Abstract
The structure of life's first genetic polymer is a question of intense ongoing debate. The “RNA world theory” suggests RNA was life's first nucleic acid. However, ribonucleotides are complex chemical structures, and simpler nucleic acids, such as threose nucleic acid (TNA), can carry genetic information. In principle, nucleic acids like TNA could have played a vital role in the origins of life. The advent of any genetic polymer in life requires synthesis of its monomers. Here we demonstrate a high‐yielding, stereo‐, regio‐ and furanosyl‐selective prebiotic synthesis of threo‐cytidine 3, an essential component of TNA. Our synthesis uses key intermediates and reactions previously exploited in the prebiotic synthesis of the canonical pyrimidine ribonucleoside cytidine 1. Furthermore, we demonstrate that erythro‐specific 2′,3′‐cyclic phosphate synthesis provides a mechanism to photochemically select TNA cytidine. These results suggest that TNA may have coexisted with RNA during the emergence of life.
Highlights
The structure of lifes first genetic polymer is a question of intense ongoing debate
These properties of threose nucleic acid (TNA) have enabled the in vitro evolution of TNAs, which can be synthesized by DNA polymerases,[10,17,18,19] RNA-dependent RNA polymerases,[20] and even TNA polymerases.[21]
TNA is a simpler structure than RNA, with one fewer chiral carbon atom in its sugar moiety, and conceptually, TNAs sugar moiety can be assembled from two achiral C2 building blocks.[8]
Summary
Chemie to tetrose anhydronucleosides 6 and 7 would regioselectively position a sulfur atom at C2 on the nucleobase and enable photochemical anomerization to yield the TNA monomer 3 (via thiocytidine 8). In the ribo-series, photoanomerization and conversion of thiocytidine 2 to cytidine 1 must occur prior to phosphorylation.[24] These constraints are imposed by the formation of 2’,3’-cyclic phosphates which, when in a transconfiguration with respect to the 2-thiocytidine nucleobase, undergo (destructive) cyclization to 2,2’-thioanhydronucleotides.[29] We envisage that this process, in the tetrose cytidines, could furnish the selectivity required to synthesize the threoisomer (i.e. TNA cytidine) by selective destruction of the erythro-isomer of thiocytidine. We irradiated a mixture of erythro-cyclic phosphate 13 and threo-9; after 3 days 8 was the major nucleoside (47 %), whilst 13 was observed to degrade in only 1 day (Figure 6 and Supplementary Figures 16 and 17), demonstrating that irra-. The high temperature required for urea-mediated phosphorylation resulted in some conversion of 9 back to anhydrocytidine 6 and concomitant phosphorylation and thermal rearrangement to yield photostable a-erythro-cytidine-2’,3’-cyclic phosphate 14 (Supplementary Figure 20). We have demonstrated that prebiotic photoanomerization can selectively furnish TNA cytidine, and our results warrant further investigation of selective TNA synthesis in the context of the origins of life
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