Nucleic-Acid Analogs with Constraint Conformational Flexibility in the Sugar-Phosphate Backbone 'Tricyclo-DNA' - Part 1: Preparation of [(5′ R,6′ R)-2′-Deoxy-3′,5′-ethano-5′,6′-methano-β-D- ribofuranosyl]thymine and -adenine, and the Corresponding Phosphoramidites for Oligonucleotide Synthesis

Article abstract of DOI:10.1002/hlca.19970800812

The synthesis of the tricyclo-deoxynucleoside analogs 1 and 2 and of the corresponding cyanoethyl phosphoramidite building blocks 16 and 21 for oligonucleotide synthesis is described. These tricyclic deoxynucleoside analogs differ from the recently introduced bicyclo-deoxynucleosides by an additional cyclopropane unit joined to the centers C(5′) and C(6′) of the latter (see Fig. 1), and thus represent a further member of the class of nucleoside analogs with constraint conformational flexibility. The synthesis of the tricyclo-deoxynucleosides was achieved by a diastereoselective carbene addition to the enantiomerically pure silyl enol either 8/9 and a Vorbru?ggen condensation of the tricyclic carbohydrate unit 10/11 with in situ persilylated thymine and N⁶-benzoyladenine. Selective tritylation of the tertiary OH-C(5′) and phosphinylation of OH-C(3′) of 1 and 2 afforded the corresponding phosphoramidites 16 and 21. The 'exo'-configuration of the newly introduced cyclopropane ring was confirmed by ¹H-NMR-NOE spectroscopy. The α-D- and β-D-configuration at C(1′) of the nucleoside analogs 1 and 14 (2 and 19, resp.) was assigned by ¹H-NMR-NOE spectroscopy and NOESY. Modeling studies of the β-D-anomeric nucleoside analog 1 indicate a preference for the 2′-endo-conformation of the furanose ring and a partial correction of the torsion angle γ to the anti-clinal range compared to bicyclo-deoxynucleosides.