Ribonucleotides

Abstract

It has normally been assumed that ribonucleotides arose on the early Earth through a process in which ribose, the nucleobases, and phosphate became conjoined. However, under plausible prebiotic conditions, condensation of nucleobases with ribose to give beta-ribonucleosides is fraught with difficulties. The reaction with purine nucleobases is low-yielding and the reaction with the canonical pyrimidine nucleobases does not work at all. The reasons for these difficulties are considered and an alternative high-yielding synthesis of pyrimidine nucleotides is discussed. Fitting the new synthesis to a plausible geochemical scenario is a remaining challenge but the prospects appear good. Discovery of an improved method of purine synthesis, and an efficient means of stringing activated nucleotides together, will provide underpinning support to those theories that posit a central role for RNA in the origins of life.

Figure 1.

Activated ribonucleotides in the potentially prebiotic assembly of RNA. Potential P–O bond forming polymerization chemistry is indicated by the curved arrows.

Figure 2.

One of the synthetic routes to β-ribocytidine-2′,3′-cyclic phosphate 2 (B=C) implied by the assumption that nucleosides can self-assemble by nucleobase ribosylation. The general synthetic approach has been supported by the experimental demonstration of most of its steps. However, prebiotically plausible conditions under which the key nucleobase ribosylation step works have not been found despite numerous attempts over several decades.

Figure 3.

The difficulties of assembling β-ribonucleosides by nucleobase ribosylation. (A) The many different forms of ribose 3 adopted in aqueous solution. The pyranose (p) and furanose (f) forms interconvert via the open-chain aldehyde (a), which is also in equilibrium with an open-chain aldehyde hydrate (not shown). (B) Adenine tautomerism and the ribosylation step necessary to make the adenosine 11 (B=A) thought to be needed for RNA assembly. The low abundance of the reactive entities 13 and 14 is partly responsible for the low yield of 11 (B=A). (C) The reason for the lower nucleophilicity of N1 of the pyrimidines, and the conventional synthetic chemist’s solution to the problems of ribosylation.

Figure 4.

The recently uncovered route to activated pyrimidine nucleotides 2. The nucleobase ribosylation problem is circumvented by the assembly proceeding through 2-aminooxazole 21, which can be thought of as the chimera of half a pentose sugar and half a nucleobase. The second half of the pentose—glyceraldehyde 5—and the second half of the nucleobase—cyanoacetylene 7—are then added sequentially to give the anhydronucleoside 23. Phosphorylation and rearrangement of 23 then furnishes 2 (B=C), and UV irradiation effects the partial conversion of 2 (B=C) to 2 (B=U).

Figure 5.

Mechanistic details of each of the five steps—(A) through (E)—of the recently uncovered route to activated pyrimidine nucleotides 2. In E), resonance arrows are shown in red and reaction arrows in black.

Figure 5.

Mechanistic details of each of the five steps—(A) through (E)—of the recently uncovered route to activated pyrimidine nucleotides 2. In E), resonance arrows are shown in red and reaction arrows in black.