Synthesis of phosphoramidites of isoGNA, an isomer of glycerol nucleic acid.

IsoGNA, an isomer of glycerol nucleic acid GNA, is a flexible (acyclic) nucleic acid with bases directly attached to its linear backbone. IsoGNA exhibits (limited) base-pairing properties which are unique compared to other known flexible nucleic acids. Herein, we report on the details of the preparation of isoGNA phosphoramidites and an alternative route for the synthesis of the adenine derivative. The synthetic improvements described here enable an easy access to isoGNA and allows for the further exploration of this structural unit in oligonucleotide chemistry thereby spurring investigations of its usefulness and applicability.

Chemical etiology of nucleic acid structure: the pentulofuranosyl oligonucleotide systems: the (1'→3')-ß-L-ribulo, (4'→3')-α-L-xylulo, and (1'→3')-α-L-xylulo nucleic acids.

Under potentially prebiotic scenarios, ribose (pentose), the component of RNA is formed in meager amounts, as opposed to ribulose and xylulose (pentuloses). Consequently, replacement of ribose in RNA, with pentulose sugars, gives rise to prospective oligonucleotide candidates that are potentially prebiotic structural variants of RNA that could be formed by the same type of chemical pathways that gave rise to RNA from ribose. The potentially natural alternative (1'→3')-ribulo oligonucleotides and (4'→3')- and (1'→3')-xylulo oligonucleotides consisting of adenine and thymine were synthesized and found to exhibit no self-pairing or cross-pairing with RNA. This signifies that even though pentulose sugars may have been abundant in a prebiotic scenario, the pentulose nucleic acids (NAs), if and when formed, would not have been competitors of RNA, or interfered with the emergence of RNA as a functional informational system. The reason for the lack of base pairing in pentulose NA highlights the contrasting and central role played by the furanosyl ring in RNA and pentulose NA, enabling and optimizing the base pairing in RNA, while impeding it in pentulose NA.

Hydrogen-bond symmetry in difluoromaleate monoanion.

The symmetry of the hydrogen bond in hydrogen difluoromaleate monoanion is probed by X-ray crystallography and by the NMR method of isotopic perturbation in water, in two aprotic organic solvents, and in an isotropic liquid crystal. The X-ray crystal structure of potassium hydrogen difluoromaleate shows a remarkably short O-O distance of 2.41 Å and equal O-H distances of 1.206 Å, consistent with a strong and symmetric hydrogen bond. Incorporation of (18)O into one carboxyl group allows investigation of the symmetry of the H-bond in solution by the method of isotopic perturbation. The (19)F NMR spectra of the mono-(18)O-substituted monoanion in water, CD(2)Cl(2), and CD(3)CN show an AB spin system, corresponding to fluorines in different environments. The difference is attributed to the perturbation of the acidity of a carboxylic acid by (18)O, not to the mere presence of the (18)O, because the mono-(18)O dianion shows equivalent fluorines. Therefore, it is concluded that the monoanion exists as an equilibrating pair of interconverting tautomers and not as a single symmetric structure not only in water but also in organic solvents. However, in the isotropic liquid crystal phase of 4-cyanophenyl 4-heptylbenzoate, tetrabutylammonium hydrogen difluoromaleate-(18)O shows equivalent fluorines, consistent with a single symmetric structure. These results support earlier studies, which suggested that the symmetry of hydrogen bonds can be determined by the local environment.

Diastereoselective self-condensation of dihydroxyfumaric acid in water: potential route to sugars.

Jack of all trades: water-soluble salts of DHF underwent self-condensation to afford the threo diastereomer of pentulosonic acid, through differing reaction pathways contingent on the metal salt used. This transformation exemplifies the diverging roles of DHF as a nucleophile (a synthon for α-hydroxyacetyl anion) and an electrophile (an α-carboxyglycolaldehyde equivalent).

Position-specific secondary deuterium isotope effects on basicity of pyridine.

Secondary isotope effects (IEs) on basicities of various deuterated pyridine isotopologues and of 2,6-lutidine-2,6-(CD(3))(2) have been accurately measured in aqueous solution by an NMR titration method applicable to a mixture. Deuteration at any position of pyridine increases the basicity, but the IE per deuterium is largest for substitution at the 3-position and smallest for the 2-position, which is closest to the site of N-protonation, smaller even than that for 2-CD(3) substitution. Computations at the B3LYP/cc-pVTZ level overestimate the magnitude of the measured IEs but largely reproduce the variability with isotopic position. Because the calculated IEs are based on changes in vibrational frequencies on N-protonation, the correspondence between calculated and experimental IEs implies that they arise from zero-point energies, rather than from inductive effects.

Are there single-well hydrogen bonds in pyridine-dichloroacetic acid complexes?

The (18)O-induced isotope shifts in (13)C NMR spectra of 1:1 complexes of Cl(2)CHC(18)O(2)H with a series of substituted pyridines in CD(2)Cl(2) at low temperature reach a maximum when the acidities of the hydrogen-bond donors are matched, consistent with a mixture of tautomers, and with no drop that would indicate a single-well H-bond.

Asymmetry of the "strongest" OHO hydrogen bond, in the monoanion of (+/-)-alpha,alpha'-di-tert-butylsuccinate.

The large pK(a) difference between first and second deprotonations of (+/-)-alpha,alpha'-di-tert-butylsuccinic acid has been interpreted as evidence for a short, strong intramolecular hydrogen bond in the monoanion. Incorporation of (18)O into one carboxyl group allows investigation of the symmetry of the H-bond in solution by the method of isotopic perturbation. Relative to the intrinsic (18)O-induced isotope shift at the carboxyl carbon, as measured in the diacid, an additional isotope shift of 8 ppb in methanol, 14 ppb in acetone, and 5 ppb in THF is observed for potassium hydrogen (+/-)-alpha,alpha'-di-tert-butylsuccinate-(18)O. This increase indicates that the ion exists as an equilibrating pair of interconverting tautomers and not as a single symmetric resonance hybrid. The X-ray crystal structures of the tetrapropylammonium, tetrabutylammonium, tetrabutylphosphonium, magnesium, and calcium hydrogen (+/-)-alpha,alpha'-di-tert-butylsuccinate salts show a remarkably short O-O distance of 2.41 A, consistent with a strong hydrogen bond. However, the dicesium salt of the (+/-)-alpha,alpha'-di-tert-butylsuccinate dianion also shows the short O-O distance of 2.41 A, so this cannot be taken as evidence for a strong hydrogen bond in the monoanion. Moreover, the two O-H distances in the monoanions are unequal, and the hydrogen bond is asymmetric in these crystals. It is concluded that there is no evidence for any special stabilization associated with symmetric H-bonds. The large Delta pK(a) difference is therefore not due to any feature of the H-bond itself but is attributed to the electrostatic repulsion between the carboxylates in the dianion, which is relieved in the monoanion by inserting a proton between the carboxylates.