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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999

Chemical Etiology of the Structure of Nucleic Acids

A. Eschenmoser, R. Krishnamurthy, H. Wippo, O. Jungmann, M. Stanek, S. Guntha, R. Kudick, H. Huynh, A. Luther

In its third year, research in our group focused on the following projects:

Pentopyranosyl-(4´→2´) Ol Igonucleotide Systems

We extended the synthesis of pentopyranosyl nucleic acid alternatives to l-(α)-arabino- and l-(α)-lyxopyranosyl-(4´→2´) oligonucleotide systems containing 4 canonical bases and found that guanine-cytosine pairing in these systems is consistent with the conclusions drawn earlier from studies on adenine-thymine pairing.

We found promiscuous cross-pairing among all 4 members of the pentopyranosyl family (Fig. 1). Nevertheless, systems in which the conformation of the phosphodiester junction at the 4´ position (equatorial in ribo and xylo and axial in lyxo and arabino) is the same have a preference for each other. No cross-pairing of the pentopyranosyl-(4→2´) systems with RNA occurs. Conspicuously strong self-pairing of sequences such as 4´-TATTTTAA-2´ and 4´-TTAAAATA-2´ occurs. This finding indicates a pronounced tolerance to mismatches in the family of (4´→2´)-pentopyranosyl nucleic acid alternatives.

We have included in our studies the l-α-lyxopyranosyl-(3´→4´) oligonucleotide system in which the repetitive unit of the backbone contains only 5 covalent bonds rather than the 6 bonds characteristic of the (4→2´)-pentopyranosyl systems and of RNA. In sharp contrast to the d-ß-ribopyranosyl-(3´→4´) system investigated earlier, the corresponding lyxopyranosyl system is a surprisingly strong base-pairing system, one that even shows (weak) cross-pairing with DNA. It is the first oligonucleotide system known with only 5 covalent bonds in the backbone unit that has the property of base pairing. The explanation for this special is the diaxial conformation of the (3→4´)-phosphodiester junction. This finding promotes a revision of present views about the constitutional constraints thought to determine the base-pairing capability of oligonucleotide systems.

Chemistry of Pyranosyl-RNA

In studies on the properties of the pyranosyl isomer of RNA (pyranosyl oligonucleotide), we examined the relative incorporation of the monomers pyranosyl-guanosine, pyranosyl-guanosine-2´-phosphate, and pyranosyl-guanosine-2´,3´-cyclophosphate into a single-unit gap of a duplex containing a template strand and 2 primer strands; one of the primer strands was activated at the single-unit gap site as 2´,3´-cyclophosphate. The relative ease of monomer incorporation increases from the nonphosphorylated monomer to the 2´-phosphate to the 2´,3´-cyclophosphate; the 2´,3´-cyclophosphate monomer connects by 2 ligations the 2 primer sequences into a full template complement. The template system used in these ligation reactions serves as a scaffold in ongoing acyl migration studies.

Regioselective Phosphorylation of Aldosugars

We recently described the phosphorylation of glycolaldehyde by amidotriphosphate to form glycolaldehyde phosphate. This regioselective phosphorylation is the first example of a phosphorylation process now extensively studied in our laboratory. In this process, the activated phosphorylating reagent is brought into the constitutional neighborhood of the phosphorylation site by a transient attachment of the reagent to the sugar carbonyl group. With this method, a strict regioselectivity in the phosphorylation of the hydroxyl group of the sugar is achieved. We hypothesize that this type of phosphorylation could have etiologic relevance.


Beier, M., Reck, F., Wagner, T., Krishnamurthy, R., Eschenmoser, A. Chemical etiology of nucleic acid structure: Comparing pentopyranosyl-(2´→4´) oligonucleotides with RNA. Science 283:699, 1999.

Krishnamurthy, R., Arrhenius, G., Eschenmoser, A. Formation of glycolaldehyde phosphate from glycolaldehyde in aqueous solution. Origins Life Evol. Biosphere 29:333, 1999.

Micura, R., Kudick, R., Pitsch, S., Eschenmoser, A. Opposite orientation of backbone inclination in pyranosyl-RNA and homo-DNA correlates with opposite directionality of duplex properties. Angew. Chem. Int. Ed. 38:680, 1999.



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