Screening the Structural Space of Bicyclo‐DNA: Synthesis and Thermal Melting Properties of bc⁴,³‐DNA

In attempts to screen the structural and functional properties of bicyclo‐DNA, in which the ribose C(3′) and C(5′) centers are integrated into an additional five‐membered carbocyclic ring ([3.3.0]‐series) we have now synthesized and investigated a ring enlarged analogue in which C(5′) and C(3′) are spanned by a six‐membered carbocyclic ring ([4.3.0]‐series). The synthesis of the corresponding bc 4,3 ‐T nucleoside 13 was performed in 12 steps by starting from known allyl furanose 1 . X‐ray analysis of its benzyl protected precursor 12 showed the cyclohexane ring to adopt a chair conformation with the O(5′) substituent in an axial position. The furanose part shows clearly S‐type sugar pucker. This nucleoside was converted into the corresponding phosphoramidite building block 15 and incorporated into oligodeoxynucleotides by standard phosphoramidite chemistry. The thermal stabilities of oligonucleotides with single or double incorporations of bc 4,3 ‐T residues, paired to complementary DNA or RNA, were found to be similar to those of unmodified oligonucleotides (–2.3 to +0.7 °C per modification) and to those with the known bc‐T modifications. We also found that mismatch discrimination in the bc 4,3 ‐T series was similar to that of the natural series but less discriminative in comparison to the known bc‐T series.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)