7‐Halogenated 7‐Deaza‐2′‐deoxyxanthine 2′‐Deoxyribonucleosides

Abstract

The synthesis of the 7-halogenated derivatives 1b (7-bromo) and 1c (7-iodo) of 7-deaza-2'-deoxyxanthosine (1a) is described. A partial Br 3 I exchange was observed when the demethylation of 6-methoxy precursor compound 4b was performed with Me 3 SiCl/NaI. This reaction is circumvented by the nucleophilic displacement of the MeO group under strong alkaline conditions. The halogenated 7-deaza-2'-deoxyxanthosine derivatives 1b,c show a decreased S-conformer population of the sugar moiety compared to the nonhalogenated 1a. They are expected to form stronger triplexes when they replace 1a in the 1 ¥ dA ¥ dT base triplet.Introduction. ± The synthesis of 7-deaza-2'-deoxyxanthosine (1a) via the glycosylation of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine was already reported from our laboratory in 1985 [1]. Later the nucleoside was prepared by a deamination/ demethylation route from 4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine 2'-deoxyribonucleoside 2a [2]. Compound 1a was incorporated into oligonucleotides without base protection by solid-phase synthesis by using phosphonate chemistry [2]. Triplexes containing 7-deazaxanthine in place of thymine showed a high third-strand-binding affinity under neutral conditions [2]. Contrary to the extremely labile 2'-deoxyxanthosine (3), in which the glycosylic bond hydrolyzes spontaneously under physiological conditions [3 ± 5], the glycosylic bond of the 7-deazapurine nucleoside 1a is resistant to −depurination× [1] [2].

Oligonucleotides Containing 7-Deaza-2′-deoxyxanthosine: Synthesis, Base Protection, and Base-Pair Stability

“…This results from the influence of the Br-substituents and not from the additional amino group as it was already demonstrated with compounds incorporating base pairs of 4 with dT [29]. It is expected that duplexes are further stabilized when the nucleoside 3 bears 7-halogen or 7-alkynyl substituents [36].…”

7-Functionalized 7-Deazapurine Ribonucleosides Related to 2-Aminoadenosine, Guanosine, and Xanthosine: Glycosylation of Pyrrolo[2,3-d]pyrimidines with 1-O-Acetyl-2,3,5-tri-O-benzoyl-d-ribofuranose

“…Two methods, Me 3 SiCl/NaI in CH 3 CN or aq NaOH, 32 were employed for the demethylation (15a-d f 4a-d). Compound 15a was demethylated to give 7-deazaxanthosine 4a with Me 3 SiCl/NaI/CH 3 CN (90% yield).…”

7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine, and 2′‐Deoxyisoguanosine: Syntheses and Properties

“…Different protocols have been described for the conversion of the MeO to C¼O groups in nucleosides: a) acidic cleavage, HBr/AcOH in absolute THF [37]; b) Me 3 SiCl/NaI in MeCN [46]; c) 2n NaOH, reflux [46]. Efforts to use protocols a) and b) for the cleavage of 9b failed due to the decomposition of the compounds.…”

“…Milder conditions (lower concentration of the reactant, see Exper. Part) must be used to avoid the decomposition and halogen exchange as reported [46]. Compounds 5b and 5c were obtained in 69 and 65% yields, respectively (Scheme 6).…”

“…The C-atoms of the 7-halogenated heterocycles were assigned according to the influence of the halogen substituents as well as on the basis of 1 H/ 13 C-NMR gateddecoupled spectra. The chemical shifts of the sugar moieties of the deprotected nucleosides were assigned according to [20] [46] and on the basis of 1 H/ 13 C-NMR gateddecoupled spectra of compounds 10b and 10d ( Table 5). Table 4 shows that the 7-halogen substituents shifts the C(5), C (7), and C(8) signals significantly, while other C-atoms are not affected.…”