Roberts, Samuel; (2018) Towards the prebiotic synthesis of furanosyl-nucleosides. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The prebiotic synthesis of self-replicating genetic molecules is an unsolved, but essential, challenge in origins of life research. Whilst many oligonucleotides (including RNA, p-RNA, TNA, PNA) have been postulated to play a role at the origins of life, and have been studied as genetic polymers, the prebiotic syntheses of their constituent monomers remain elusive. A divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides has been recently reported. Building upon this work, we elucidate a further point of divergence affording arabinosides ara-80A/G/C/U. Importantly, these nucleosides contain all four canonical nucleobases and are produced in high yield, under mild prebiotically plausible conditions in water. These monomers could conceivably be feedstocks for a prebiotic synthesis of arabino-nucleic-acids (ANA’s), a genetically and catalytically competent (non-canonical) polymer, suggesting that ANA may have played an important role bridging the gap between prebiotic chemistry and extant life. We demonstrate the selective C8-thiolysis of anhydropurines ara-95A/G/I (affording 8-mercapto-arabino-purines ara-126), followed by effective reduction with either UV light (λ = 254 nm or 300 nm) or with H2O2 yields arabino-purines ara-80A/G/C/U in high yield. Reduction by UV also showed remarkable selectivity for guanosine ara-80G and adenosine ara-80A over inosine ara-80I. This suggests photo-chemical reduction could have contributed to selection of extant nucleobases. We find that the concomitant anhydropyrimidine chemistry (H2S, then H2O2) enables simultaneous access to both arabino-pyrimidines and arabino-purines. Hydrolysis of anhydro-cytidine ara-95C in water furnishes arabino-cytidine ara-80C. Subsequent thiolysis of ara-80C affords 4-thio-uridine ara-129, which upon reaction with H2O2 undergoes C4-hydrolysis furnishing ara-80U in high yield. Aqueous thiolysis of anhydro-pyrimdines yielded different selectivity to a previously reported thiolysis at C2 in formamide. We also observed that aqueous reaction with H2O2 selectively repairs C2-thiolysed anhydropyrimidines. Our combined studies demonstrate the first prebiotic synthesis of a complete set of Watson-Crick base pairing nucleosides (containing all four canonical nucleobases) in one pot.

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