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

Abstract

AbstractThe 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 (se Fig. 1), and thus represent a further member of the class of nucleoside analogs with constraint conformational flexibility. The synthesis of the tricyclo‐deoxynucleoside was achieved by a diastereoselective carbene addition to the enantiomerically pure silyl enol either 8/9 and a Vorbrüggen 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 spectroscoy. 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.