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Spectacular advances in structural and molecular biology have added support to the 'RNA world hypothesis', and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early Earth. The 'molecular biologist's dream' - a phrase introduced by Jerry Joyce and Leslie Orgel - refers to a scenario in which prebiotic chemistry somehow furnishes pools of enantiopure beta-D-ribonucleosides. There is still a long way to go from such nucleosides to RNA, but the experimental demonstration of in vitro RNA evolution suggests that once RNA has arisen, its evolution might be relatively easy. Several groups worldwide are investigating the evolution of simple RNA polymerase ribozymes, and the general impression is that, although this is difficult, there is reason for optimism. There has, however, been little optimism about the chances of a prebiotic synthesis of beta-D-ribonucleosides and the corresponding nucleotides, indeed the mood has been distinctly pessimistic. This is because of the intractable mixtures that result from most attempts to make nucleosides using conditions that simulate the chemistry of the early Earth - the 'prebiotic chemist's nightmare'. The one glimmer of hope has been a derivative of ribose known as ribose amino-oxazoline (RAO), this is more stable than free ribose, and is a potential nucleotide intermediate. How to make the ribose required for RAO synthesis has been a mystery however. Very recently, we found that pentose amino-oxazolines, including RAO, can be produced in a reaction that bypasses the corresponding sugars. 2-Amino-oxazole, a condensation product of glycolaldehyde and cyanamide, reacts with glyceraldehyde under mild conditions in a remarkable process that is essentially quantitative, and is highly stereoselective for RAO and its arabinose analogue. Furthermore, the RAO crystallises spontaneously from the reaction mixture, and, if the ee of the input glyceraldehyde is > 60%, the RAO that crystallises is enantiopure (Angewandte Chemie, in press). We now want to extend this work by finding a plausible route to such optically enriched glyceraldehyde, and a route from RAO to beta-D-nucleosides. Although the glycolaldehyde and cyanamide required for our current RAO synthesis are presumed to be prebiotically available, the glyceraldehyde is not. This is because glyceraldehyde is thermodynamically unstable with respect to dihydroxyacetone (DHA). DHA is considered to be a prebiotically available compound; it can be detected in the interstellar medium and has been found in the Murchison meteorite for example. We want to find a catalyst that enables DHA to be equilibrated with glyceraldehyde because, although the latter will only be a minor component at equilibrium, it reacts much faster than DHA with 2-amino-oxazole. It should therefore be possible to convert DHA to RAO via glyceraldehyde. Since DHA is achiral, but glyceraldehyde is chiral, it should further be possible to find an asymmetric catalyst that equilibrates DHA with one enantiomer of glyceraldehyde faster than the other. In this way, we plan to demonstrate a synthesis of enantiopure RAO from DHA and 2-amino-oxazole. We also want to convert RAO to nucleosides. Reaction of RAO with cyanoacetylene produces alpha-cytidine by way of an intermediate anhydronucleoside. We can see two potential routes to beta-ribonucleosides, one from this anhydronucleoside, and the other from the alpha-cytidine. Both routes involve stereochemical inversion, the first by nucleophilic substitution, the second by photoanomerisation. If we are successful in finding a route from RAO to beta-ribonucleosides, we will apply it enantiopure RAO and thereby realise the molecular biologist's dream.
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