Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conformation of 2 `-deoxy-2 `-fluoro-beta-D-arabinonucleosides

Abstract

The stereoselective syntheses of 5-halogenated 7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidi ne 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-alpha-D- arabinofuranosyl bromide ( 6) exclusively gave the beta-D-anomer 7, which was deblocked (. 8), aminated at C( 4) (--> 3a) and selectively deaminated at C( 2) to yield 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl7-deazaisoguanine ( 2). Condensation of the 5-halogenated 4-chloro-2-pivaloylamino-7H-pyrrolo[2,3-d] pyrimidines 9a - c with 6 furnished the N-7-nucleosides 10a - c together with N-2, N-7-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-methoxynucleosides 4a - c. Conformational analysis of the sugar moiety of the nucleosides 2 and 3a - d was performed on the basis of vicinal [H-1, H-1] 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.