Ribose aminooxazoline

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Ribose aminooxazoline
Ribose aminooxazoline (ROA).png
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
  • InChI=1S/C6H10N2O4/c7-6-8-5-4(12-6)3(10)2(1-9)11-5/h2-5,9-10H,1H2,(H2,7,8)
    Key: IVFVSTOFYHUJRU-UHFFFAOYSA-N
  • C(C1C(C2C(O1)N=C(O2)N)O)O
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Ribose aminooxazoline (RAO) is a bicyclic pentose aminooxazoline that plays a central role in the prebiotic synthesis of RNA. RAO is a key intermediate in the cyanosulfidic synthesis pathway leading to the prebiotic formation of canonical pyrimidine ribonucleosides. The formation of RAO within the cyanosulfidic reaction network bypasses an otherwise improbable formation of N-glycosidic bonds between nucleobases and ribose sugars. RAO possesses low solubility in comparison to other pentose aminooxazolines, forming chemically stable RAO crystals capable of undergoing chiral enrichment under ambient conditions. RAO's enantiomers form distinct crystals with unique lattice arrangements, which can interact with magnetic surfaces to preferentially make homochiral RAO. Because of this, RAO has emerged as a compelling intermediate of prebiotic synthesis to explain the early emergence of biochemical homochirality inherited by all life on Earth.

Contents

Chemical structure, properties, and synthesis pathway

RAO is a bicyclic heterocyclic compound consisting of a pentose oxazoline with an amine group attached at the C2' position (2-aminooxazoline) and a ribose configured pentose sugar. The hydroxyl bearing carbons are in the C2' and C3' positions in a cis arrangement distinguishing this from arabino-aminooxazoline (AAO) where the hydroxyl bearing carbons are in a trans configuration.

Synthesis pathway

The synthesis pathway, first described by Powner et al. 2009, [1] begins with a standing stock of cyanamide, glycolaldehyde, and glyceraldehyde with inorganic phosphate in an aqueous solution. First, a condensation reaction of cyanamide with glycolaldehyde yields 2-aminooxazole. The 2-aminooxazole then acquires glyceraldehyde yielding the bicyclic pentose aminooxazoline. In addition to RAO, three other aminooxazoline stereoisomers are also produced through this reaction pathway, arabino-, xylose-, and lyxose-. Powner et al. 2009 [1] report an exceptionally high yield of pentose aminooxazoline when in the presence of inorganic phosphate buffering the solution at neutral pH. While all four stereoisomers are synthesized in a racemic mixture, ribo- and arabino- stereoisomers dominated the product solution. [2]

Synthesis pathway from standing stocks of cyanamide and glycolaldehyde adapted from Powner et al. (2009). Reaction pathway is performed in the presence of inorganic phosphate acting as a buffer. Glycolaldehyde and cyanamide react to form 2-aminooxazole via condensation. 2-aminooxazole then adds to glyceraldehyde, forming RAO (along with arabino-, xylose-, and lyxose-oxazoline stereoisomers). Pathway ROA labeled.png
Synthesis pathway from standing stocks of cyanamide and glycolaldehyde adapted from Powner et al. (2009). Reaction pathway is performed in the presence of inorganic phosphate acting as a buffer. Glycolaldehyde and cyanamide react to form 2-aminooxazole via condensation. 2-aminooxazole then adds to glyceraldehyde, forming RAO (along with arabino-, xylose-, and lyxose-oxazoline stereoisomers).

While produced in comparable proportions (~30% and 40% yield for ribo- and arabino-, respectively), RAO possesses comparatively lower solubility in water. [2] [3] This low solubility results in pure RAO crystals effectively removing the RAO from the bulk solution mixture. Crystallization of RAO provides a mechanism of chemical purification whereby RAO becomes efficiently isolated from the other stereoisomers in solution. Further work by Xu et al. 2016 [4] found that, given a non-racemic mixture of glyceraldehyde during synthesis, RAO can crystallize with enantiomeric enrichment. This is due to the fact that the enantiomers of RAO form separate and distinct crystals, providing not only a mechanism for bulk chemical purification but also for chiral enrichment. [4]

Role in cyanosulfidic protometabolism

Classical prebiotic synthesis pathway to nucleosides. Here ribose and the nucleotide are formed by way of two independent pathways requiring them to finally join via a thermodynamically difficult N-glycosidic bond (marked with an asterisk). Figure adapted from Pereto (2019). RAO pathway single.png
Classical prebiotic synthesis pathway to nucleosides. Here ribose and the nucleotide are formed by way of two independent pathways requiring them to finally join via a thermodynamically difficult N-glycosidic bond (marked with an asterisk). Figure adapted from Peretó (2019).

