Oligonucleosides with Integrated Backbone and Base: Foldamers with a Novel Architecture

6-(Diazomethyl)-1,3-bis(methoxymethyl)uracil (5) was prepared from the known aldehyde 3 by hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3-d]pyrimidine-5,7-diones 7a and 7b. Rh 2 (OAc) 4 catalyzed the transformation of 5 into to a 2 : 1 (Z)/ (E) mixture of 1,2-diuracilylethenes 9 (67%). Heating (Z)-9 in 12n HCl at 958 led to electrocyclisation, oxidation, and deprotection to afford 73% of the pyrimido[5,4-f]quinazolinetetraone 12. The Rh 2 (OAc) 4 -catalyzed reaction of 5 with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran gave endo/exomixtures of the 2-oxabicyclo[4.1.0]heptane 13 (78%) and the 2-oxabicyclo[3.1.0]hexane 15 (86%), Their treatment with AlCl 3 or Me 2 AlCl promoted a vinylcyclopropane -cyclopentene rearrangement, leading to the pyrano-and furanocyclopenta[1,2-d]pyrimidinediones 14 (88%) and 16 (51%), respectively. Similarly, the addition product of 5 to 2-methoxypropene was transformed into the 5-methylcyclopentapyrimidinedione 18 (55%). The Rh 2 (OAc) 4 -catalyzed reaction of 5 with thiophene gave the exoconfigured 2-thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8-oxabicyclo[3.2.1]oct-2-ene 20 (73%), and the reaction with (E)-2-styrylfuran yielded a diastereoisomeric mixture of hepta-1,4,6-trien-3-ones 21 (75%) that was transformed into the (1E,4E,6E)-configured hepta-1,4,6-trien-3-one 21 (60%) at ambient temperature.

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“…Introduction. -6-Formyluridines are intermediates in the synthesis of novel oligoribonucleotide analogues (ONIBs; see [1] [2] and refs. cit.…”

mentioning

confidence: 99%

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil, Synthesis and Transformation into Annulated Pyrimidinediones

Zhang

Kulesza

Rani

et al. 2008

Helvetica Chimica Acta

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Oligonucleotide Analogues with Integrated Bases and Backbone. Part 13

Zhang

Bernet

Vasella

2006

Helvetica Chimica Acta

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The self‐complementary UA and AU dinucleotide analogues 41–45, 47, 48, and 51–60 were prepared by Sonogashira coupling of 6‐iodouridines with C(5′)‐ethynylated adenosines and of 8‐iodoadenosines with C(5′)‐ethynylated uridines. The dinucleotide analogues associate in CDCl3 solution. The C(6/I)‐unsubstituted AU dimers 51 and 54 prefer an anti‐oriented uracilyl group and form stretched linear duplexes. The UA propargyl alcohols 41 and 43–45 possess a persistent intramolecular O(5′/I)H⋅⋅⋅N(3/I) H‐bond and, thus, a syn‐oriented adeninyl and a gt‐ or tg‐oriented ethynyl moiety; they form corrugated linear duplexes. All other dimers form cyclic duplexes characterized by syn‐oriented nucleobases. The preferred orientation of the ethynyl moiety (the C(4′),C(5′) torsion angle) defines a conformation between gg and one where the ethynyl group eclipses O(4′/I). The UA dimers 42, 47, and 48 form Watson–Crick H‐bonds, the AU dimers 56 and 58–60 H‐bonds of the Watson–Crick‐type, the AU dimers 53 and 55 reverse‐Hoogsteen, and 57 Hoogsteen H‐bonds. The pairing mode depends on the substituent of C(5′/I) (H, OSiiPr3; OH) and on the H‐bonds of HOC(5′/I) in the AU dimers. Association constants were derived from the concentration‐dependent chemical shift for HN(3) of the uracilyl moiety; they vary from 45–104 M−1 for linear duplexes to 197–2307 M−1 for cyclic duplexes. The thermodynamic parameters were determined by van't Hoff analysis of the temperature‐dependence of the (concentration‐dependent) chemical shift for HN(3) of the uracilyl moiety. Neglecting stacking energies, one finds an average energy of 3.5–4.0 kcal/mol per intermolecular H‐bond. Base stacking is evidenced by the temperature‐dependent CD spectra. The crystal structure of 54 shows two antiparallel chains of dimers connected by Watson‐Crick H‐bonds. The chains are bridged by a strong H‐bond between the propargylic OH and OC(4) and by weak reverse A ⋅ A Hoogsteen H‐bonds.

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Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

Ritter

Egli

Bernet

et al. 2008

Helvetica Chimica Acta

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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°.

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Oligonucleosides with Integrated Backbone and Base: Foldamers with a Novel Architecture

Cited by 5 publications

References 31 publications

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil, Synthesis and Transformation into Annulated Pyrimidinediones

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil, Synthesis and Transformation into Annulated Pyrimidinediones

Oligonucleotide Analogues with Integrated Bases and Backbone. Part 13

Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

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