NUCLEIC-ACID ANALOGS WITH CONSTRAINT CONFORMATIONAL FLEXIBILITY IN THE SUGAR-PHOSPHATE BACKBONE TRICYCLO-DNA - PART-1 - PREPARATION OF -ETHANO-5',6'-METHANO-BETA-D-RIBOFURANOSYL]THYMINE AND ETHANO-5',6'-METHANO-BETA-D-RIBOFURANOSYL]ADENINE, AND THE CORRESPONDING PHOSPHORAMIDITESFOR OLIGONUCLEOTIDE SYNTHESIS

The synthesis of the tricyclo-deoxynucleoside analogs 1 and 2 and of t he corresponding cyanoethyl phosphoramidite building blocks 16 and 21 for oligonucleotide synthesis is described. These tricyclic deoxynucle oside analogs differ from the recently introduced bicyclo-deoxynucleos ides by an additional cyclopropane unit joined to the centers C(5') an d C(6') of the latter (see Fig. 1), and thus represent a further membe r of the class of nucleoside analogs with constraint conformational fl exibility. 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-benz oyladenine. Selective tritylation of the tertiary OH-C(5') and phosphi nylation of OH-C(3') of 1 and 2 afforded the corresponding phosphorami dites 16 and 21. The 'exo'-configuration of the newly introduced cyclo propane ring was confirmed by H-1-NMR-NOE spectroscopy. The alpha-D- a nd 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. Mo deling studies of the beta-D-anomeric nucleoside analog 1 indicate a p reference for the l-endo-conformation of the furanose ring and a parti al correction of the torsion angle gamma to the anti-clinal range comp ared to bicyclo-deoxynucleosides.