Oligonucleotide Analogues with Integrated Bases and Backbones Part 24 Synthesis, Conformational Analysis, and Association of Aminomethylene-Linked Self-Complementary Adenosine and Uridine Dinucleosides

Inspection of Maruzen models and force-field calculations suggest that oligonucleotide analogues integrating backbone and bases (ONIBs) with an aminomethylene linker form similar cyclic duplexes as the analogous oxymethylene linked dinucleosides. The self-complementary adenosine- and uridine-derived aminomethylene-linked A*[N]U dinucleosides 15 17 were prepared by an aza-Wittig reaction of the aldehyde 10 with an iminophosphorane derived from azide 6. The sequence-isomeric U*[N]A dinucleosides 18-20 were similarly prepared from aldehyde 3 and azide 12. The N-ethylamine 5, the acetamides 7 and 14, and the amine 13 were prepared as references for the conformational analysis of the dinucleosides. In contradistinction to the results of calculations, the N-ethylamine 5 exists as intramolecularly H-bonded hydroxyimino tautomer. The association in CDCl3 of these dinucleosides was studied by H-1-NMR and CD spectroscopy. The A*[N]U dinucleosides 16 and 17 associate more strongly than the sequence isomers 19 and 20; the cyclic duplexes of 16 form preferentially Watson - Crick-type base pairs, while 17, 19, and 20 show both Watson-Crick- and Hoogsteen-type base pairing. The cyclic duplexes of the aminomethylene-linked dinucleosides prefer a gg-orientation of the linker. No evidence was found for an intramolecular H-bond of the aminomethylene group. The CD spectra of 16 and 17 show a strong, those of 19 a weak, and those of 20 almost no temperature dependence.