Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conformation of 2′-deoxy-2′-fluoro-β-d-arabinonucleosides

Abstract

The stereoselective syntheses of 5-halogenated 7-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine nucleosides 3b–d, 4a–c as well as 7-deaza-2′-deoxyisoguanosine 2 are described. Nucleobase anion glycosylation of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide (6) exclusively gave the β-D-anomer 7, which was deblocked (→ 8), aminated at C(4) (→ 3a) and selectively deaminated at C(2) to yield 2′-deoxy-2′-fluoro-β-D-arabinofuranosyl 7-deazaisoguanine (2). Condensation of the 5-halogenated 4-chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidines 9a–c with 6 furnished the N⁷-nucleosides 10a–c together with N²,N⁷-bisglycosylated compounds 11a–c. The former was converted to the corresponding 2,4-diamino-compounds 3b–d, and the latter was deblocked by NaOMe/MeOH to yield the 4-methoxy-nucleosides 4a–c. Conformational analysis of the sugar moiety of the nucleosides 2 and 3a–d was performed on the basis of vicinal [¹H,¹H] coupling constants. The fluorine atom in the sugar moiety shifts the sugar conformation from S towards N by about 10%, while the halogen substituents in the base moiety increase the hydrophobicity and polarizability of the nucleobases.