7-halogenated 7-deazapurine 2 `-deoxyribonucleosides related to 2 `-deoxyadenosine, 2 `-deoxyxanthosine, and 2 `-deoxyisoguanosine: Syntheses and properties

Abstract

A series of 7-fluorinated 7-deazapurine 2'-deoxyribonucleosides related to 2'-deoxyadenosine, 2'-deoxyxanthosine, and 2'-deoxyisoguanosine as well as intermediates 4b-7b, 8, 9b, 10b, and 17b were synthesized. The 7-fluoro substituent was introduced in 2,6-dichloro-7-deaza-9H-purine (11a) with Selectfluor (Scheme 1). Apart from 2,6-dichloro-7-fluoro-7-deaza-9H-purine (11b), the 7-chloro compound 11c was formed as by-product. The mixture 11b/11c was used for the glycosylation reaction; the separation of the 7-fluoro from the 7-chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N-halogenosuccinimides (11a -> 11c-11e). Nucleobase-anion glycosylation afforded the nucleoside intermediates 13a-13e (Scheme 2). The 7-fluoro- and the 7-chloro-7-deaza-2'-deoxyxanthosines, 5b and 5c, respectively, were obtained from the corresponding MeO compounds 17b and 17c, or 18 (Scheme 6). The 2'-deoxyisoguanosine derivative 4b was prepared from 2-chloro-7-fluoro-7-deaza-2'-deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK(a) values of the halogenated nucleosides were determined (Table 3). C-13-NMR Chemical-shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7-halogen substituents (Fig. 3). In aqueous solution, 7-halogenated 2'-deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).