoretical and experimental study of the conformational and vibrational properties of benzoin. Chem. Phys. 287, 143–153 (2003).

    Article  CAS  Google Scholar 

  40. Campbell, T. D. et al. Prebiotic condensation through wet–dry cycling regulated by deliquescence. Nat. Commun. 10, 4508 (2019).

    Article  PubMed  Google Scholar 

  41. Drew, K. N., Zajicek, J., Bondo, G., Bose, B. & Serianni, A. S. 13C-labeled aldopentoses: detection and quantitation of cyclic and acyclic forms by heteronuclear 1D and 2D NMR spectroscopy. Carbohydr. Res. 307, 199–209 (1998).

    Article  CAS  Google Scholar 

  42. Eschenmoser, A. & Dobler, M. Why pentose and not hexose nucleic acids? Part I. Introduction to the problem, conformational analysis of oligonucleotide single strands containing 2',3'-dideoxyglucopyranosyl building blocks (‘homo-DNA’), and reflections on the conformation of A- and B-DNA. Helv. Chim. Acta 75, 218–259 (1992).

    Article  CAS  Google Scholar 

  43. Eschenmoser, A. Chemical etiology of nucleic acid structure. Science 284, 2118–2124 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Bean, H. D. et al. Formation of a β-pyrimidine nucleoside by a free pyrimidine base and ribose in a plausible prebiotic reaction. J. Am. Chem. Soc. 129, 9556–9557 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Nam, I., Lee, J. K., Nam, H. G. & Zare, R. N. Abiotic production of sugar phosphates and uridine ribonucleoside in aqueous microdroplet. Proc. Natl Acad. Sci. USA 114, 12396–12400 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Cabrera, J. M., García, P. E., Pedrozo, F. L. & Queimaliños, C. P. Dynamics of the dissolved organic matter in a stream-lake system within an extremely acid to neutral pH range: Agrio-Caviahue watershed. Spectrochim. Acta A Mol. Biomol. Spectrosc. 234, 118278 (2020).

    Article  Google Scholar 

  47. Geller, W., Klapper, H. & Schultze, M. in Acidic Mining Lakes. Environmental Science and Engineering (eds Geller, W. et al.) 3–14 (Springer, 1998).

  48. Schinteie, R. Siliceous Sinter Facies and Microbial Mats from Acid-Sulfate-Chloride Springs, Parariki Stream, Rotokawa Geothermal Field, Taupo Volcanic Zone. MSc thesis, Univ. of Auckland (2005).

  49. Kleint, C. et al. Geochemical characterization of highly diverse hydrothermal fluids from volcanic vent systems of the Kermadec intraoceanic arc. Chem. Geo. 528, 119289 (2019).

    Article  CAS  Google Scholar 

  50. Sriaporn, C. et al. Stromatolitic digitate sinters form under wide-ranging physicochemical conditions with diverse hot spring microbial communities. Geobiology 18, 619–640 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Srivastava, S., Dong, H. & Briggs, B. R. The effect of spring water geochemistry on copper proteins in Tengchong hot springs, China. Appl. Environ. Microbiol. https://doi.org/10.1128/AEM.00581-20 (2020).

    Article  PubMed  Google Scholar 

  52. Herschy, B. et al. Archean phosphorus liberation induced by iron redox geochemistry. Nat. Commun. 9, 1346 (2018).

    Article  PubMed  Google Scholar 

  53. Von Damm, K. L. Seafloor hydrothermal activity: black smoker chemistry and chimneys. Annu. Rev. Earth Planet. Sci. 18, 173–204 (1990).

    Article  Google Scholar 

  54. Morse, J. W. & Mackenzie, F. T. Hadean ocean carbonate geochemistry. Aquat. Geochem. 4, 301–319 (1998).

    Article  CAS  Google Scholar 

  55. Fialho, D. M., Roche, T. P. & Hud, N. V. Prebiotic syntheses of noncanonical nucleosides and nucleotides. Chem. Rev. 120, 4766–4805 (2020).

    Article  Google Scholar 

  56. Nowak, M. J., Lapinski, L., Kwiatkowski, J. S. & Leszczynski, J. Molecular structure and infrared spectra of adenine. Experimental matrix isolation and density functional theory study of adenine 15N isotopomers. J. Phys. Chem. 100, 3527–3534 (1996).

    Article  CAS  Google Scholar 

  57. Farfan-Arribas, E. & Madix, R. J. Characterization of the acid-base properties of the TiO2(110) surface by adsorption of amines. J. Phys. Chem. B 107, 3225–3233 (2003).

    Article  CAS  Google Scholar 

  58. Gladysiak, A. et al. Shedding light on the protonation states and location of protonated N atoms of adenine in metal–organic frameworks. Inorg. Chem. 57, 1888–1900 (2018).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21872068 to X.W.) and the Technology Innovation Fund of Nanjing University (020514807001 to X.W.).

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  1. School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Qian-Qian Chen, Ze-Run Zhao, Yeersen Patehebieke & Xiao Wang

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Contributions

X.W. conceived the project. Q.-Q.C., Z.-R.Z. and Y.P. carried out the experiments and analysed the data. All authors discussed the results and contributed to the writing of the manuscript.

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Correspondence to Xiao Wang.

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Nature Synthesis thanks Thomas Carell, Raffaele Saladino and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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General information, experimental procedures, and Supplementary Figs. 1–23, Tables 1–7 and Appendix (NMR spectra, HPLC traces, HRMS data).

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Chen, QQ., Zhao, ZR., Patehebieke, Y. et al. Regioselective ribonucleoside synthesis through Ti-catalysed ribosylation of nucleobases. Nat. Synth 2, 348–356 (2023). https://doi.org/10.1038/s44160-022-00206-1

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