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

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 Vorbruggen condensation of the tricyclic carbohydrate unit 10/11 with in situ persilylated thymine and N-6-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 H-1-NMR-NOE spectroscopy. The alpha-D- and beta-D-configuration at C(1') of the nucleoside analogs 1 and 14 (2 and 19, resp.) was assigned by H-1-NMR-NOE spectroscopy and NOESY. Modeling studies of the beta-D-anomeric nucleoside analog 1 indicate a preference for the l-endo-conformation of the furanose ring and a partial correction of the torsion angle gamma to the anti-clinal range compared to bicyclo-deoxynucleosides.