The origin of life requires a route from simple molecules to complex biological polymers. Cyanosulfidic protometabolism is a prebiotic synthesis pathway from simple monomers to polymers eventually leading to the origin of precursor molecules of the key building blocks of life, amino acids, ribonucleotides, and lipids. The proposed cyanosulfidic pathway has received considerable attention because it needs only a small number of starting reagents, which are all compatible with plausible early Earth conditions. [6] Specifically, cyanosulfidic protometabolism requires only three initial standing stocks: (1) hydrogen cyanide, (2) hydrogen sulfide, and (3) inorganic phosphate in the presence of water and ultraviolet light. Within the cyanosulfidic reaction framework, RAO is an environmentally stable RNA precursor.

Experimental pathway from ribose aminooxazoline (RAO) to canonical pyrimidine nucleotides. Figure is adapted from Xu et al. (2017). Blue arrows represent chemical constituents added with each step in the reaction pathway. Green arrows represent the chemical processes occurring to achieve each sequential compound in the pathway. RAO pathway tonucleo witharrows.png
Experimental pathway from ribose aminooxazoline (RAO) to canonical pyrimidine nucleotides. Figure is adapted from Xu et al. (2017). Blue arrows represent chemical constituents added with each step in the reaction pathway. Green arrows represent the chemical processes occurring to achieve each sequential compound in the pathway.

Variations of cyanosulfidic synthesis can make both pyrimidine and purine ribonucleosides, and RAO is a key intermediate for pyrimidine synthesis. [6] For discussion on the synthesis pathway for purine ribonucleosides, see Stairs et al. (2017) [8] and Feldmann et al. (2023). [9] Prior to the cyanosulfidic protometabolic pathway being introduced, it was assumed that ribonucleotides were synthesized from two independently formed components, a nucleobase produced from hydrogen cyanide [10] and a pentose sugar produced from formaldehyde. [11] However, this idea does not work. The final step requires a ribose and a nucleobase to combine by way of a N-glycosidic bond which has been experimentally proven to be extraordinarily difficult, [12] rendering this prebiotic pathway to ribonucleoside formation highly improbable.

The cyanosulfidic reaction scheme offers a means in which to bypass the need for a ribose and a nucleobase to directly react via N-glycosidic bond via the formation of RAO. Pyrimidine ribonucleotides are synthesized in of the following steps: [4]

  1. RAO reacts with a standing stock of cyanoacetylene producing ribose anhydronucleoside.
  2. Ribose anhydronucleoside undergoes thiolysis in the presence of hydrogen sulfide and formamide producing α-2-thioribocytidine.
  3. α-2-thioribocytidine then undergoes photoanomerization to β-2-thioribocytidine upon exposure to ultraviolet light.
  4. In the presence of inorganic phosphate and formamide, β-2-thioribocytidine undergoes phosphorylation to the canonical pyrimidine nucleotide, cytidine monophosphate.
  5. Finally, irradiation by ultraviolet light transforms cytidine monophosphate to an additional canonical pyrimidine nucleotide, uridine monophosphate.

Role in the emergence of homochirality

RAO offers a plausible solution to the prebiotic need for homochirality. [13] Its ability to become enantiomerically enriched offers a route to chirally pure monomers, and subsequent polymers, early in the origin of life. This early chiral amplification enables the inheritance of enantiomeric preference in emerging RNA, laying the foundation for the modern correlation between nucleic acid and amino acid handedness. RAO's role in the early emergence of homochirality is especially compelling due to the fact that its enantiomeric enrichment has been explained purely by means of environmental conditions plausible on early Earth. [14] Once homochiral RNA forms, data suggest that right handed (D-) transfer RNA's preferentially bind with left handed (L-) amino acids thus leading to left handed proteins. So, homochiral RNA propogates homochially in proteins. [15]

