6'-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations.

Here we report on the synthesis, biophysical properties and molecular modeling of oligonucleotides containing unsaturated 6'-fluoro[4.3.0]bicyclo nucleotides (6'F-bc-DNA). Two 6'F-bc phosphoramidite building blocks (T and C) were synthesized starting from a previously described [3.3.0]bicyclic sugar. The conversion of this sugar to a -difluorinated tricyclic intermediate via difluorocarbene addition followed either by a NIS-mediated or Vorbrüggen nucleosidation yielded in both cases the β-tricyclic nucleoside as major anomer. Subsequent desilylation and cyclopropane ring opening of these tricyclic intermediates afforded the unsaturated 6'F-bc nucleosides. The successful incorporation of the corresponding phosphoramidite building blocks into oligonucleotides was achieved with -butyl hydroperoxide as oxidation agent. Thermal melting experiments of the modified duplexes disclosed a destabilizing effect versus DNA and RNA complements, but with a lesser degree of destabilization versus complementary DNA (Δ /mod = -1.5 to -3.7 °C). Molecular dynamics simulation on the nucleoside and oligonucleotide level revealed the preference of the C1'-/C2'- alignment of the furanose ring. Moreover, the simulation of duplexes with complementary RNA disclosed a DNA/RNA-type duplex structure suggesting that this modification might be a substrate for RNase H.