Abstract
Understanding prebiotic nucleotide synthesis is a long standing challenge thought to be essential to elucidating the origins of life on Earth. Recently, remarkable progress has been made, but to date all proposed syntheses account separately for the pyrimidine and purine ribonucleotides; no divergent synthesis from common precursors has been proposed. Moreover, the prebiotic syntheses of pyrimidine and purine nucleotides that have been demonstrated operate under mutually incompatible conditions. Here, we tackle this mutual incompatibility by recognizing that the 8-oxo-purines share an underlying generational parity with the pyrimidine nucleotides. We present a divergent synthesis of pyrimidine and 8-oxo-purine nucleotides starting from a common prebiotic precursor that yields the β-ribo-stereochemistry found in the sugar phosphate backbone of biological nucleic acids. The generational relationship between pyrimidine and 8-oxo-purine nucleotides suggests that 8-oxo-purine ribonucleotides may have played a key role in primordial nucleic acids prior to the emergence of the canonical nucleotides of biology.
Highlights
IntroductionA prebiotically plausible synthesis of both pyrimidine ribonucleotides has been established[4,5,6], the glycosidations of adenine and hypoxanthine generate a complex mixture of nucleoside-like products, and there is no literature precedent for the direct glycosidation of guanine to furnish guanosine (G)[3,11]
Understanding prebiotic nucleotide synthesis is a long standing challenge thought to be essential to elucidating the origins of life on Earth
Given the lack of specificity observed during direct glycosidation of purine nucleobases, we have previously suggested that a tethered purine synthesis would overcome the limitation of intramolecular glycosidation[13,14]
Summary
A prebiotically plausible synthesis of both pyrimidine ribonucleotides has been established[4,5,6], the glycosidations of adenine and hypoxanthine generate a complex mixture of nucleoside-like products, and there is no literature precedent for the direct glycosidation of guanine to furnish guanosine (G)[3,11]. A notable proposed pathway to the purine nucleotides, that achieves excellent N9-selectivity during ribosylation[7], remains problematic because of an unselective ribosylation (that furnished a mixture of natural furanosyl and non-natural pyranosyl isomers, and a mixture of natural b-anomers and non-natural a-anomers) This strategy, a variant of the classic Traube purine synthesis[8], generates a wide spectrum of glycone isomers, homologues and anomers alongside a low yield of natural nucleosides from prebiotically plausible sugar mixtures[7]. We demonstrate a divergent, prebiotically plausible reaction strategy for the synthesis of both pyrimidine and purine ribonucleotides (3) on a single oxazoline scaffold
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