Experimental basis for RAO as a homochiral precursor

RAO playing a central role in the emergence in RNA homochriality is based on fact that both D-RAO and L-RAO form distinct crystals with unique crystallographic properties. [2] [7] The electron density of a chiral molecule supplies a dipole moment as it approaches a surface. In the presence of a magnetic field, chiral symmetry is broken due to the chiral-induced spin selectivity effect (CISS). [14] [16] This results in a single enantiomeric interaction with a magnetic surface being energetically favorable, leading to a kinetic entrapment of that enantiomer at the surface. Because of RAO's low solubility, the entrapped enantiomer begins to precipitate onto the magnetic surface with enantiomeric enrichment, like a seed crystal. The handedness of the kinetically trapped RAO depends on the direction of the magnetic field applied.

Environmental setting facilitating RAO's homochirality on early Earth

A shallow, closed-basin evaporative lake has been proposed as the most plausible environmental scenario in facilitating RAO's magnetically induced homochirality. [17] Within such an environment, anoxic waters rich in dissolved iron facilitate the precipitation of authigenic magnetite aligned with Earth's magnetic field. [17] A stream flowing into a closed basin might carry a racemic mixture of pentose aminooxazolines. As the lake evaporates, crystallization of RAO occurs, purifying RAO from the pentose aminooxazoline mixture. Wet-dry cycles can re-dissolve and re-precipitate RAO on the magnetite-rich the surface. This process allows for a positive feedback between the magnetic surface to make homochiral RAO crystals. Higher magnetization induces higher enantiomeric enrichment with each crystallization cycle, eventually reaching an enantiopure D-RAO pool for subsequent homochiral RNA synthesis.

