Nucleic‐Acid Analogs with Restricted Conformational Flexibility in the Sugar‐Phosphate Backbone (‘Bicyclo‐DNA’). Part 6 . Probing the influence of torsion angle γ on DNA‐duplex stability: Syntheis and properties of oligodeoxynucleotides containing [(3′ S ,5′ S )‐2′‐deoxy‐3′,5′‐ethano‐β‐ D ‐ribofuranosyl]adenine and ‐thymine (‘5′‐epi‐bicyclodeoxynucleosides’)

The synthesis of the thymine‐ and adenine‐containing 5′‐epi‐bicyclodeoxynucleosides 7 and 8 as well as of the corresponding building blocks 13 and 14 for oligonucleotide syntheis according to the phosphoramidite methodology is described. A conformational analysis of 7 and 8 by 1 H‐NMR spectroscopy, refined by molecular modeling, shows the preferred conformation of the furanose unit in these nucleosides to be of the 1′‐ exo /2′‐ endo type. The 5′‐OH group on the carbocyclic ring prefers to be axially oriented, thus placing torsion angle γ in the unusual – syn ‐clinal (– sc ) range. These epi‐bicyclodeoxynucleosides were successfully incorporated into DNA decamers. From UV/melting curves of such decamers with DNA and RNA complements, a duplex destabilization of −2 to −9° per residue was observed. An oligonucleotide built completely from 5′‐epi‐bicyclothymidine shows no detectable affinity to its DNA or RNA complement anymore. CD Spectra of duplexes containing 5′‐epi‐bicyclodeoxynucleotide units are very similar to the natural reference systems, indicating no major structural changes. A molecular‐dynamics simulation of a heptamer duplex containing one 5′‐epibicyclothymidine residue in the center reveals a conformational change of its carbocyclic unit placing torsion angle γ in the (for the free mononucleoside unfavorable) – anti ‐clinal (– ac ) conformation in the duplex. The role of torsion angle γ on DNA duplex stability is discussed.