Oligonucleotide Analogues with Integrated Bases and Backbones. Part 24

Abstract

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 uridinederived 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 CDCl 3 of these dinucleosides was studied by 1 H-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.Helvetica Chimica Acta -Vol. 93 (2010) 668 2010 Verlag Helvetica Chimica Acta AG, Zürich 1 ) Conventions for abbreviated notation: The substitution at C(6) of pyrimidines and C(8) of purines is denoted by an asterisk (*); for example, A* and U* for thiomethylated adenosine and uridine derivatives, respectively. The moiety x linking C(6)ÀCH 2 or C(8)ÀCH 2 of unit II and C(5') of unit I is indicated in square brackets, i.e., [c] for a C-, [o] for a O-, [n] for a N-, and [s] for a S-atom.

Oligonucleotide Analogues with Integrated Bases and Backbones. Part 26

“…The resulting imines were directly reduced with NaBH 3 CN to yield 22 (75% from 8). Similarly as observed during the synthesis of the C(6)-unsubstituted A*[n]U dinucleoside [9], formation of the imines required a high concentration of the mononucleosides. The 1 H-NMR spectrum of 22 shows two AB systems, one corresponding to the C(6/I)ÀCH 2 group resonating at 3.99 and 3.92 ppm (J gem ¼ 12.6 Hz) and the other corresponding to the C(8/II)ÀCH 2 group resonating at 4.17 and 4.13 ppm (J gem ¼ 14.1 Hz; see Table 8 in the Exper.…”

“…The syn-conformation is expected on account of the substitution at C (6). Similarly to the C(5')ÀOAc and C(5')ÀSAc analogues [7], 6 shows a preference for the gg-conformation (gg/gt/tg 51 : 28 : 21; calculated according [7] [9]) 3 ), suggesting that these esters are sterically less demanding than silyl ethers.…”

“…As for the analogous C(6)-unsubstituted N-ethylamine [9], there is no signal of the imido NH group of 7. The OH signal of the tautomeric hydroxyimino structure of 7 in CDCl 3 is not visible (it is expected at ca.…”

“…Pairing of partially protected, selfcomplementary dinucleosides in CDCl 3 depends on the structure of the linker, the synorientation of the nucleobases, and the conformation of the ribose unit [7]. The resulting cyclic duplexes form Watson -Crick (WC), reverse-Watson -Crick (rWC), p-toluenesulfonate 6 with EtNH 2 in DMF (88%) [9], and the acetamide 9 (59%) by hydrogenation of 8 in the presence of Pd/C and Ac 2 O [9].…”

“…Desilylation of 12 with Bu 4 NF yielded 91% of the selectively protected alcohol 13 that provided the p-toluenesulfonate 15 (75%) under standard conditions [9]. However, a range of conditions failed to transform the C(8)-substituted alcohol 13 or the p-toluenesulfonate 15 into the desired azidodeoxy-adenosine.…”