References

  1. 1 2 3 Powner, Matthew W.; Gerland, Béatrice; Sutherland, John D. (May 2009). "Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions" . Nature. 459 (7244): 239–242. Bibcode:2009Natur.459..239P. doi:10.1038/nature08013. ISSN   0028-0836. PMID   19444213.
  2. 1 2 3 Anastasi, Carole; Crowe, Michael A.; Powner, Matthew W.; Sutherland, John D. (2006-09-18). "Direct Assembly of Nucleoside Precursors from Two- and Three-Carbon Units" . Angewandte Chemie International Edition. 45 (37): 6176–6179. doi:10.1002/anie.200601267. ISSN   1433-7851. PMID   16917794.
  3. ↑ Fuller, William D.; Sanchez, Robert A.; Orgel, Leslie E. (June 1972). "Studies in prebiotic synthesis" . Journal of Molecular Biology. 67 (1): 25–33. Bibcode:1972JMBio..67...25F. doi:10.1016/0022-2836(72)90383-X. PMID   4339529.
  4. 1 2 3 Xu, Jianfeng; Tsanakopoulou, Maria; Magnani, Christopher J.; Szabla, Rafał; Šponer, Judit E.; Šponer, Jiří; Góra, Robert W.; Sutherland, John D. (April 2017). "A prebiotically plausible synthesis of pyrimidine β-ribonucleosides and their phosphate derivatives involving photoanomerization". Nature Chemistry. 9 (4): 303–309. Bibcode:2017NatCh...9..303X. doi:10.1038/nchem.2664. ISSN   1755-4330. PMC   5576532 . PMID   28338689.
  5. ↑ Peretó, Juli (2018-12-07), Kolb, Vera M. (ed.), "Prebiotic Chemistry That Led to Life" , Handbook of Astrobiology (1 ed.), Boca Raton, Florida : CRC Press, [2019]: CRC Press, pp. 219–233, doi:10.1201/b22230-18, ISBN   978-1-315-15996-6 , retrieved 2025-12-02{{citation}}: CS1 maint: location (link)
  6. 1 2 Peretó, Juli (2018-12-07), Kolb, Vera M. (ed.), "Prebiotic Chemistry That Led to Life" , Handbook of Astrobiology (1 ed.), Boca Raton, Florida : CRC Press, [2019]: CRC Press, pp. 219–233, doi:10.1201/b22230-18, ISBN   978-1-315-15996-6 , retrieved 2025-11-29{{citation}}: CS1 maint: location (link)
  7. 1 2 Xu, Jianfeng; Tsanakopoulou, Maria; Magnani, Christopher J.; Szabla, Rafał; Šponer, Judit E.; Šponer, Jiří; Góra, Robert W.; Sutherland, John D. (April 2017). "A prebiotically plausible synthesis of pyrimidine β-ribonucleosides and their phosphate derivatives involving photoanomerization". Nature Chemistry. 9 (4): 303–309. Bibcode:2017NatCh...9..303X. doi:10.1038/nchem.2664. ISSN   1755-4330. PMC   5576532 . PMID   28338689.
  8. ↑ Stairs, Shaun; Nikmal, Arif; Bučar, Dejan-Krešimir; Zheng, Shao-Liang; Szostak, Jack W.; Powner, Matthew W. (2017-05-19). "Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides". Nature Communications. 8 (1) 15270. Bibcode:2017NatCo...815270S. doi:10.1038/ncomms15270. ISSN   2041-1723. PMC   5454461 . PMID   28524845.
  9. ↑ Feldmann, Jonas; Skaanning, Mads K.; Lommel, Marcus; Kernmayr, Tobias; Mayer, Peter; Carell, Thomas (July 2023). "A Unifying Concept for the Prebiotic Formation of RNA Pyrimidine Nucleosides". ChemistryEurope. 1 (1) e202300013. doi:10.1002/ceur.202300013. ISSN   2751-4765.
  10. ↑ Robertson, Michael P.; Miller, Stanley L. (June 1995). "An efficient prebiotic synthesis of cytosine and uracil" . Nature. 375 (6534): 772–774. Bibcode:1995Natur.375..772R. doi:10.1038/375772a0. ISSN   0028-0836. PMID   7596408.
  11. ↑ Breslow, Ronald (January 1959). "On the mechanism of the formose reaction" . Tetrahedron Letters. 1 (21): 22–26. Bibcode:1959TetL....1...22B. doi:10.1016/S0040-4039(01)99487-0.
  12. ↑ Leslie E., Orgel (January 2004). "Prebiotic Chemistry and the Origin of the RNA World" . Critical Reviews in Biochemistry and Molecular Biology. 39 (2): 99–123. doi:10.1080/10409230490460765. ISSN   1040-9238. PMID   15217990.
  13. ↑ Saplakoglu, Yasemin. "Magnetic Minerals May Have Given Life Its Molecular Asymmetry". Wired. ISSN   1059-1028 . Retrieved 2025-12-06.
  14. 1 2 Ozturk, S. Furkan; Liu, Ziwei; Sutherland, John D.; Sasselov, Dimitar D. (2023-06-09). "Origin of biological homochirality by crystallization of an RNA precursor on a magnetic surface". Science Advances. 9 (23) eadg8274. arXiv: 2303.01394 . Bibcode:2023SciA....9G8274O. doi:10.1126/sciadv.adg8274. ISSN   2375-2548. PMC   10246896 . PMID   37285423.
  15. ↑ Ozturk, S. Furkan; Sasselov, Dimitar D. (2025-08-26). "Life's homochirality: Across a prebiotic network". Proceedings of the National Academy of Sciences. 122 (34) e2505126122. Bibcode:2025PNAS..12205126O. doi:10.1073/pnas.2505126122. PMC   12403148 . PMID   40828029.
  16. ↑ Bloom, Brian P.; Paltiel, Yossi; Naaman, Ron; Waldeck, David H. (2024-02-28). "Chiral Induced Spin Selectivity". Chemical Reviews. 124 (4): 1950–1991. doi:10.1021/acs.chemrev.3c00661. ISSN   0009-2665. PMC   10906005 . PMID   38364021.
  17. 1 2 Ozturk, S. Furkan; Sasselov, Dimitar D. (2022-07-12). "On the origins of life's homochirality: Inducing enantiomeric excess with spin-polarized electrons". Proceedings of the National Academy of Sciences. 119 (28) e2204765119. arXiv: 2203.16011 . Bibcode:2022PNAS..11904765O. doi: 10.1073/pnas.2204765119 . ISSN   0027-8424. PMC   9282223 . PMID   35787048.
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