Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

Abstract

The formation of cyclic duplexes (pairing) of known oxymethylene‐linked self‐complementary U*[o]A(*) dinucleosides contrasts with the absence of pairing of the ethylene‐linked U*[ca]A(*) analogues. The origin of this difference, and the expected association of U*[x]A(*) and A*[x]U(*) dinucleosides with x=CH2, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson–Crick, reverse Watson–Crick, Hoogsteen, or reverse Hoogsteen H‐bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH2, O, or S were analysed. U*[x]A(*) dinucleosides with x=CH2 do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg‐conformation about the C(4′)C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt‐conformation about this bond. The temperature dependence of the chemical shift of HN(3) of the self‐complementary, oxymethylene‐linked U*[o]A(*) dinucleosides 1–6 in CDCl3 in the concentration range of 0.4–50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3, between the monoplex and cyclic duplexes for 6, and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4, and 5. The self‐complementary, thiomethylene‐linked U*[s]A(*) dinucleosides 27–32 and the sequence isomeric A*[s]U(*) analogues 33–38 were prepared by S‐alkylation of the 6‐(mesyloxymethyl)uridine 12 and the 8‐(bromomethyl)adenosine 22. The required thiolates were prepared in situ from the C(5′)‐acetylthio derivatives 9, 15, 19, and 25. The association in CHCl3 of the thiomethylene‐linked dinucleoside analogues was studied by 1H‐NMR and CD spectroscopy, and by vapour‐pressure osmometric determination of the apparent molecular mass. The U*[s]A(*) alcohols 28, 30, and 31 form cyclic duplexes connected by Watson–Crick H‐bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H‐bonds, and the resulting ribbons are cross‐linked by H‐bonds between HOCH2C(8/I) and N(3/I). Among the A*[s]U(*) dimers, only the C(8/I)‐hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34–36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl3. Temperature‐dependent CD spectra of 28, 30, 31, and 37 evidence π‐stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl3 solution is evidenced by a melting temperature of ca. 2°.

Oligonucleotide Analogues with Integrated Bases and Backbones. Part 26

“…This was shown by analysing the association in CDCl 3 of partially protected, self-complementary di-and tetranucleosides of the type U*[x]A ( * )1 ) and A*[x]U ( * ) , possessing a variety of linking elements [1 -9]. A conformational analysis of the diastereoisomers of the constitutionally isomeric cyclic duplexes of self-complementary ethylene-, oxymethylene-, thiomethylene-, and aminomethylene-linked dinucleosides rationalized the propensity of pairing, i.e., the formation of cyclic duplexes [7]. 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].…”

“…A conformational analysis of the diastereoisomers of the constitutionally isomeric cyclic duplexes of self-complementary ethylene-, oxymethylene-, thiomethylene-, and aminomethylene-linked dinucleosides rationalized the propensity of pairing, i.e., the formation of cyclic duplexes [7]. 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].…”

“…Reduction [7] [20] of aldehyde 10 gave 11 (93%) that was transformed into the (monomethoxy)trityl ether 12 (85%; Scheme 2). 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].…”

“…Part). Debenzoylation [7] of 22 yielded 68% of dinucleoside 23 that was desilylated with (HF) 3 · Et 3 N in THF to the alcohol 24 (70%). Detritylation of 23 with Cl 2 CHCOOH and Et 3 SiH yielded 73% of the silyl ether 25; similarly, 24 yielded 78% of diol 26.…”

“…Similarly to 2 and 3, the monomethoxytrityl ethers 5 -9 adopt a syn-conformation. HOÀC(5') of 5 forms a partially persistent H-bond to C(2)¼O, leading to a more extensive population of the gg-conformer (J(4',5'a) þ J(4',5'b) ¼ 7.9 Hz) [7] and to a less pronounced (N)-conformation of the ribose ring of 5 than for the corresponding azides 3 and 8, p-toluenesulfonates 2 and 6, and acetamide 9. The syn-conformation is expected on account of the substitution at C (6).…”